Functionalized fluorenes via dicationic electrophiles

Article abstract of DOI:10.1016/j.tetlet.2019.05.046

Dicationic fluorenyl cations are shown to react with nitriles to provide amide-functionalized fluorenes. A similar reaction with alcohols gives ether derivatives. The chemistry is initiated by the reactions of N-heterocyclic ketones in a superacidic solution. This leads to cyclizations involving 2-biphenyl groups and formation of the reactive fluorenyl cations.

Full text of DOI:10.1016/j.tetlet.2019.05.046

Accepted Manuscript
Functionalized fluorenes via dicationic electrophiles
Michael R. Stentzel, Douglas A. Klumpp
PII:
S0040-4039(19)30491-5
https://doi.org/10.1016/j.tetlet.2019.05.046
TETL 50818
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Tetrahedron Letters
Received Date:
Revised Date:
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26 March 2019
20 May 2019
23 May 2019
Please cite this article as: Stentzel, M.R., Klumpp, D.A., Functionalized fluorenes via dicationic electrophiles,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.046
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Functionalized fluorenes via dicationic
electrophiles
Michael R. Stentzel and Douglas A. Klumpp*

1
Tetrahedron Letters
Functionalized fluorenes via dicationic electrophiles
Michael R. Stentzel and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois, 60115
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Dicationic fluorenyl cations are shown to react with nitriles to provide amide-functionalized
fluorenes. A similar reaction with alcohols gives ether derivatives. The chemistry is initiated by
the reactions of N-heterocyclic ketones in a superacidic solution. This leads to cyclizations
involving 2-biphenyl groups and formation of the reactive fluorenyl cations.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Carbocation
Heterocycle
Superacid
Superelectrophile
Introduction
Results and Discussion
The fluorene ring system is a useful scaffold for many
applications. It is a common ring system in natural products and
Our previous study showed that dicationic fluorenyl cations
could be generated conveniently through the condensation of
diaryl ketones in superacid. The required ketones (4) have been
prepared via two routes (Fig. 2). In one synthetic method, 2-
phenylbenzonitrile is reacted with an organolithium reagent, and
after hydrolytic workup, the desired ketone 4 is produced. The
1
,2
8
,9
its derivatives are frequent synthetic targets. Its photo-physical
3
properties make it highly useful in dyes/pigments, light
4
5
harvesting arrays, and solar cell applications. It has also been
used as a building block for polymers, electronics, and material
6
science applications. Due to the broad utility of the fluorene ring
system, there has been considerable interest in the development
7
of synthetic methods leading to these compounds. Recently, we
described a superacid-promoted route to diarylfluorenes from
8
aromatic ketones (Fig. 1). For example, the reaction of 2-pyridyl
ketone (1) with benzene in triflic acid (CF SO H) provides
3
3
diarylfluorene (3) in high yield (91%). The chemistry involves
formation of the superelectrophilic fluorenyl
Figure 2. The synthesis of biaryl ketone substrates.
other approach involves generating 2-lithiobiphenyl from 2-
bromobiphenyl and utilizing aldehydes to build the structure. The
intermediate product alcohol is then oxidized to the ketone 4.
Our initial experiments sought to generate the reactive
fluorenyl cations and produce amide products via nucleophilic
reactions involving nitriles (Ritter reaction, Table 1). Using
ketone 1 and acetonitrile, the expected amide-functionalized
fluorene 5 was isolated in 82% yield. Optimization experiments
revealed that the best conditions for generating the fluorenyl
cations were in excess CF SO H (35 equiv.) at -35 °C. If more
weakly acidic media is used, the diaryl ketone (1) is recovered
unreacted in the product mixtures. These included sulfuric acid,
methanesulfonic acid, trifluoroacetic acid (TFA), or mixtures of
TFA and triflic acid. Thus, the heterocyclic ketone is
Figure 1. The preparation of diarylfluorene 3.
cation 2 from condensation of the 2-pyridyl ketone in the
13
superacid. Using stable ion conditions and low temperature
C
9
NMR, the dicationic species (2) was directly observed. We
demonstrated that the dication 2 was a useful electrophile for
reactions with carbon nucleophiles such as benzene. Based on the
electrophilic reactivities of 2 and related fluorenyl dications, we
sought to determine if synthetic methodologies could be
developed with other nucleophilic reagents. The results of these
studies are presented in this letter.
3
3

