Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

Article abstract of DOI:10.3762/BJOC.16.173

3-Aryl-1-(trifluoromethyl)prop-2-yn-1-iminium triflate salts represent a novel, highly reactive class of acetylenic iminium salts. Herein we present several reactions which are based on the electron-poor acetylenic bond and on the high electrophilicity of the CF₃-substituted iminium group. These salts were found to be highly reactive dienophiles in Diels–Alder reactions with cyclopentadiene, 2,3-dimethylbutadiene and even anthracene. At higher temperature, the cycloadducts undergo an intramolecular S_E(Ar) reaction leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and some substituted styrenes, cascade reactions take place, which likely include cyclobutene and several cationic intermediates and mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene as the substrate.

Full text of DOI:10.3762/BJOC.16.173

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium
salts with 1,3-dienes and styrenes
Thomas Schneider, Michael Keim, Bianca Seitz and Gerhard Maas*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2064–2072.
Institute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee
11, D-89081 Ulm, Germany
https://doi.org/10.3762/bjoc.16.173
Received: 29 June 2020
Accepted: 10 August 2020
Published: 24 August 2020
Email:
Gerhard Maas* - gerhard.maas@uni-ulm.de
* Corresponding author
Associate Editor: D. Y.-K. Chen
Keywords:
© 2020 Schneider et al.; licensee Beilstein-Institut.
License and terms: see end of document.
alkynes; aromatic substitution; cyclization; cycloaddition; iminium salts
Abstract
3-Aryl-1-(trifluoromethyl)prop-2-yn-1-iminium triflate salts represent a novel, highly reactive class of acetylenic iminium salts.
Herein we present several reactions which are based on the electron-poor acetylenic bond and on the high electrophilicity of the
CF3-substituted iminium group. These salts were found to be highly reactive dienophiles in Diels–Alder reactions with cyclopenta-
diene, 2,3-dimethylbutadiene and even anthracene. At higher temperature, the cycloadducts undergo an intramolecular SE(Ar) reac-
tion leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and
some substituted styrenes, cascade reactions take place, which likely include cyclobutene and several cationic intermediates and
mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene
as the substrate.
Introduction
In recent years, a trifluoromethyl substituent has been included Two major strategies exist to introduce a CF3 group into a
quite often in the design of compounds which were developed target molecule: formation of a carbon‒ or heteroatom‒CF3
for applications in various fields, such as biological and medici- bond [8,9] and the use of preformed CF3-substituted building
nal chemistry, agrochemicals, transition metal ligands, and ma- blocks. During our studies on acetylenic iminium salts, among
terials science [1-5]. The particular characteristics of the C‒F the numerous CF3-substituted building blocks α-(trifluoro-
bond [6,7] are the basis for the electronic and steric properties methyl)iminium salts RCH(CF3)=N+R’2 X− attracted our atten-
of the CF3 group, such as a strong electron-withdrawing tion, because a) the CF3 group should significantly increase the
(−I) effect, the accumulation of negative charge density in a rel- electrophilicity of the iminium functional group and b) these
atively small volume and the low polarizability of the fluoro salts are known to react with a variety of nucleophiles to afford
atoms. These and other substituent effects can modulate the products containing a C(CF3)NR2 moiety. In particular
conformational, physicochemical and electronic properties of a C(CF3)NHR and C(CF3)NH2 groups are of interest as pharma-
molecule.
cophores in the design of bioactive compounds [10-13].
2064

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
Simple α-(trifluoromethyl)iminium salts (RCH(CF3)=N+Me2
X−, R= H, CF3) with weakly nucleophilic or non-nucleophilic
anions can be isolated [14,15], but in organic synthesis, they are
most often generated in situ from suitable precursors and are
directly exposed to diverse nucleophiles. Such transformations
have been achieved using CH2(CF3)NR2 as the iminium ion
precursors [15], trifluoroacetaldehyde hemiaminals [16-18],
N,O-acetals [19] and N,N-acetals [20], 2-(trifluoromethyl)-1,3-
oxazolidines [21], and N-(tert-butylsulfinyl)trifluoroacet-
aldimine [11,22]. Other synthetic approaches to α-CF3-substi-
tuted amines include nucleophilic trifluoromethylation strate-
gies [17], such as the reaction of trifluoroacetaldehyde hemi-
aminals with enolizable carbonyl compounds in the presence of
a strong base [23], the reaction of aldiminium salts with (tri-
fluoromethyl)trimethylsilane/Lewis base [24], and the prepara-
tion of secondary α-(trifluoromethyl)propargylamines from
imines CF3CH=NR and lithium acetylides [25]. By a
photoredox-catalytic process, primary α-(trifluoromethyl)-α-(4-
Scheme 1: Diels–Alder reaction of propyn-1-iminium salt 1a com-
pared with the reported [29] reaction of 4-phenyl-1,1,1-trifluorobut-3-
yn-2-one.
