Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-Difunctionalization versus Rare Bis(cyclization)

Article abstract of DOI:10.1002/chem.201800630

Functionalized ynones can be activated by Tf₂C=CH₂, which was generated in situ, to form zwitterionic species. These species were trapped in an intramolecular fashion by several nucleophiles to generate two major types of triflones in a divergent manner. Through fine-tuning of the reaction temperature, bis(triflyl)-6-membered- or (triflyl)-5-membered-fused-heterocycles were achieved in reasonable yields in a totally selective manner. In this way, bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones, (triflyl)benzothienopyrans, (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and (triflyl)pyranoindoles were constructed. Conceivable mechanistic pathways were suggested on the basis of the isolation of several intermediates and the results from control experiments.

Full text of DOI:10.1002/chem.201800630

A Journal of
Accepted Article
Title: Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-
Difunctionalization versus Rare Bis(cyclization)
Authors: Pedro Almendros, Benito Alcaide, Carlos Lázaro-Milla, and
Patricia Delgado-Martínez
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To be cited as: Chem. Eur. J. 10.1002/chem.201800630
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
█ Synthetic Methods
Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-
Difunctionalization versus Rare Bis(cyclization)
Benito Alcaide,*[a] Pedro Almendros,*[b] Carlos Lázaro-Milla,[a] and Patricia Delgado-Martínez[c],§
Dedication ((optional))
Abstrac: Functionalized ynones can be activated by in situ bis(triflyl)flavones,
bis(triflyl)thioflavones,
generated Tf2C=CH2 to form zwitterionic species, which were bis(triflyl)selenoflavones,
(triflyl)benzothienopyrans,
trapped in an intramolecular fashion by several nucleophiles (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and
to generate in a divergent way two main types of triflones. (triflyl)pyranoindoles were built. Conceivable mechanistic
Through fine-tuning the temperature, bis(triflyl)-6-membered- proposals were suggested based in the isolation of several
or (triflyl)-5-membered-fused-heterocycles were achieved in intermediates and control experiments.
reasonable yields in a totally selective manner. In this way,
Introduction
fluoroorganic moieties in organic compounds notably influences
the physicochemical properties.[3] This modification usually results
in alteration of the pharmacological properties of the fluorinated
derivatives. Particular attention has been paid to the strong
electron-withdrawing triflyl functionality, which also exhibited mild
lipophilicity with the subsequent bioavailability improvement. In
this context, the group of Yanai has recently developed an
innovative methodology disclosing the use of 2-(pyridinium-1-yl)-
1,1-bis(perfluoroalkylsulfonyl)ethan-1-ides as a stable source of
Tf2C=CH2,[4] while we developed a route for the preparation of
bis(triflyl)cyclobutenes[5] (Scheme 1a). Based on these previous
observations, we decided to study the reactivity of functionalized
ynones. Unexpectedly, divergent paths with respect to previous
results were encountered. A detailed study of this chemistry
unveiled novel aspects of the unique reactivity of ynones,
allowing the direct preparation of various heterocyclic cores
decorated with fluorinated moieties (Scheme 1b).
Tuning selectivity in organic synthesis is difficult considering the
usual inherent preference for the creation of a specific type of
product. In some cases, a divergent synthesis can be achieved
through modification of the promoter, additive, and reagent.
Consequently, the discovery of novel strategies for divergent
reactions is appealing. Ynones, a versatile acetylenic platform
readily available from acyl chlorides and metal acetylides, have a
great potential in organic synthesis in nucleophilic additions,
cycloadditions, and condensation reactions.[1],[2] However, less
conventional reactivities are underexplored. The presence of
[a]
Prof. Dr. Benito Alcaide, Carlos Lázaro-Milla
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de
Química Orgánica I, Unidad Asociada al CSIC, Facultad de Química
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax: (+34) 91-3944103
E-mail: alcaideb@quim.ucm.es
[b]
Prof. Dr. Pedro Almendros
Instituto de Química Orgánica General
Consejo Superior de Investigaciones Científicas, IQOG-CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34) 91-5644853
E-mail: Palmendros@iqog.csic.es
[c]
§
Dr. P. Delgado-Martínez
CAI Difracción de Rayos X
Facultad de Química
Universidad Complutense de Madrid
Responsible for X-ray crystal-structure determination.
Supporting information for this article and ORCIDs for the authors
can be found under http://dx.doi.org/10.1002/chem.2018xxxxx.
1
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
Tf
Tf
Previous literature (a)
O
O
S
Na
+
CH3CN
RT
silica
gel
F
N
R
Y
SMe
R
CTf2
ref. 4
ref. 5
Y
+
+
F
F
N
N
1
2a–l
3a–i-Na
R1
Y = OH, NR2
Tf
2C
R1
CTf2
CTf2
Tf
Tf
Tf
O
Tf
Tf
Tf
O
S
O
S
Na
Na
Na
Tf
Tf
R2
R1
S
OMe
Br
R2
R1
3a-Na
3b-Na
3c-Na
(39%, 7 h)
(41%, 5 h)
(70%, 1 h)
Tf
Tf
Tf
Tf
Tf
O
Tf
Tf
Tf
Current work (b)
O
S
O
O
Y
Na
Na
Na
Ar
S
S
O
RT
R
R
S
Me
OMe
3f-Na
(67%, 2 h)
3d-Na
3e-Na
Ar
(74%, 2 h)
(77%, 3 h)
+
110 o
F
N
R
C
YZ
O
Tf
CTf2
Tf
Tf
Tf
Tf
Na
Tf
Tf
Na
YZ = OH, OMe,
O
S
O
O
S
Ar
NHG, SMe, SeMe
Na
Y
S
Scheme 1. Background and current design for the synthesis of triflones using 2-
Fe
3i-Na
(39%, 1 h)
S
N
(2-fluoropyridinium-1-yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-ide.