2
Tetrahedron
Table 1. Products and yields for the reactions of diaryl ketones
Table 2. Products and yields for the reactions of diaryl ketones
in the Ritter reaction.
with alcohols.
reacted with superacid at -35 °C followed by the addition of
excess acetonitrile. Using the optimized procedure, other nitriles,
such as trichloroacetonitrile, isopropylnitrile, and decylnitrile,
provided the respective fluorenyl amides (6-8). Using deuterated
acetonitrile, the corresponding amide (9) is isolated in good
yield. With an imidazole-based ketone, the fluorenyl amides 10
and 11 are prepared. Although several efforts were made to
extend the chemistry with aromatic nitrile, such as benzonitrile,
the superacidic media gave large amounts of the trimeric
equivalents of superacid lead to formation of the dicationic
carboxonium ion 22. The high electrophilic reactivity of the
carboxonium group leads to rapid ring closure via an
intramolecular Friedel-Crafts reaction. Proton transfer steps then
provide the dicationic oxonium ion 23. In our previous NMR
studies of this system, neither dication 22 or 23 were visible by
low temperature NMR in FSO H-SbF solution – indicating that
3
5
9
both were extremely short-lived intermediates. Loss of water
1
0
from 23 provides the reactive fluorenyl dication (2) - a cleanly
products (i.e.- 1,3,5-triphenyltriazine).
9
formed ion, observable by NMR studies. Quenching the solution
With the use of alcohols, the superelectrophilic fluorenyl
dications gives ether products (Table 2). Thus, ketone 1
undergoes conversion to the fluorenyl cation (2) which can be
trapped with methanol to provide the fluorenyl ether 12.
Similarly, the deuterated ether (13) is prepared from D4-
methanol. This procedure involves reacting the heterocyclic
ketone with superacid at -35 °C followed by the addition of
excess methanol to the mixture. Products 12 or 13 are then
isolated by column chromatography. With the addition of ethanol
or trifluoroethanol, products 14 and 15 are isolated in good
yields. Isopropanol and its fluorinated derivative also provide the
expected ethers (16 and 17) in good yields from ketone 1. Amino
alcohols are effective nucleophiles for this coupling reaction, as
the amine group is readily solvated/protonated in the acid phase.
Thus, the prolinol derivative provides 19 in fair yield and the
piperidine derivative gives alcohol 20. As with the Ritter
reaction, the imidazole-based ketones provide ether products (18
and 21) in good yield from the reaction with isopropanol.
with methanol leads to another oxonium dication
The conversions described above involve a series of dicationic
intermediates (Fig. 3). In the reactions of ketone 1, two
Figure 3. Proposed mechanism for the formation of amide and
ether products.