pyridyl)benzylamines were obtained from α-(trifluoromethyl)- The Diels–Alder reaction of alkyne 1a with 2,3-dimethylbuta-
benzaldoximes and 4-cyanopyridine [26].
diene also occurred under very mild conditions and yielded the
iminium-substituted 1,4-cyclohexadiene 4-Ch (Scheme 2),
We have recently introduced a new class of acetylenic iminium which, due to its high sensitivity toward moisture, was not puri-
salts, namely 1-(trifluoromethyl)prop-2-yn-1-iminium triflates fied but was further converted in two steps into cyclohexadi-
R‒C≡C‒C(CF3)=N+Me2 TfO− [27]. As a first synthetic appli- enyl ketone 5-Ch by intentional hydrolysis followed by dehy-
cation, we have reported the phospha-Michael addition provid- drogenating aromatization leading to biphenyl-2-yl trifluoro-
ing 3-(triphenylphosphonio)-1-(trifluoromethyl)-1-(dimethyl- methyl ketone 6. The latter product was more effectively pre-
amino)allenes, which were subsequently transformed into α-(tri- pared in a one-pot cycloaddition/hydrolysis/aromatization se-
fluoromethyl)pyrroles. In the present paper, we consider the re- quence. 1H NMR spectra of unpurified 1,4-cyclohexadien-1-
activity of the electrophilic (“electron-poor”) acetylenic bond iminium salt 4-Ch and 1,4-cyclohexadien-1-yl ketone 5-Ch in-
toward 1,3-dienes, and show how the expected [4 + 2] or [2 + 2] dicated the presence of a minor byproduct. In the case of 5-Ch,
cycloaddition products can enter subsequent cascade reactions obtained as an oil, the two components could not be separated
toward carbocycles which incorporate a C(CF3)NMe2 struc- by column chromatography; however, the 1H NMR spectrum
tural unit.
suggested the cyclobutene structure 5-Cb for the byproduct.
Thus, signals of the two methyl groups (δ 1.63, 1.78 ppm) and
two terminal olefinic protons (δ 4.88 ppm, m) are observed, and
Results and Discussion
The Diels–Alder reaction of 1-CF3-substituted propyn-1- the ring-CH2 protons appear as an AB spin system (δ 2.75 and
iminium salt 1a with cyclopentadiene was carried out in order 2.92 ppm, 2J = 15.2 Hz). Obviously, 4-Cb and 5-Cb result from
to assess the dienophilic reactivity of the cation. High conver- a formal [2 + 2] cycloaddition of 1a and 2,3-dimethylbutadiene
sion into cycloaddition product 2 was observed already within (DMBD), the regioselectivity of which is as expected for a
one hour at 0 °C. Because of its high hydrolytic lability, adduct highly asynchronous transition state with effective stabilization
2 was not isolated but directly converted into the norbornadi- of the positive charge or a two-step ionic process (vide infra).
enyl trifluoromethyl ketone 3 (Scheme 1). The smooth [4 + 2] The high electrophilic power of the 1-CF3-substituted propyn-1-
cycloaddition of 1a as compared to comparably harsh thermal iminium ion presumably renders an ionic [2 + 2] cycloaddition
conditions of other propyne ketiminium salts with an internal pathway competitive with the Diels–Alder reaction. The few re-
acetylenic bond reveals the activating influence of the CF3 ported examples of cyclobutene formation from alkynes and
group, which has both an electronic (electron-withdrawing) and unactivated 1,3-dienes include the sensitized photocycloaddi-
steric (e.g., CF3 vs a phenyl substituent [28]) component. More- tion of phenylacetylene and DMBD [30] and the gold(I)-cata-
over, a comparison with the thermal conditions of the lyzed reaction of phenylacetylene and DMBD or isoprene [31].