3g-Na
Me
(64%, 2 h)
(57%, 1 h)
3h-Na
Results and Discussion
Tf
Tf
Na
Tf
Tf
O
O
Na
To explore the feasibility of the use of ynones as precursors, 1-[2-
(methylthio)phenyl]-3-phenylprop-2-yn-1-one 2a[2a] was treated
S
S
with
2-(2-fluoropyridinium-1-yl)-1,1-
EWG
3l-Na
(0%, 24 h)
bis[(trifluoromethyl)sulfonyl]ethan-1-ide 1 in acetonitrile at room
temperature. Interestingly, the formation of bis(triflyl)thioflavone
3a was observed (Scheme 1) rather than Friedel-Crafts-type
bis(triflyl)alkylation or cyclobutene construction. It should be noted
the mild formation of a carbon–sulfur (C–S) bond,[6] which is
present in a vast array of natural products and bioactive
molecules such as thioflavones. The organofluorine substituent is
also incorporated in the same step under metal free conditions
via dual functionalization of the alkyne moiety. With these
cyclization conditions in hand, we examined the scope of MeS-
functionalized ynones susceptible to thioflavone generation. First,
the scope and limitations were evaluated through different
substitution patterns at the alkyne site. Various substituents in the
aromatic ring at the terminal akyne, such as methoxy, methyl and
bromo were well tolerated, providing the desired fluorinated
thioflavones 3a–d in isolated yields of 41% to 77% (Scheme 2).
Besides, naphthalene-, indole-, thiophene-, and ferrocene-linked
, 0%, 24 h)
, 0%, 24 h)
3j-Na
3k-Na
(EWG = NO2
(EWG = CF3
Scheme 2. Controlled preparation of bis(triflyl)thioflavones 3a–i.
The generality of the reaction was also explored through
modification of the MeS-alkynone tether. Variation of the benzene
linker was viable, with pyridine-, cyclohexene-, indole-, and
thiophene-tethered alkynones all affording the desired
organofluorine thioflavones 3m–q in reasonable yields (Scheme
3).
alkynes
2e–i
were
prone
sequence
to
suffer
(Scheme
the
2).
thiacyclization/functionalization
Compounds 3a–i easily dissociate the acidic hydrogen and
provide the corresponding metal salts 3a–i-Na after column
chromatography.[7] The highly deactivating 4-NO2C6H4 and 4-
CF3C6H4 moieties attached to the alkyne group did not afford the
corresponding thioflavones 3j and 3k. Unfortunately, alkynones
bearing an alkyl substituent at the alkyne such as 2l were also
inert in the presence of zwitterion 1.
2
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
Tf
Tf
strong acidic compounds by column chromatography on silica gel
gives their calcium salts.[7a] Yanai has reported that Tf2CH-bearing
compounds were strongly acidic and eluted as the corresponding
Ca2+ salts during silica gel chromatography.[7b] In our case, the
metal cation is sodium, as we previously reported in a related
cyclobutenyl-[Tf2CCH2]–Na+ derivative based in its X-ray
crystallographic analysis.[5c] In addition, sodium was detected in
representative flavone derivatives such as 3m-Na, 5c-Na, and
7b-Na through the use of two different analytical techniques,
namely SEM-EDX and 23Na NMR (see Supporting Information for
details).
O
O
Na
+
CH3CN
RT
silica
gel
F
N
R
SMe
R
S
CTf2
1
2m–q
3m–q-Na
PMP
S
Tf
Tf
Tf
O
Tf
O
Tf
Tf
O
N
PMP
(64%, 1 h)
S
N
S
PMP
Me
3m-Na
3n-Na
3o-Na
(56%, 1 h)
(71%, 1 h)
Tf
Tf
O
O
Tf
Tf
Tf
Tf
Na
+
CH3CN
RT
O
silica
gel
O
F
N
R
S
S
PMP = 4-MeOC6H4
R
OZ
O
CTf2
1
6a–e-Me
7a–e-Na
(Z = Me)
(Z = H)
PMP
S
Ph
(40%, 4 h)
S
6a–e
3p-Na
3q-Na
(61%, 3 h)
Tf
Tf
Tf
O
Tf
Tf
Tf
O
O
Scheme 3. Controlled preparation of bis(triflyl)thioflavones 3m–q.
Na
Na
Na
O
O
O
7c-Na
7a-Na
Taking into account the rich chemistry and the important
biological properties of organoselenium compounds, the nature of
the nucleophile was investigated by replacing the –SMe group for
a –SeMe. Noticeably, starting from (methylseleno)-alkynones 4a–
c and zwitterion 1 the desired fluorinated selenoflavones 5a–c
were smoothly obtained as the exclusive products (Scheme 4).
7b-Na
MeO
OMe
6a-Me
6c-Me
)
(56%, 4 h; from
(61%, 3 h; from
)
6b-Me
(73%, 3 h; from
(78%, 3 h; from
(74%, 2 h; from
(79%, 1 h; from
)
6a
)
6c
)
6b
)
Tf
O
Tf
Tf
Tf
O
O
Na
Na
Tf
Tf
O
O
O
S
7d-Na
7e-Na
OMe
Na
+
CH3CN
RT
silica
gel
F
N
6e-Me
(76%, 1 h; from
(84%, 1 h; from
)
6d-Me
(67%, 3 h; from
(81%, 2 h; from
)
R
6e
)
R
SeMe
Se
6d
CTf2
)
1
4a–c
5a–c-Na
Tf
Tf
O
O
Tf
Tf
Tf
Tf
Na
Tf
Tf
O
O
O
CH3CN
X
Na
F
N
+
Na
Ar
RT
NHZ
N
Z
Ar
CTf2
Se
Se
Se
1
8
Me )
(Z = Ac, Ms, Ts, CO2
S
OMe
OMe
5c-Na
(55%, 1 h)
5a-Na
5b-Na
(65%, 2 h)
(60%, 1 h)
Scheme 5. Controlled preparation of bis(triflyl)flavones 7a–e.
Scheme 4. Controlled preparation of bis(triflyl)selenoflavones 5a–c.
Having
probed
the
feasibility
of
this
cyclization/functionalization sequence, and tested several
structural variations within the acyclic precursors, investigations
into a tunable reactivity were initiated moving towards variation in
the solvent and temperature. Initially, MeS-alkynone 2a was
treated with zwitterion 1 in acetonitrile at 80o C, resulting in a
The nature of the nucleophile could also be modified to
oxygen derivatives with (methoxy)-alkynones 6a–e-Me and
(hydroxy)-alkynones 6a–e both found to be feasible cyclization
precursors. The preparation of bis(triflyl)flavones 7a–e was
accomplished in yields ranging from 56% to 84% (Scheme 5).