3
(24). While it is conceivable that an equilibrium exists between
References and notes
ions 2 and 24, this type of equilibrium likely favors the oxonium
dication (24). Computational studies indicated that dication 2
possesses some anti-aromatic character due to electrostatic
1. Zhou, A.-H.; Pan, F.; Zhu, C. Ye, Chem. Eur. J. 2015, 21, 10278-
0288.
2. Shi, Y.; Gao, S. Tetrahedron 2016, 72, 1717-1735.
Kurdyukova, I. V.; Ishchenko, A. A. Russ. Chem. Rev. 2012, 81,
58-290.
4. Justin Thomas, K. R.; Baheti, A. Mat. Technol. 2013, 28, 71-87.
5. Rodriguez-Seco, C.; Cabau, L.; Vidal-Ferran, A.; Palomares, E.
Acct. Chem. Res. 2018, 51, 869-880.
1
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effects on the fluorenyl cation -system. This type of electronic
3
.
destabilization should tend to enhance the reactivity of the
fluorenyl cation towards nucleophilic attack – forcing the
equilibrium toward oxonium ion 24. In the Ritter reaction,
acetonitrile reacts to form the dicationic nitrilium ion 25. There
have been reports to suggest dicationic nitrilium ions, such as 25,
2
6
.
Fischer, I.; Schenning, A. P. H. J. Org. Elect. 2013, 1-25.
1
1
7. a. Xu, S.; Chen, R.; Fu, Z.; Zhou, Q.; Zhang, Y.; Wang, J. ACS
Catal. 2017, 7, 1993-1997. b. Giuglio-Tonolo, A. G.; Terme, T.;
Vanelle, P. Molecules 2016, 21, 1408/1-1408/11. c. Corrie, T. J.
A.; Ball, L. T.; Russell, C. A.; Lloyd-Jones, G. C. J. Am. Chem.
Soc. 2017, 139, 245-254. d. Yao, S.; Kim, B.; Yue, X.; Colon
Gomez, M. Y.; Bondar, M. V.; Belfield, K. D. ACS Omega
may form adducts with the triflate ion. Nevertheless, ion 25 or
the corresponding triflate adduct provides the amide product
from aqueous workup. The proposed mechanism may explain
why excess superacid is needed to carry out the transformations.
The high acidity is necessary to generate an appreciable
concentration of the initial dicationic carboxonium ion (22).
Moreover, the superacidity is associated with conditions of
2
016, 1, 1149-1156. e. Li, C.; Zeng, H. J. Heterocyclic
Chem. 2016, 53, 1706-1714. f. Shi, G.; Chen, D.; Jiang, H.;
Zhang, Y.; Zhang, Y. Org. Lett. 2016, 18, 2958-2961.
1
2
extremely low nucleophilicity. This allows the fluorenyl
dication (2) to form in high concentrations, enabling good
conversions with the nitrile and alcohol nucleophiles.
8. Gasonoo, M.; Sumita, A.; Giuffre, K.; Boblak, K.; Ohwada, T.;
Klumpp, D. A., J. Org. Chem. 2017, 82, 6044-6053.
9
1
1
.
Sumita, A.; Ohwada, T.; Boblak, K.; Gasonoo, M.; Klumpp, D.
A., Chem. Eur. J. 2017,23, 2566-2570.
0. Tanaka, H.; Shizu, K.; Nakanotani, H.; Adachi, C. J. Phys. Chem.
C, 2014, 118, 15985-15994.
1. a. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113,
Conclusion
In summary, we have found that functionalized fluorenes may
be prepared by the reactions of superelectrophilic fluorenyl
cations with nitrogen (nitriles) and oxygen (alcohols)
nucleophiles. This work compliments our earlier study involving
6
4
91-698. b. Raja, E.; Klumpp, D. A. Tetrahedron 2011, 67, 4494-
497.
12. Olah, G. A.; Prakash, G. K. S.; Molnar, A. Sommer, J. Superacids,
nd
2
Ed.; Wiley: NY, NY, 2009.
3. Booth, B. L.; El-Fekky, T. L. J. Chem. Soc., Perkin Trans. 1,
979, 2441-2443.
1
the S Ar reactions of superelectrophilic fluorenyl cations and
E
1
their reactions with carbon nucleophiles (arenes). The chemistry
is only promoted by the use of excess triflic acid, which is
necessary to generate the dicationic intermediates in this
chemistry. Previously, the quantitative recycling of triflic acid
Supplementary Material
1
3
Experimental procedures, analytical data, and NMR spectra of
new compounds.
has been described.
Acknowledgments
We gratefully acknowledge the support of the NIH-NIGMS
for support of this work (1R15GM126498-01). We also thank Dr.
Makafui Gasonoo for preliminary studies in this chemistry.
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4
*
Tetrahedron
Highlights:
Functionalized fluorenes are prepared in a
superacid-promoted reaction.
*
Cyclization of biaryl ketones leads to reactive 9-
fluorenyl carbocations.
*
The 9-fluorenyl carbocations react with alcohols
to give ethers and nitriles to give amides.