Diels–Alder reaction of 4-phenyl-1,1,1-trifluorobut-3-yn-2-one On the other hand, the 1,1-diphenylpropargyl cation was found
and cyclopentadiene [29] confirms the expected accelerating to react with 2,4-dimethyl-1,3-pentadiene to afford a product
effect of the iminium activation.
derived from an initial [4 + 2] cycloaddition [32].
2065

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
Scheme 2: Sequential Diels–Alder/intramolecular SE(Ar) reaction of propyn-1-iminium triflates 1a,b. Conditions: a) CH3CN, aqueous K2CO3, 15 min;
b) 1. 1a + 2,3-dimethylbutadiene, dry CH2Cl2, 0 °C, 30 min, then rt, 2 h; 2. o-chloranil, CH2Cl2, rt, 20 h; 3. K2CO3, CH3CN/H2O, rt, 2 h; c) o-chloranil,
dry CH2Cl2, rt, 22 h, then K2CO3, H2O; d) 1. dry CH3CN, rt, 1 h; 2. 50 °C, 22 h; 3. o-chloranil, CH2Cl2, rt, 12 h.
When the Diels–Alder reaction of 1a with DMBD was carried iminium-ion induced SE(Ar) reactions shown in Scheme 2 were
out at room temperature instead of 0 °C, 19F NMR monitoring not applicable to the iminium-substituted norbornadiene 2,
of the reaction’s progress indicated the appearance of a second which suffered undefined polymerization on moderate heating
product beside the 1,4-cyclohexadien-1-iminium salt 4-Ch. in various solvents.
Further investigations revealed that the new product was the
dihydrofluorene 7, resulting from 4-Ch by an intramolecular In contrast to so far unknown 9‑amino-9-(trifluoromethyl)-9H-
electrophilic aromatic substitution with the reactive (trifluoro- fluorenes, compounds containing a 9-(trifluoromethyl)-9H-
methyl)iminium group as the electrophile (Scheme 2). The ther- fluoren-9‑ol partial structure can be found in the patent litera-
mal conversion of 4-Ch into 7 was optimized and finally ture [33-35], where they have been claimed for their pyruvate
allowed the preparation of the latter from 1a in a one-pot, two- dehydrogenase kinase (PDHK) inhibitory activity.
step, temperature-dependent Diels–Alder reaction/intramolecu-
lar SE(Ar) reaction sequence in good yield. Dehydrogenation of The remarkable dienophilic reactivity of 1-CF3-substituted
7 with chloranil then provided 9-(dimethylamino)-9-(trifluoro- propyn-1-iminium salts is also exemplified by the Diels–Alder
methyl)fluorene 8.
reaction of 1a with anthracene (Scheme 3). After 12 h at room
temperature, a 91% conversion was observed, and subsequent
In an analogous reaction sequence, 11H-benzo[a]fluorene de- moderate heating gave the cycloaddition product 10 in 95%
rivative 9 was obtained from 3-(2-naphthyl)propyn-1-iminium yield. The subsequent iminium-induced electrophilic cycliza-
salt 1b and 2,3-dimethylbutadiene (Scheme 2) in a one-pot tion required extended heating in refluxing toluene and finally
three-step sequence. On the other hand, the successful thermal furnished the neutral polycycle 11 in good yield. The paddle-
2066

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
wheel-shaped structure of 11 was established by an XRD struc- The thermal cyclization of Diels–Alder adducts as shown in
ture determination and is shown in Figure 1.
Scheme 2 and Scheme 3 appear to be the first intramolecular
SE(Ar) reactions of an α-(trifluoromethyl)iminium functional
group. Analogous intermolecular reactions of CF3-substituted
iminium groups with electron-rich (hetero)aromatics are known
[18,24]. Furthermore, 1-(trifluoromethyl)indenes have recently
been generated by cationic cyclization of β-aryl trifluoromethyl
enones under superacid conditions [42-44].
Styrenes are also known to behave as dienes in [4 + 2] cycload-
dition reactions [45]. Thus, while styrene and maleic anhydride
react only at elevated temperatures, with the more electrophilic
(methoxycarbonyl)maleic anhydride two 2:1 adducts are
already formed at room temperature: one by two consecutive
Diels–Alder reactions, the other one by a Diels–Alder/ene reac-
tion sequence [46]. Taking into account the presumably high
electrophilic character of the 1-(trifluoromethyl)propyn-1-
iminium ion, for its reaction with styrenes we could not exclude
a priori an initial electrophilic addition at the olefinic bond
(with formation of a benzyl cation intermediate).