Unfortunately, the amide functionality in HN-Ac, HN-Ms, HN-Ts,
and HN-CO2Me protected amido-alkynones 8 was unreactive
under the above conditions, not providing access to fluorinated
quinolin-4-ones. It should be noted the lack of the signal
corresponding to the highly acidic hydrogen on the sulfone alpha-
carbon (Tf2CH) in the 1H NMR spectra of compounds 3, 5, and 7,
which should be attributed to chromatographic purification without
re-acidification. Ishihara et al. reported that the purification of
mixture
(2:1)
of
bis(triflyl)thioflavone
3a
and
3-
[(trifluoromethyl)sulfonyl]-2H-benzo[4,5]thieno[3,2-b]pyran
9a.
With this promising result in hand, we hope that fine tuning of this
reaction outcome might be achieved and would result in the sole
construction of tricycle 9a. Zwitterion 1 is almost unsoluble in
apolar or halogenated solvents at rt, but can be used in these
solvents at reflux temperature. Replacing acetonitrile by another
solvents was found to be useful. To our satisfaction, upon adding
3
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
zwitterion 1 at one time to a boiling solution of alkynone 2a in
toluene the tricycle 9a was exclusively obtained without any trace
of bicycle 3a (Scheme 6). Noticeably, simple temperature and
solvent alterations give rise to the divergent formation of two
entirely distinct fluorinated heterocyclic cores from a common
cyclization precursor. This second domino process allows a direct
metal-free access to a tricyclic framework with the simultaneous
formation of C–S, C–O, and C–C bonds. A variety of MeS-
alkynones 2 bearing various functional groups and tethers were
also submitted to bis(cyclization). Various fused thieno[3,2-
b]pyrans 9 were achieved with exquisite selectivity in reasonable
yields, with the exception of ferrocene derivative 9i which was
obtained in a decreased 22% yield (Scheme 6). The reaction was
even extended to the symmetrical bis(MeS-alkynone) 2s in which
a two-fold sequence takes place to afford benzothiophene-linked
bis(tricycle) 9s (Scheme 6). To the best of our knowledge, a
general access to fused tricyclic benzothienopyrans from acyclic
precursors in one synthetic operation seems to be lacking in the
literature. The structure of tricycle 9a was confirmed through its
X-ray crystallographic study (Figure 1).[8]
Figure
1.
ORTEP
drawing
of
3-[(trifluoromethyl)sulfonyl]-2H-
benzo[4,5]thieno[3,2-b]pyran 9a. Thermal ellipsoids shown at 50% probability.
We conceived that bicycles of type 3 could be converted into
fused tricycles 9 at elevated temperature. However, the treatment
of a toluene solution of bicycle 3a at 110 C resulted in absence
o
of reaction. Even more puzzling would appear the obtention of
cyclobutenes 10p and 10q in almost quantitative yields from
thiophene-tethered MeS-alkynones 2p and 2q under the
optimized conditions for the formation of tricycles 9. Fortunately,
the treatment of an acetonitrile solution of 10p and 10q in a
sealed tube at 110 oC resulted in full conversion towards 6-(triflyl)-
7H-thieno[2',3':4,5]thieno[3,2-b]pyrans 9p and 9q (Scheme 7).
Therefore, it may be inferred that cyclobutenes 10 and not
bicycles 3 are intermediates in the formation reaction of fused
pyrans 9.
O
O
Tf
toluene
F
N
+
110 o
C
R
R
S
SMe
CTf2
O
1
2a–s
9a–s
O
O
Tf
Tf
Tf
R
O
O
S
S
Me
S
Tf
Tf
S
S
toluene
110 o
F
N
+
R
C
SMe
SMe
R
CTf2
9d
(75%, 15 min)
9e
OMe
(67%, 20 min)
O
9a
9b
9c
1
2p
10p
10q
R = Ph
(R = H, 53%, 15 min)
(R = Ph, 94%, 20 min)
R = PMP
(R = OMe, 82%, 10 min)
(R = Br, 56%, 15 min)
2q
(R = PMP, quant., 10 min)
acetonitrile
110 o
sealed tube
Tf
O
O
C
Tf
Tf
Tf
Tf
O
O
Tf
Ph
S
toluene
110 o
O
S
S
X
Tf
S
N
S
C
S
Ph
S
S
Me
R
9g
S
(71%, 10 min)
O
9a
9f
9h
3a
(64%, 20 min)
(76%, 15 min)
9p
9q
(R = Ph, 75%, 5 min)
PMP
O
(R = PMP, 86%, 5 min)
O
Tf
Tf
Tf
PMP
(71%, 15 min)
S
S
S
N
Scheme 7. Controlled preparation of bis(triflyl) cyclobutenes 10p,q and triflyl-
(bis-thieno)pyrans 9p,q.
Fe
Me
9n
9o
(55%, 15 min)
[a]
9i
(22%, 10 min)
O
PMP = 4-MeOC6H4
O
It should be important to extend the current method for the
synthesis of tricyclic thienopyrans to other relevant heterocyclic
cores. For example, replacement of the S atom for a bulkier Se
normally increases the semiconducting properties of the resulting
less aromatic selenophenes in comparison with their thiophene
counterparts. We initiated our study by variation of the alkynone
partner to (methylselanyl)phenyl-propynones 4a–c. Gratifyingly,
the use of heat did allow the efficient synthesis of 3-(triflyl)-2H-
Tf
Tf
S
S
S
N
Tf
S
O
9s
9r
(77%, 15 min)
(65%, 10 min)
benzo[4,5]selenopheno[3,2-b]pyrans
11a–c
(Scheme
8).
Scheme 6. Controlled preparation of tricyclic triflyl-benzothienopyrans 9. [a]
Partial decomposition during chromatographic purification.
Consequently, MeSe-alkynones were proven to be excellent
substrates for the bis(cyclization) because changing the
heteroatom from S to Se has not effect on the reactivity pattern.
4
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
F
N
O
Tf2C
1
O
O
Tf
Tf
oC
(2 equiv)
O
O
i) toluene, 110
X
Tf
R
ii) K2CO3
toluene
110 o
R
R
O
O
OH
F
N
CH3CN, 110 o
sealed tube
C
+
R
C
R
13
6a–e
14a–e
Se
SeMe
4a–c
CTf2
1
11a–c
O
O
O
Tf
Tf
Tf
O
O
O
Tf
Tf
Tf
O
O
O
MeO
14c
14a
14b
Se
Se
Se
OMe
S
(61%; i) 15 min, ii) 10 min)
(76%; i) 15 min, ii) 10 min)
(78%; i) 15 min, ii) 10 min)
OMe
11c
(81%, 20 min)
O
O
OMe
11a
(68%, 10 min)
11b
(91%, 30 min)
Tf
Tf
O
O
Scheme 8. Preparation of triflyl-benzoselenophenopyrans 11.
S
14d
14e
OMe
(67%; i) 15 min, ii) 20 min)
(83%; i) 15 min, ii) 10 min)
O
The reaction of zwitterion 1 with substrates 6-Me, containing a
methoxy group at the alkynone side, in toluene at 110o C gave
rise to an intractable mixture of products. A beneficial effect is
provoked by moving from the MeO moiety of 6-Me to hydroxy-
F
O
N
Tf
Tf2C
1
O
toluene, 110 o
15 min
C
alkynones 6. The treatment of hydroxy-alkynones
6 with
OH
zwitterion 1 in boiling toluene did not allow a direct preparation of
the expected tricycles, because several unstable products were
formed. Interestingly, in one case we were able to isolate a
putative intermediate, namely, spirocyclic cyclobutene 12d
(Scheme 9). Fortunately, the reaction of hydroxy-alkynones 6 was
encountered to be suitable in the presence of a base, which
probably enhances the nucleophilicity of the oxygenated
functionality. Among several bases tested, potassium carbonate
provided best results. In this way, (hydroxy)-alkynones 6a–e
suffer a rearrangement reaction to form adducts 14a–e (Scheme
9). Surprisingly, the expected tricycles 13 were not obtained.
Compounds 14 bearing an open-chain conjugated dienone
structure, as confirmed by X-ray diffraction analysis of 14e
(Figure 2),[9] were formed instead. The occurrence of such
unanticipated result could be tentatively explained invoking bond
lengths. The C−S and the C−Se bonds are larger than the C−O
bond, which may disfavour the final cyclization in this last case.
Interestingly, adducts 14 are (triflyl)vinyl aurones, a group of
flavonoids. When the proposed intermediate 12d was heated in
acetonitrile at 110o C in a sealed tube, compound 14d was
formed (Scheme 9); thus confirming the intermediation of
spirocyclic cyclobutene species of type 12.
OMe
6d
[a]
12d
(23%) OMe
sealed tube
10 min
CH3CN
110 o
C
14d
(quantitative yield)
Scheme 9. Controlled preparation of triflyl-allylidenebenzofuranones 14a–e and
spirocyclic cyclobutene 12d. [a] Partial decomposition during chromatographic
purification.
Figure
2.
ORTEP
drawing
of
(E)-2-(1-(thiophen-2-yl)-2-
((trifluoromethyl)sulfonyl)allylidene)benzofuran-3(2H)-one
14e.
Thermal
ellipsoids shown at 50% probability.
Next, we used amido-alkynone substrates 8 hoping that they
proved applicable to the preparation of fused indoles. In the event,
derivatives 8 did not give the desired aza-tricycles at rt in
presence of zwitterion 1, because the reaction did not proceed.
Fortunately, under similar conditions as developed for the
preparation of functionalized aurones 14, various aza-tricycles 15
were obtained in synthetically valuable yields (Scheme 10).
Consequently, both heat as well as the presence of a base are
crucial for the success of the cyclization/rearrangement sequence.
5
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
The PMP group in 15a could be replaced with naphthyl, thienyl,
or phenyl, without attenuation in reaction efficiency. Besides, our
protocol could accommodate different N-protected functionalities,
including acetamides and sulphonamides. The tricyclic structure
of 2,5-dihydropyrano[3,2-b]indole 15b was confirmed by X-ray
diffraction analysis (Figure 3).[10] In order to obtain direct evidence
of the intermediacy of a cyclobutene-type product, the reactions
between amido-alkynones 8a–c and 1 were carried out at 110o C
with suppression of the base treatment. We were lucky enough to
isolate cyclobutene derivatives 16a–c in good yields.
Providentially, a thermal treatment of strained derivatives 16a–c
in acetonitrile under basic conditions (K2CO3) resulted in the
formation of tricycles 15a–c (Scheme 10), suggesting that
adducts 16 are key intermediates.
Figure
3.
ORTEP
drawing
of
1-(4-(thiophen-2-yl)-3-
((trifluoromethyl)sulfonyl)pyrano[3,2-b]indol-5(2H)-yl)ethan-1-one 15b. Thermal
ellipsoids shown at 50% probability.
A possible pathway for the metal-free formation of bicyclic
triflones 3, 5, and 7 is outlined in Scheme 11. Formation of 1,1-
bis((trifluoromethyl)sulfonyl)ethene I from 2-(2-fluoropyridinium-1-
yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-ide 1 would trigger the
nucleophilic attack of the C2 carbon atom of propynones 2, 4, and
6 to the terminal carbon atom of alkene I. The so-formed
zwitterionic species II would suffer a selective intramolecular
heterocyclization to generate bicycles 3, 5, and 7 (path A). From
common intermediate II,
a different path which implies a
carbocyclization reaction to generate intermediate cyclobutenes
III could be operative (path B). This alternative cyclobutene
formation is not achievable at rt. Next, the regioselective
O
O
Tf
oC
i) toluene, 110
(3 equiv)
F
N
+
nucleophilic addition of
functionality to the
bis((trifluoromethyl)sulfonyl)cyclobut-1-en-1-yl)methanones
a –SMe, –SeMe, –OH, or –NHP
R2
R2
ii) K
2CO3
N
R1
N
H
R1
CH3CN, 90 o
C
CTf2
C1
carbon
atom
of
III
1
sealed tube
15a–e
8a–e
occurs to form spirocyclic cyclobutene intermediates IV.
Subsequent rearrangement with cyclobutene ring-opening gives
rise to dienone intermediates V. Final 6π-electrocyclic ring-
closure afford tricyclic triflones 9, 11, and 15. This second path
must be driven by alleviation of the ring strain linked to the
cyclobutene moiety, on forming deeply conjugated dienone
intermediates V. Although the obtention of cyclobutenes 10p,q
(Scheme 7) and 16a–c (Scheme 10), spirocyclic cyclobutene 12d
(Scheme 9), and dienones 14a–e (Scheme 9) was serendipitous,
these finding are in agreement with the mechanism of Scheme 11,
because detectable intermediates were isolated.