Scheme 3: Diels–Alder reaction of 1a and anthracene followed by an
intramolecular SE(Ar) reaction.
The reaction of propyn-1-iminium salt 1a with styrene in aceto-
nitrile was considered first and was monitored by 19F NMR
spectroscopy. Whereas no reaction appeared to occur at room
temperature, a slow transformation into two fluorine-containing
products was observed at 70 °C, which after neutralization and
work-up were identified by their NMR and analytical data
as 2-(1-phenylvinyl)indene 12a and a small amount of
benzo[a]fluorene 13a (δF = −69.74 and −69.20 ppm, respective-
ly).
The results obtained with styrenes bearing a substituent at the
olefinic bond provide useful information with respect to the
reaction mechanism. Thus, the reaction of 1a with α-methyl-
styrene or 1,1-diphenylethene proceeded at a faster rate than
with styrene and yielded 3-methyl- and 3-phenyl-2-vinylin-
denes 12b and 12c (structure confirmed by an XRD analysis,
see Figure 2) in high yields. Benzo[a]fluorenes were found to a
minor extent (13c) or not at all (13b) (Scheme 4). A remark-
able stereochemical aspect accompanied the reaction of 1a with
(E)-1-phenyl-1-propene leading to 2-((E)-1-phenylprop-1-
enyl)indene 12d, where trans(Ph,Me)→cis isomerization at the
olefinic bond has occurred. The E-configuration was assigned
based on NOESY NMR experiments and confirmed by an
X-ray structure determination (see Figure 3).
Figure 1: Solid-state molecular structure of 11 (ORTEP plot).
The reactivity of 1a in the Diels–Alder reaction with anthracene
may be compared with that of other dienophiles. Thus, other
propyn-1-iminium salts with an internal C,C triple bond and not
containing a CF3 substituent (toluene, 120 °C, several hours
[28]), DMAD (no solvent, 170–180 °C, 1 h [36]) and hexa-
fluoro-2-butyne (200 °C, 2 h [37]) react only under harsher
conditions, whereas terminal propyn-1-iminium salts (CH2Cl2,
rt, 2‒4 h [38]) and tetracyanoethylene (rt, 12 h [39]) were found
to react equally well or even faster than 1a. Although these
comparisons are only qualitative, they suggest that 1-CF3-
substituted propyn-1-iminium salts have a high electrophilicity
power and therefore, are candidates for polar Diels–Alder reac-
tions [40,41].
A mechanistic scheme for the formation of indenes 12 and
benzo[a]fluorenes 13 is proposed in Scheme 5. The electrophil-
ic propyn-1-iminium ion 1a adds chemoselectively (by conju-
gate addition) and regioselectively (Markovnikov-type addition)
at the olefinic bond of the styrene to form the resonance-stabi-
2067

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
Scheme 4: Reactions of propyn-1-iminium salt 1a with styrenes.
lized benzyl cation 14 which can add intramolecularly to the
nucleophilic central carbon atom of the aminoallene moiety,
either by an electrophilic 1,4-cyclization yielding a cyclobutene
15 or by an 1,6-cyclization yielding a dihydronaphthalene 16.
Formally speaking, 15 results from a [2 + 2] cycloaddition and
16 from a [4 + 2] cycloaddition (Diels–Alder reaction). Under
the reaction conditions, cyclobutene 15 undergoes a fast electro-
cyclic ring opening leading to a butadiene 17, which is finally
transformed into 2-(1-phenylvinyl)indene 12 through an intra-
molecular iminium ion-induced 1,5-cyclization. The same cycli-
zation type together with oxidative aromatization converts
dihydronaphthalenes 16 into benzo[a]fluorenes 13. The stereo-
chemistry of 12d can be explained by a stereoselective forma-
tion of trans-3,4-disubstituted cyclobutene 15d and subsequent
conrotatory electrocyclic ring-opening, from which
Z(1,2),E(3,4)-configured butadiene intermediate 17d results.
Figure 2: Solid-state molecular structure of 12c (ORTEP plot).