O
O
O
Tf
Tf
Tf
S
N
N
N
15c
15b
O
O
O
15a
MeO
Me
Me
OMe
OMe
(67%; i) 15 min, ii) 10 min)
(81%; i) 15 min, ii) 7 min)
(83%; i) 20 min, ii) 7 min)
O
O
Tf
Tf
N
N
O
O
S
S
O
O
Me
15e
15d
OMe
Tf
I
Tf
Tf
O
O
O
(72%; i) 20 min, ii) 7 min)
Tf
Me
1
Tf
Tf
+ 2F-py
path B
∆
(64%; i) 20 min, ii) 10 min)
Ar
Ar
Ar
R
YZ
YZ
R
YZ
R
F
III
II
2, 4, 6, 6-Me, 8
O
O
isolated intermediates for
N
(YZ = SMe, SeMe,
OH, OMe, NHG)
rt
Tf
Tf
c
)
path A
–
16a
YZ =
SMe (
10p,q
) and NHG (
Tf
2C
1
–
ZTf
R2
Tf
Tf
(3 equiv)
toluene, 110 o
15–20 min
C
O
Y
N
H
R1
K
2CO3
R2
NH
R1
O
CH3CN, 90 o
C
Ar
= Ac, R2 = PMP
sealed tube
7–10 min
8a R1
16a
16b
16c
Tf
Ar
(85%, 15 min)
(80%, 20 min)
(83%, 15 min)
R
R1 = Ac, R2 = 2-thienyl
R1 = MeOCO, R2 = PMP
Y
8b
8c
3, 5, 7
R
IV
(Y = S, Se, O)
isolated intermediate
15a–c
Y =
12d
O (
for
-electrocyclic
ring-opening
)
(quantitative yield)
π
4
Scheme 10. Controlled preparation of triflyl-2,5-dihydropyrano[3,2-b]indoles
15a–e and cyclobutenes 16a–c. purification.
O
O
Tf
π
Tf
6
-electrocyclic
Ar
Ar
ring-closing
R
Y
Y
R
V
9, 11, 15
(Y = S, Se, NG)
e
–
14a
isolated for Y = O (
)
Scheme 11. Rationalization for the formation of bicyclic triflones 3, 5, 7 and
tricyclic triflones 9, 11, 15.
Conclusion
In summary, we have unveiled the reaction of Tf2C=CH2 with ynones,
giving rise to a divergent preparation of two main kinds of triflone-
6
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
based products. The selectivity of the product can be completely
switched through adjusting the reaction temperature. In this way,
bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones,
7.57 (m, 1H, CHAr), 7.46 (m, 2H, 2CHAr), 7.31 (d, 1H, J = 2.4 Hz, CHAr), 7.16 (dd,
1H, J = 8.9, 2.6 Hz, CHAr), 3.90 (s, 3H, OCH3), 3.76 (s, 2H, CH2); 13C NMR (125
MHz, acetone-d6, 25 oC): δ = 183.5 (C=O), 159.7 (CAr-q-OMe), 151.8 (S-C=C),
137.7 (CAr-q), 135.8 (CAr-q), 135.0 (S-C=C), 134.5 (CAr-q), 133.6 (CAr-q), 132.2
(CHAr), 131.5 (CHAr), 130.9 (CHAr), 129.2 (CAr-q), 129.2 (CHAr), 128.5 (CHAr),
128.1 (2CHAr), 127.5 (CHAr), 122.4 (q, JCF = 329.7 Hz, 2CF3), 120.4 (CHAr),
106.8 (CHAr), 64.2 (CTf2), 55.9 (OCH3), 28.8 (CH2); 19F NMR (282 MHz,
acetone-d6, 25 oC): δ = –79.8 (s, 6F, 2CF3); 77Se-NMR (95 MHz, CDCl3, 25 oC)
δ: 400.3 (s, 1Se, Se); IR (acetone): ν = 1726 (C=O), 1371, 1110 (O=S=O), 1211
(C-F) cm–1; HRMS (ES): calcd for C24H17F6O6S2Se [M + H]+: 658.95308; found:
658.95286.
(triflyl)benzothienopyrans,
(triflyl)benzoselenophenopyrans,
(triflyl)vinyl aurones, and (triflyl)pyranoindoles were built. Based on
control experiments and the trapping of several intermediates, we
have proposed two conceivable reaction mechanisms.
Experimental Section
General methods: 1H NMR and 13C NMR spectra were recorded on a Bruker
Avance AVIII-700 with cryoprobe, Bruker AMX-500, Bruker Avance-300, or
Varian VRX-300S. NMR spectra were recorded in CDCl3 solutions, except
otherwise stated. Chemical shifts are given in ppm relative to TMS (1H, 0.0
ppm), or CDCl3 (1H, 7.27 ppm; 13C, 76.9 ppm), or C6D6 (1H, 7.16 ppm; 13C,
128.0 ppm), or acetone-d6 (1H, 2.05 ppm; 13C, 206.3 ppm), or CD3CN (1H, 1.94
ppm; 13C, 118.2 ppm). Low and high resolution mass spectra were taken on an
AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer using the electronic
impact (EI) or electrospray modes (ES) unless otherwise stated. IR spectra
were recorded on a Bruker Tensor 27 spectrometer. X-Ray crystallographic
Bis(trifluoromethylsulfonyl)flavone 7b. From 20 mg (0.08 mmol) of alkynone
6b, and after flash chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent (with further disolution in Et2O and precipitation with hexanes)
gave compound 7b-Na (36 mg, 79%) as a colorless solid; mp 223–225 ºC; 1H
NMR (300 MHz, CD3CN, 25 oC): δ = 8.22 (dd, 1H, J = 8.0, 1.5 Hz, CHAr), 7.80
(m, 1H, CHAr), 7.57 (d, 1H, J = 8.0 Hz, CHAr), 7.46 (m, 3H, 3CHAr), 7.06 (m, 2H,
2CHAr), 3.91 (s, 3H, OCH3), 3.67 (s, 2H, CH2); 13C NMR (75 MHz, CD3CN, 25
oC): δ = 179.7 (C=O), 165.2 (O-C=C), 162.0 (CAr-q-OMe), 156.8 (CAr-q-O), 134.7
(CHAr), 132.0 (2CHAr), 126.5 (CAr-q), 126.1 (CHAr), 125.7 (CHAr), 123.6 (CAr-q),
121.9 (q, JCF = 328.3 Hz, 2CF3), 119.4 (O-C=C), 118.8 (CHAr), 114.2 (2CHAr),
63.4 (CTf2), 56.0 (OCH3), 25.4 (CH2); 19F NMR (282 MHz, CD3CN, 25 oC): δ = –
80.5 (s, 6F, 2CF3); IR (CH3CN): ν = 1719 (C=O), 1376, 1109 (O=S=O), 1209
(C-F) cm–1; HRMS (ES): calcd for C20H15F6O7S2 [M + H]+: 545.01579; found:
545.01488.
data were collected on
a Bruker Smart CCD difractomer using graphite-
monochromated Mo-Kα radiation (λ = 0.71073 Å) operating at 50 Kv and 35 mA
with an exposure of 30.18 s in ω. All commercially available compounds were
used without further purification.
General procedure for the reaction between alkynones 2a–q, 4a–c, 6a–e,
and 6a–e-Me with pyridinium salt 1 at room temperature. Preparation of
bis(triflyl)thioflavones 3a–i, 3m–q, bis(triflyl)selenoflavones 5a–c, and
General procedure for the reaction between alkynones 2a–i, 2n–s, and 4a–
c with pyridinium salt 1 at 110 ºC. Preparation of triflyl-benzothienopyrans
9a–i, 9n–s, and triflyl-benzoselenophenopyrans 11a–c. 2-(2-Fluoropyridin-1-
ium-1-yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-ide 1 (0.2 mmol) was added to
a hot solution (110 ºC) of the appropriate alkynone 2a–i, 2n–s, and 4a–c (0.2
mmol) in refluxing toluene (4 mL). The reaction was stirred at 110 ºC until
disappearance of the starting material (TLC), and then the mixture was
concentrated under reduced pressure. Adducts 2p and 2q required an extra
heating in acetonitrile in sealed tube at 110 oC because after the initial heating
in toluene, cyclobutenes 10p and 10q were isolated. Chromatography of the
residue eluting with hexanes/ethyl acetate or hexanes/toluene mixtures gave
analytically pure compounds. Spectroscopic and analytical data for adducts 9a–
i, 9n–s, and 4a–c follow.
bis(triflyl)flavones
7a–e.
2-(2-Fluoropyridin-1-ium-1-yl)-1,1-
(0.2 mmol) was added at room
bis[(trifluoromethyl)sulfonyl]ethan-1-ide
1
temperature to a solution of the appropriate alkynone 2a–q, 4a–c, 6a–e, and
6a–e-Me (0.2 mmol) in acetonitrile (4 mL). The reaction was stirred at room
temperature until disappearance of the starting material (TLC), and then the
mixture was concentrated under reduced pressure. Chromatography of the
residue eluting with hexanes/ethyl acetate mixtures followed by further
disolution in Et2O, precipitation with hexanes and filtration, gave analytically
pure compounds. Spectroscopic and analytical data for adducts 3a–i-Na, 3m–
q-Na, 5a–c, and 7a–e-Na follow.[11]
Bis(trifluoromethylsulfonyl)thioflavone 3b. From 40 mg (0.14 mmol) of
alkynone 2b, and after flash chromatography of the residue using hexanes/ethyl
acetate (1:1) as eluent (with further disolution in Et2O and precipitation with
hexanes) gave compound 3b-Na (57 mg, 70%) as a colorless solid; mp 219–
221 ºC; 1H NMR (300 MHz, CD3CN, 25 oC): δ = 8.51 (m, 1H, CHAr), 7.73 (m, 2H,
2CHAr), 7.60 (m, 1H, CHAr), 7.32 (m, 2H, 2CHAr), 7.04 (m, 2H, 2CHAr), 3.90 (s,
3H, OCH3), 3.67 (s, 2H, CH2); 13C NMR (75 MHz, CD3CN, 25 oC): δ = 181.3
(C=O), 161.4 (CAr-q-OMe), 152.1 (S-C=C), 138.3 (CAr-q), 132.4 (CHAr), 132.2 (S-
C=C), 131.8 (2CHAr), 131.5 (CAr-q), 129.6 (CAr-q), 129.4 (CHAr), 128.2 (CHAr),
126.4 (CHAr), 122.0 (q, JCF = 328.9 Hz, 2CF3), 114.3 (2CHAr), 63.5 (CTf2), 55.9
(OCH3), 27.6 (CH2); 19F NMR (282 MHz, CD3CN, 25 oC): δ = –80.4 (s, 6F,
Triflyl-benzothienopyran 9b. From 40 mg (0.14 mmol) of alkynone 2b, and
after flash chromatography of the residue using hexanes/ethyl acetate (97:3) as
eluent gave compound 9b (49 mg, 82%) as a yellow solid; mp 155–157 ºC; 1H
NMR (300 MHz, CDCl3, 25 oC): δ = 7.89 (m, 1H, CHAr), 7.71 (m, 1H, CHAr), 7.47
(m, 2H, 2CHAr), 7.33 (m, 2H, 2CHAr), 6.98 (m, 2H, 2CHAr), 5.37 (s, 2H, OCH2),
3.88 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3, 25 oC): δ = 161.0 (CAr-q-OMe),
155.3 (CAr-q), 154.9 (CAr-q), 142.2 (CAr-q), 130.4 (2CHAr), 128.9 (CHAr), 128.5 (CAr-
q), 125.5 (CAr-q), 125.2 (CHAr), 123.3 (CHAr), 122.9 (CHAr), 120.0 (q, JCF = 326.8
Hz, CF3), 119.9 (C=C-Tf), 113.2 (CHAr), 105.0 (C=C-Tf), 67.4 (OCH2), 55.3
(OCH3); 19F NMR (282 MHz, CDCl3, 25 oC): δ = –79.0 (s, 3F, CF3); IR (CHCl3): ν
= 1379, 1110 (O=S=O), 1209 (C-F) cm–1; HRMS (ES): calcd for C19H14F3O4S2
[M + H]+: 427.02801; found: 427.02737.
2CF3); IR (CH3CN): ν = 1723 (C=O), 1379, 1110 (O=S=O), 1215 (C-F) cm–1
HRMS (ES): calcd for C20H15F6O6S3 [M + H]+: 560.99295; found: 560.99056.