The intermediacy of a cyclobutene 15 in the mechanistic
scenario of Scheme 5 is corroborated by the isolation of
cyclobutene 18 from the reaction of 1a with 1,2-dihydronaph-
thalene, a cyclic styrene derivative (Scheme 6; compare also the
cyclobutene byproduct in Scheme 2). The structure of 18 was
derived from its 1H and 13C NMR chemical shifts; a NOE NMR
experiment indicated the vicinity of the phenyl ring and the
CH2CH part or the molecule in line with the expected orienta-
tion of the cycloaddition. Cis-annelated cyclobutene 18
(1H NMR: 3JH,H = 3.8 Hz for the angular protons) and the
iminium-substituted primary cycloadduct are not expected to
undergo a fast ring opening under moderate thermal conditions,
because the orbital-symmetry-allowed concerted conrotatory
process [47,48] would create a strained cis,trans-dihydro-
benzo[8]annulene ring system.
Figure 3: Solid-state molecular structure of 12d (ORTEP plot). Both
the R and the S enantiomer are present in the acentric unit cell of the
crystal (space group P21, Z = 4).
2068

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
iminium salts with cyclic enol ethers [49] and of other very
electrophilic alkynes (i.e., Lewis acid-activated acetylenic esters
[50], 1-(trifluoroacetyl)-3-haloacetylenes [44] and 4-chloro-2-
oxobut-3-ynoic esters [51-53] with unactivated alkenes (includ-
ing cyclohexene [51], which did not react with 1a). For the
3-arylpropyn-1-iminium ions 1, a charge delocalization can be
assumed, which is described by the resonance structure of a
1-aryl-3-aminoallenyl cation, hence their electronic structure
shows a certain analogy to the triphenylpropargyl/triphenylal-
lenyl cation. It has been reported that this cation reacts with
cyclopentadiene in two different ways: concerted [4 + 2] cyclo-
addition and a stepwise [2 + 2] cycloaddition via an allenyl-
cyclopentenyl cation (which could be trapped with OH−)
[54,55].
Styrene structural moieties are also present in (E,E)-1,4-
diphenylbuta-1,3-diene. Therefore, it was of interest to know
whether it would react with propyn-1-iminium salts 1 as a
styrene or a 1,3-diene. With 3-(4-bromophenyl)propyn-1-
iminium salt 1c in acetonitrile, no reaction was observed at
20 °C, but within two hours at 45 °C, an unclean reaction took
place, which became evident by a multitude of 19F NMR
signals. Assuming that some of the signals represented prod-
ucts that would easily undergo further thermal reactions, the
solution was additionally heated at 70 °C for 40 hours. The re-
sulting reaction mixture still contained several products, of
which only the major fluorine-containing component
(δF = −46.76 ppm, a value quite different from those of prod-
ucts 12 and 13) could finally be isolated in modest yield and
was identified by an X-ray structure analysis as the CF3-substi-
tuted fulvene 19 (Scheme 7).
A reaction pathway leading to fulvene 19 is proposed in
Scheme 8. It begins with the formal [2 + 2] cycloaddition of 1c
and the diene component, which is probably a two-step process
as shown in Scheme 5. Cyclobutene 20 is prone to a thermally
induced conrotatory electrocyclic ring-opening, which yields
iminium-substituted triene 21. In a similar reaction, an
α-phenyliminium salt structurally analogous to 21 could be iso-
lated [56]. A cationic 1,5-cylization converts 21 into cyclopen-
tene 22, from which fulvene 19 is formed by deprotonation and
a formal 1,4-shift of the NMe2 group. The details of this rear-
rangement are not known, an N,N-dimethyldihydropyrrolium
intermediate may be involved.
Scheme 5: A mechanistic proposal for the reaction of alkyne 1a with
styrenes.
Conclusion
This study has uncovered new applications of 3-aryl-1-(tri-
Scheme 6: Reaction of alkyne 1a with 1,2-dihydronaphthalene.
fluoromethyl)prop-2-yn-1-iminium ions as CF3-substituted C3
Cyclobutenes resulting from a [2 + 2] cycloaddition of electro- building blocks. They are not only very electrophilic dieno-
philic alkynes and alkenes under moderate thermal conditions philes in Diels–Alder reactions with normal electron demand
have been isolated also from the reaction of CF3-free propyn- (HOMOdiene‒LUMOdienophile controlled, in the language of
2069

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
Scheme 7: Synthesis and solid-state molecular structure (ORTEP plot) of pentafulvene 19; selected bond distances (Å), see molecule plot for atom
numbering: C8‒C7 1.370(2), C7‒C17 1.481(2), C17‒C18 1.343(2), C18‒C5 1.471(2), C5‒C6 1.374(2), C6‒C7 1.496(2).
Supporting Information
Supporting Information File 1
Experimental procedures, NMR (1H, 13C, 19F) and IR
spectra of synthesized compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-173-S1.pdf]
Supporting Information File 2
Crystal and structure refinement data for compounds 11,
12c, 12d and 19.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-173-S2.pdf]
Acknowledgements
We thank Bernhard Müller for the X-ray data collection and Dr.
Scheme 8: Proposed mechanistic pathway leading to fulvene 19.
Markus Wunderlin for the mass spectra.
FMO theory), but also represent powerful 1,3-biselectrophiles. Funding
Thus, Diels–Alder reactions followed by an intramolecular This work was supported by the University of Ulm.
SE(Ar) reaction of the α-(trifluoromethyl)iminium functional
group were achieved as a two-step one-pot synthesis. On the
ORCID® iDs
other hand, an electrophilic (Markownikow type) addition of
the propyn-1-iminium ion via its C3-position to the olefinic
bond of styrenes initiated a reaction cascade which was again
terminated by the already mentioned cyclization step through
intramolecular electrophilic aromatic substitution, resulting in
the formation of 2-(1-phenylvinyl)-1-(trifluoromethyl)-1-
(dimethylamino)indenes as the major products. Various other
synthetic applications of these reactive propyn-1-iminium salts
will be reported in due course.
Thomas Schneider - https://orcid.org/0000-0001-6158-7149
Bianca Seitz - https://orcid.org/0000-0002-0865-7272
Gerhard Maas - https://orcid.org/0000-0002-9289-4210
References
1. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2013.
doi:10.1002/9783527651351
2070

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
2. Haufe, G.; Leroux, F., Eds. Fluorine in Life Sciences: Pharmaceuticals,
Medicinal Diagnostics, and Agrochemicals; Academic Press: Oxford,
U.K., 2019.
26.Nicastri, M. C.; Lehnherr, D.; Lam, Y.-h.; DiRocco, D. A.; Rovis, T.
J. Am. Chem. Soc. 2020, 142, 987–998. doi:10.1021/jacs.9b10871
27.Schneider, T.; Seitz, B.; Schiwek, M.; Maas, G. J. Fluorine Chem.
2020, 235, 109567. doi:10.1016/j.jfluchem.2020.109567
28.Nikolai, J.; Schlegel, J.; Regitz, M.; Maas, G. Synthesis 2002, 497–504.
doi:10.1055/s-2002-20964
3. Ojima, I., Ed. Fluorine in Medicinal Chemistry and Chemical Biology;
Wiley-Blackwell: Chichester, U.K., 2009. doi:10.1002/9781444312096
4. Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of
Fluorine; John Wiley & Sons: Hoboken, NJ, USA, 2008.
5. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.;
Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643.
doi:10.1002/cbic.200301023
29.Zenova, A. Y.; Borisenko, A. A.; Platonov, V. V.; Proskurnina, M. V.;
Zefirov, N. S. Russ. J. Org. Chem. 1996, 32, 951–954.
Zh. Org. Khim. 1996, 32, 992–995.
30.Akbulut, N.; Hartsough, D.; Kim, J.-I.; Schuster, G. B. J. Org. Chem.
1989, 54, 2549–2556. doi:10.1021/jo00272a017
6. O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319.
doi:10.1039/b711844a
31.de Orbe, M. E.; Echavarren, A. M. Eur. J. Org. Chem. 2018,
2740–2752. doi:10.1002/ejoc.201800170
7. Hunter, L. Beilstein J. Org. Chem. 2010, 6, No. 38.
doi:10.3762/bjoc.6.38
32.Gassman, P. G.; Singleton, D. A. Tetrahedron Lett. 1987, 28,
5969–5972. doi:10.1016/s0040-4039(00)96839-4
8. Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52,
8214–8264. doi:10.1002/anie.201206566
33.Motomura, T.; Nagamori, H.; Suzawa, K.; Ito, H.; Morita, T.;
Kobayashi, S.; Shinkai, H. Fluorene Compound and Use Thereof for
Medical Purposes. WO Patent WO2010041748, April 15, 2010.
34.Motomura, T.; Matsuo, T.; Shomi, G.; Inoue, M. Pyrazole Alcohol
Compounds and Pharmaceutical Use Thereof. U.S. Patent
US20150025120, Jan 20, 2015.