;
Triflyl-benzoselenophenopyran 11b. From 30 mg (0.079 mmol) of alkynone
4b, and after flash chromatography of the residue using hexanes/ethyl acetate
(95:5) as eluent gave compound 11b (39 mg, 91%) as a yellow oil; 1H NMR
(300 MHz, CDCl3, 25 oC): δ = 7.94 (m, 1H, CHAr), 7.78 (m, 4H, 4CHAr), 7.45 (m,
3H, 3CHAr), 7.22 (m, 2H, 2CHAr), 5.44 (d, 1H, J = 12.7 Hz, OCHH), 5.38 (d, 1H,
J = 12.7 Hz, OCHH), 3.96 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3, 25 oC): δ =
Bis(trifluoromethylsulfonyl)selenoflavone 5b. From 30 mg (0.079 mmol) of
alkynone 4b, and after flash chromatography of the residue using hexanes/ethyl
acetate (1:1) as eluent (with further disolution in Et2O and precipitation with
hexanes) gave compound 5b-Na (35 mg, 65%) as a colorless solid; mp 196–
198 ºC; 1H NMR (500 MHz, acetone-d6, 25 oC): δ = 8.50 (dd, 1H, J = 8.1, 1.3 Hz,
CHAr), 7.86 (s, 1H, CHAr), 7.81 (m, 2H, 2CHAr), 7.76 (d, 1H, J = 7.9 Hz, CHAr),
7
This article is protected by copyright. All rights reserved.

10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
158.8 (CAr-q-OMe), 156.8 (CAr-q), 156.4 (CAr-q), 142.7 (CAr-q), 135.1 (CAr-q), 131.3
(CAr-q), 130.3 (CAr-q), 130.0 (CHAr), 129.0 (CHAr), 127.9 (CHAr), 127.7 (CAr-q),
126.3 (CHAr), 126.2 (CHAr), 126.1 (CHAr), 125.6 (CHAr), 125.0 (CHAr), 120.1 (q,
JCF = 326.9 Hz, CF3), 119.9 (C=C-Tf), 119.7 (CHAr), 105.8 (CHAr), 105.6 (C=C-
Tf), 67.0 (OCH2), 55.4 (OCH3); 19F NMR (282 MHz, CDCl3, 25 oC): δ = –78.9 (s,
3F, CF3); 77Se-NMR (95 MHz, CDCl3, 25 oC) δ: 441.7 (s, 1Se, Se); IR (CHCl3): ν
= 1371, 1109 (O=S=O), 1210 (C-F) cm–1; HRMS (ES): calcd for C23H16F3O4SSe
[M + H]+: 524.98819; found: 524.98730.
(CAr-q), 142.2 (CAr-q), 135.1 (CHAr), 132.5 (CHAr), 131.7 (CHAr), 127.3 (CHAr),
124.7 (CHAr), 122.6 (C=C-Tf), 120.9 (CHAr), 120.3 (q, JCF = 327.2 Hz, CF3),
117.7 (CAr-q), 116.8 (CHAr), 100.1 (C=C-Tf), 69.6 (OCH2), 25.5 (CH3); 19F NMR
(282 MHz, CDCl3, 25 oC): δ = –78.5 (s, 3F, CF3); IR (CHCl3): ν = 1665 (C=O),
1362, 1108 (O=S=O), 1209 (C-F) cm–1; HRMS (ES): calcd for C18H13F3NO4S2
[M + H]+: 428.02326; found: 428.02427.
Acknowledgements
General procedure for the reaction between alkynones 6a–e and
pyridinium salt 1 at 110 ºC. Preparation of triflyl-allylidenebenzofuranones
14a–e. 2-(2-Fluoropyridin-1-ium-1-yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-
ide 1 (0.2 mmol) was added to a hot solution (110 ºC) of the appropriate
alkynone 6a–e (0.2 mmol) in refluxing toluene (4 mL). The reaction was stirred
at 110 ºC until disappearance of the starting material (TLC), and then the
mixture was concentrated under reduced pressure. Next, K2CO3 (2 equiv.) was
added to a stirred solution of the above crude reaction in acetonitrile (4.0 mL).
The resulting mixture was heated at 110 ºC (typically 15 min) in a sealed tube.
The reaction was allowed to cool to room temperature, concentrated under
vacuum, and purified by flash column chromatography eluting with ethyl
acetate/hexanes mixtures. Spectroscopic and analytical data for adducts 14a–e
follow. After the first reaction step, spirocyclic cyclobutene 12d was isolated and
fully characterized.
Support for this work by the MINECO and FEDER (Projects
CTQ2015-65060-C2-1-P and CTQ2015-65060-C2-2-P). C. L.-M.
thanks MINECO for a predoctoral grant.
Keywords: alkynes • cyclization • fluorine • heterocycles •
synthetic methods
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Triflyl-allylidenebenzofuranone 14b. From 20 mg (0.08 mmol) of alkynone 6b,
and after flash chromatography of the residue using hexanes/ethyl acetate (8:2)
as eluent gave compound 14b (25 mg, 78%) as a yellow solid; mp 178–180 ºC;
1H NMR (700 MHz, Cl2DC–CDCl2, 60 oC): δ = 7.79 (d, 1H, J = 7.5 Hz, CHAr),
7.70 (m, 3H, 3CHAr), 7.35 (d, 1H, J = 8.3 Hz, CHAr), 7.29 (t, 1H, J = 7.4 Hz,
CHAr), 7.05 (m, 2H, 2CHAr), 6.74 (s, 2H, =CH2), 3.91 (s, 3H, OCH3); 13C NMR
(175 MHz, Cl2DC–CDCl2, 60 oC): δ = 164.6 (CAr-q-O), 161.2 (CAr-q-OMe), 145.2
(CAr-q), 136.8 (CHAr), 131.9 (2CHAr), 124.6 (CAr-q), 124.1 (CHAr), 123.9 (CHAr),
121.5 (C=C), 119.8 (q, JCF = 328.1 Hz, CF3), 114.4 (2CHAr), 113.0 (CHAr), 99.6
(C-Tf), 55.6 (OCH3); 19F NMR (282 MHz, Cl2DC–CDCl2, 25 oC): δ = –75.3 (s, 3F,
[2]
a) B. Alcaide, P. Almendros, E. Busto, F. Herrera, C. Lázaro-Milla, A.
Luna, Adv. Synth. Catal. 2017, 359, 2640; b) V. Dwivedi, M. Rajesh, R.
Kumar, R. Kantc, M. S. Reddy, Chem. Commun. 2017, 53, 11060; c) D.