9. Alonso, C.; Martínez de Marigorta, E.; Rubiales, G.; Palacios, F.
Chem. Rev. 2015, 115, 1847–1935. doi:10.1021/cr500368h
10.Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422–518.
doi:10.1021/acs.chemrev.5b00392
11.Mei, H.; Xie, C.; Han, J.; Soloshonok, V. A. Eur. J. Org. Chem. 2016,
5917–5932. doi:10.1002/ejoc.201600578
35.Motomura, T.; Matsuo, T.; Shomi, G. Fluorene-Amide Compounds and
Pharamacceutical Use Thereof. U.S. Patent US20150018403, Jan 15,
2015.
12.Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.;
Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Léger, S.;
LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.;
Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.;
Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Thérien, M.;
Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.;
Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18,
923–928. doi:10.1016/j.bmcl.2007.12.047
36.Bouffard, J.; Eaton, R. F.; Müller, P.; Swager, T. M. J. Org. Chem.
2007, 72, 10166–10180. doi:10.1021/jo702000d
37.Krespan, C. G.; McKusick, B. C.; Cairns, T. L. J. Am. Chem. Soc. 1961,
83, 3428–3432. doi:10.1021/ja01477a018
38.Keim, M.; Kratzer, P.; Derksen, H.; Isakov, D.; Maas, G.
Eur. J. Org. Chem. 2019, 826–844. doi:10.1002/ejoc.201801511
39.Roberts, R. M. G. J. Organomet. Chem. 1990, 388, 181–186.
doi:10.1016/0022-328x(90)85360-b
13.Sewald, N.; Seymour, L. C.; Burger, K.; Osipov, S. N.; Kolomiets, A. F.;
Fokin, A. V. Tetrahedron: Asymmetry 1994, 5, 1051–1060.
doi:10.1016/0957-4166(94)80055-3
40.Domingo, L. R.; Aurell, M. J.; Pérez, P.; Contreras, R. Tetrahedron
2002, 58, 4417–4423. doi:10.1016/s0040-4020(02)00410-6
41.Domingo, L. R.; Sáez, J. A. Org. Biomol. Chem. 2009, 7, 3576–3583.
doi:10.1039/b909611f
14.Henle, H.; Geisel, M.; Mews, R. J. Fluorine Chem. 1984, 26, 133–148.
doi:10.1016/s0022-1139(00)80917-3
15.Ates, C.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett. 1993, 34,
5711–5714. doi:10.1016/s0040-4039(00)73840-8
42.Kazakova, A. N.; Iakovenko, R. O.; Boyarskaya, I. A.; Ivanov, A. Y.;
Avdontceva, M. S.; Zolotarev, A. A.; Panikorovsky, T. L.; Starova, G. L.;
Nenajdenko, V. G.; Vasilyev, A. V. Org. Chem. Front. 2017, 4,
255–265. doi:10.1039/c6qo00643d
16.Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997–1000.
doi:10.1021/jo016265t
17.Langlois, B. R.; Billard, T. Synthesis 2003, 185–194.
doi:10.1055/s-2003-36812
43.Iakovenko, R. O.; Kazakova, A. N.; Boyarskaya, I. A.; Gurzhiy, V. V.;
Avdontceva, M. S.; Panikorovsky, T. L.; Muzalevskiy, V. M.;
Nenajdenko, V. G.; Vasilyev, A. V. Eur. J. Org. Chem. 2017,
5632–5643. doi:10.1002/ejoc.201701085
18.Gong, Y.; Kato, K. J. Fluorine Chem. 2002, 116, 103–107.
doi:10.1016/s0022-1139(02)00044-1
19.Fuchigami, T.; Ichikawa, S. J. Org. Chem. 1994, 59, 607–615.
doi:10.1021/jo00082a018
44.Politanskaya, L. V.; Selivanova, G. A.; Panteleeva, E. V.;
Tretyakov, E. V.; Platonov, V. E.; Nikul’shin, P. V.; Vinogradov, A. S.;
Zonov, Y. V.; Karpov, V. M.; Mezhenkova, T. V.; Vasilyev, A. V.;
Koldobskii, A. B.; Shilova, O. S.; Morozova, S. M.; Burgart, Y. V.;
Shchegolkov, E. V.; Saloutin, V. I.; Sokolov, V. B.; Aksinenko, A. Y.;
Nenajdenko, V. G.; Moskalik, M. Y.; Astakhova, V. V.; Shainyan, B. A.;
Tabolin, A. A.; Ioffe, S. L.; Muzalevskiy, V. M.; Balenkova, E. S.;
Shastin, A. V.; Tyutyunov, A. A.; Boiko, V. E.; Igumnov, S. M.;
Dilman, A. D.; Adonin, N. Y.; Bardin, V. V.; Masoud, S. M.;
Vorobyeva, D. V.; Osipov, S. N.; Nosova, E. V.; Lipunova, G. N.;
ACharushin, V. N.; APrima, D. O.; Makarov, A. G.; Zibarev, A. V.;
Trofimov, B. A.; Sobenina, L. N.; Belyaeva, K. V.; Sosnovskikh, V. Y.;
Obydennov, D. L.; Usachev, S. A. Russ. Chem. Rev. 2019, 88,
425–569. doi:10.1070/rcr4871
20.Xu, Y.; Dolbier, W. R., Jr. J. Org. Chem. 2000, 65, 2134–2137.
doi:10.1021/jo991750y
21.Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahedron Lett.
2002, 43, 2827–2830. doi:10.1016/s0040-4039(02)00330-1
22.Wu, L.; Xie, C.; Zhou, J.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y.
J. Fluorine Chem. 2015, 170, 57–65.
doi:10.1016/j.jfluchem.2015.01.001
23.Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem. 2001, 66,
4826–4830. doi:10.1021/jo015587u
24.Levin, V. V.; Kozlov, M. A.; Song, Y.-H.; Dilman, A. D.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2008, 49,
3108–3111. doi:10.1016/j.tetlet.2008.03.043
25.Magueur, G.; Crousse, B.; Bonnet-Delpon, D. Tetrahedron Lett. 2005,
46, 2219–2221. doi:10.1016/j.tetlet.2005.02.030
45.Wagner-Jauregg, T. Synthesis 1980, 769–798.
doi:10.1055/s-1980-29206
2071

Beilstein J. Org. Chem. 2020, 16, 2064–2072.
46.Hall, H. K., Jr.; Nogues, P.; Rhoades, J. W.; Sentman, R. C.; Detar, M.
J. Org. Chem. 1982, 47, 1451–1455. doi:10.1021/jo00347a014
47.Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8,
781–853. doi:10.1002/anie.196907811
Angew. Chem. 1969, 81, 797–870. doi:10.1002/ange.19690812102
48.Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C.
Acc. Chem. Res. 1996, 29, 471–477. doi:10.1021/ar9501986
49.Kratzer, P.; Gerster, H.; Maas, G. Synthesis 2015, 47, 2805–2818.
doi:10.1055/s-0034-1380223
50.Snider, B. B.; Roush, D. M.; Rodini, D. J.; Gonzalez, D.; Spindell, D.
J. Org. Chem. 1980, 45, 2773–2785. doi:10.1021/jo01302a007
51.Koldobskii, A. B.; Solodova, E. V.; Godovikov, I. A.; Kalinin, V. N.
Tetrahedron 2008, 64, 9555–9560. doi:10.1016/j.tet.2008.07.066
52.Koldobskii, A. B.; Tsvetkov, N. P.; Verteletskii, P. V.; Godovikov, I. A.;
Kalinin, V. N. Russ. Chem. Bull. 2009, 58, 1431–1437.
doi:10.1007/s11172-009-0191-3
53.Koldobskii, A. B.; Shilova, O. S.; Artyushin, O. I.; Kagramanov, N. D.;
Moiseev, S. K. J. Fluorine Chem. 2020, 231, 109463.
doi:10.1016/j.jfluchem.2020.109463
54.Bäuml, E.; Mayr, H. Chem. Ber. 1985, 118, 683–693.
doi:10.1002/cber.19851180228
55.Bäuml, E.; Mayr, H. Chem. Ber. 1985, 118, 694–703.
doi:10.1002/cber.19851180229
56.Keim, M. Terminale Propiniminium-Salze und CF3-haltige
3-Trifloxypropeniminium-Salze als reaktive C3-Bausteine zum Aufbau
neuartig funktionalisierter Carbo- und Heterocyclen. Ph.D. Thesis, Ulm
University, Ulm, Germany, 2018.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(https://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
https://doi.org/10.3762/bjoc.16.173
2072