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CF3); IR (CH2Cl2): ν = 1703 (C=O), 1365, 1106 (O=S=O), 1209 (C-F) cm–1
HRMS (ES): calcd for C19H14F3O5S [M + H]+: 411.05086; found: 411.05121.
;
[3]
[4]
[5]
a) L. K. San, S. N. Spisak, C. Dubceac, S. H. M. Deng, I. V. Kuvychko, M.
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General procedure for the reaction between alkynones 8a–e and
pyridinium salt 1 at 110 ºC. Preparation of triflyl-2,5-dihydropyrano[3,2-
b]indoles
15a–e.
2-(2-Fluoropyridin-1-ium-1-yl)-1,1-
(0.2 mmol) was added to hot
bis[(trifluoromethyl)sulfonyl]ethan-1-ide
1
a
solution (110 ºC) of the appropriate alkynone 8a–e (0.2 mmol) in refluxing
toluene (4 mL). The reaction was stirred at 110 ºC until disappearance of the
starting material (TLC), and then the mixture was concentrated under reduced
pressure. Next, K2CO3 (3 equiv.) was added to a stirred solution of the above
crude reaction in acetonitrile (4.0 mL). The resulting mixture was heated at 90
ºC (typically 15 min) in a sealed tube. The reaction was allowed to cool to room
temperature, concentrated under vacuum, and purified by flash column
chromatography eluting with ethyl acetate/hexanes mixtures. Spectroscopic and
analytical data for adducts 15a–e follow. After the first reaction step,
cyclobutenes 16a–c were isolated and fully characterized.
a) H. Yanai, R. Takahashi, Y. Takahashi, A. Kotani, H. Hakamata, T.
Matsumoto, Chem. Eur. J. 2017, 23, 8203; b) H. Yanai, T. Yoshino, M.
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125, 1600; Angew. Chem. Int. Ed. 2013, 52, 1560; c) H. Yanai, Y.
Takahashi, H. Fukaya, Y. Dobashi, T. Matsumoto, Chem. Commun.
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Taguchi, Chem. Eur. J. 2011, 17, 11747; e) H. Yanai, M. Fujita, T.
Taguchi, Chem. Commun. 2011, 47, 7245.
a) B. Alcaide, P. Almendros, I. Fernández, C. Lázaro-Milla, Chem.
Commun. 2015, 51, 3395; b) B. Alcaide, P. Almendros, C. Lázaro-Milla,
Chem. Eur. J. 2016, 22, 8998; c) B. Alcaide, P. Almendros, C. Lázaro-
Milla, Adv. Synth. Catal. 2017, 359, 2630.
Triflyl-2,5-dihydropyrano[3,2-b]indole 15b. From 35 mg (0.06 mmol) of
alkynone 8b, and after flash chromatography of the residue using hexanes/ethyl
acetate (9:1 → 8:2) as eluent gave compound 15b (22 mg, 83%) as a yellow
solid; mp 152–154 ºC; 1H NMR (700 MHz, CDCl3, 50 oC): δ = 8.34 (d, 1H, J =
8.6 Hz, CHAr), 7.78 (d, 1H, J = 7.9 Hz, CHAr), 7.67 (d, 1H, J = 5.0 Hz, CHAr),
7.64 (t, 1H, J = 7.6 Hz, CHAr), 7.52 (d, 1H, J = 1.9 Hz, CHAr), 7.40 (t, 1H, J = 7.6
Hz, CHAr), 7.17 (dd, 1H, J = 4.9, 3.4 Hz, CHAr), 5.35 (s, 2H, OCH2), 1.91 (s, 3H,
CH3); 13C NMR (175 MHz, CDCl3, 50 oC): δ = 170.0 (NC=O), 156.9 (CAr-q), 155.8
[6]
[7]
For a review on C–S bond formation under metal-free conditions, see:
D.-Q. Dong, S.-H. Hao, D.-S. Yang, L.-X. Li, Z.-L. Wang, Eur. J. Org.
Chem. 2017, 6576.
a) M. Hatano, K. Moriyama, T. Maki, K. Ishihara, Angew. Chem. 2010,
122, 3911; Angew. Chem. Int. Ed. 2010, 49, 3823; b) H. Yanai, S. Egawa,
8
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10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
K. Yamada, J. Ono, M. Aoki, T. Matsumoto, T. Taguchi, Asian J. Org.
Chem. 2014, 3, 556.
[11] Experimental procedures as well as full spectroscopic and analytical data
for compounds not included in this Experimental Section are described in
the Supporting Information. It contains compound characterization data,
experimental procedures, and copies of NMR spectra for all new
compounds.
[8]
[9]
CCDC 1528521 contains the supplementary crystallographic data for
compound 9a in this paper. These data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Received: ((will be filled in by the editorial staff))
Revised: ((will be filled in by the editorial staff))
CCDC 1815354 contains the supplementary crystallographic data for
Published online: ((will be filled in by the editorial staff))
compound 14e in this paper. These data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[10] CCDC 1817363 contains the supplementary crystallographic data for
compound 15b in this paper. These data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
9
This article is protected by copyright. All rights reserved.

10.1002/chem.201800630
Chemistry - A European Journal
DOI: 10.1002/chem.201xxxxxx
Entry for the Table of Contents
FULL PAPER
Herein, we describe the unique use of
Tf2C=CH2 as a Tf source in the
reaction with functionalized ynones to
form zwitterionic species, which were
trapped in an intramolecular fashion
by several nucleophiles to generate in
a divergent way two main types of
fluoroorganic moieties, namely,
bis(triflyl)-6-membered- or (triflyl)-5-
membered-fused-heterocycles,
through the simultaneous formation of
several carbon–carbon and carbon–
heteroatom bonds.
Synthetic Methods
B. Alcaide,* P. Almendros,* Carlos
Lázaro-Milla, and Patricia Delgado-
Martínez
Tf
Tf
O
Y
new Y–C and
C–C bonds
■■ – ■■
O
RT
R
22 examples
Y = S, Se, O
up to 84% yield
+
110 o
C
F
N
R
YZ
O
Tf new Y–C, C–C,
and C–O bonds
CTf2
Divergence in Ynone Reactivity:
Atypical Cyclization by 3,4-
Difunctionalization versus Rare
Bis(cyclization)
YZ = OH, OMe,
NHG, SMe, SeMe
R
Y
23 examples
metal-free; catalyst-free; no irradiaton
Y = S, Se, NG
up to 91% yield
10
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