Synthesis of 7-pentafluorophenyl-1 H -indole: An anion receptor for anion-π interactions

Article abstract of DOI:10.1055/s-0034-1378449

7-Pentafluorophenyl-1H-indole has the potential to be a key compound for the investigation of anion-π interactions in solution. Unfortunately, it was not possible to obtain it by aryl-aryl coupling reaction. Finally, it has been prepared by Bartoli indole synthesis. The key compound as well as analogues were submitted to preliminary studies of anion binding. Single crystals of two key receptors were obtained. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378449

LETTER
▌2075
lSetyternthesis of 7-Pentafluorophenyl-1H-indole: An Anion Receptor for Anion–π
Interactions
Synthesis of 7-Pentafluorophenyl-1H-indole
Zhan-Hu Sun,a Markus Albrecht,*a Michael Giese,a Fangfang Pan,b,c Kari Rissanenb
a
Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092385; E-mail: markus.albrecht@oc.rwth-aachen.de
b
Department of Chemistry, Nanoscience Center, University of Jyväskylä, Survontie 9, 40014 Jyväskylä, Finland
c
Institut für Anorganische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Received: 07.05.2014; Accepted after revision: 10.06.2014
Dedicated to Professor Yu Liu on the occasion of his 60th birthday
solution (Figure 1).14 In analogy to this, we identified 7-
Abstract: 7-Pentafluorophenyl-1H-indole has the potential to be a
pentafluorophenyl-1H-indole (2) and its nonfluorinated
key compound for the investigation of anion–π interactions in solu-
analogue 3 to be ideal candidates for the investigation of
anion–π interactions. The preparation and characteriza-
tion. Unfortunately, it was not possible to obtain it by aryl–aryl cou-
pling reaction. Finally, it has been prepared by Bartoli indole
synthesis. The key compound as well as analogues were submitted tion of 2 and 3 and of the related amides 4–6 including
to preliminary studies of anion binding. Single crystals of two key
receptors were obtained.
preliminary anion binding studies are described.
Key words: Bartoli indole synthesis, receptors, halides, indoles,
molecular recognition
N
H
F
F
Cation–π interactions have been investigated and applied
in various fields for several decades.1 However, until the
beginning of this millennium, corresponding anion–π in-
teractions were sparely investigated. In 2002, several
groups2,3 started thorough investigations of anion–π inter-
actions through quantum chemical calculations and crys-
tallographic studies. Potential roles in chemical and
biological systems4,5 made anion–π interactions an inter-
esting field of investigation.6,7 For example. Johnson et
al.6 and Wang et al.8 have studied anion–π interactions in
both solution and/or solid state. Reedijk and Gamez,9
Matile and Schalley,10 Ballester,11 Dunbar and Chifotides7
and coworkers have focused on exploring anion–π inter-
actions and their applications in crystal engineering and
other fields. Most recently, Ballester and coworkers ther-
modynamically characterized anion–π interactions and
validated their thermodynamics using extended ca-
lix[4]pyrroles.12 Since 2008 we have been performing de-
tailed studies on the interaction of anions with
fluorophenyl moieties in the solid state as well as in solu-
tion.13 However, the role of anion–π interactions in solu-
tion are not well and fully understood.5 In particular,
anion–π interactions are easily hidden within a concert of
various noncovalent interactions such as hydrogen bond-
ing, lone-pair π and/or π–π interactions. Therefore, the de-
sign and preparation of elaborately preorganized anion
receptors for exploring and further elucidating anion–π in-
teractions in solution is required. As a recent impressive
example, 3,6-di-tert-butyl-1,8-bis(pentafluorophenyl)car-
bazole (1) was described to show anion–π interactions in
F
F
F
F
F
F
F
F
1
N
N
F
H
H
F
F
F
3
F
2
O
NH
O
O
N
F
N
H
F
H
F
F
F
F
F
F
F
5
F
4
6
Figure 1 The already described carbazole anion receptor 1 as de-
scribed by Meyer, and the indoles 2, 3, and amide derivatives 4–6 de-
scribed in this study
Preparation of the perfluorophenylindole 2 was attempted
by copper/palladium6 or just copper-mediated Ullmann
coupling,15 which failed as well as palladium-catalyzed
Suzuki–Miyaura coupling using pentafluorophenylboron-
ic acid or potassium pentafluorophenyltrifluoroborates
and 7-bromo-1H-indole.16 Palladium-catalyzed Suzuki–
Miyaura coupling of 7-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane-2-yl)-1H-indole17 and reaction of hexafluoro-
benzene with 7-bromo-1H-indole18 were also not
SYNLETT 2014, 25, 2075–2077
Advanced online publication: 16.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378449; Art ID: st-2014-b0394-l
© Georg Thieme Verlag Stuttgart · New York

2076
Z.-H. Sun et al.
LETTER
successful. Thus, the direct coupling of indole and penta-
fluorophenyl fragments seemed to be no appropriate way
for the preparation of 2.
Ar
Ar
Ar
Pd/C, H2
CH2Cl2
pyridine, CH2Cl2
acetyl chloride
As an alternative the build-up of the indole skelton bear-
ing the pentafluorophenyl group was applied following
the Bartoli indole synthesis.19 The palladium-catalyzed
coupling of pentafluorobenzene (7) with 2-nitrobenzoic
acid (8) afforded pentafluorophenyl-2′-nitro-1,1′-biphe-
nyl (9) in 43% yield. Subsequently, 9 was reacted with vi-
nylmagnesium bromide at –40 °C to yield the indole 2 in
80% yield (Scheme 1).20
NH2
HN
NO2
O
15
16
17
12 Ar = 2-C6F5
13 Ar = 2-C6H5
14 Ar = 4-C6F5
4 83%
5 79%
6 83%
Scheme 2 Preparation of the acetamides 4–6
F
resonances are observed at δ = –142.01 (m, 2 F), –158.24
(m, 1 F), –164.51 (m, 2 F).
F
F
F
O2N
F
F
F
F
PdCl2, Ag2CO3
Results of the crystal-structure analyses of 2 and 4 are
shown in Figure 2. In both structures the NH units are well
orientated in order to interact with an anion flanked by the
pentafluorophenyl moiety. Due to the bicyclic ring system
of the indole 2, this conformation cannot change in solu-
tion which due to the flexibility of the acetamide is possi-
ble in 4.
+
F
F
PPh3, DMSO
43%
HOOC
NO2
8
7
F
9
F
F
F
BrMg
–40 °C
1.
F
2. NH4Cl
80%
H
N
2
Br
BF3K
H
N
3
2
2
H
+
N
MeOH
47%
11
10
3
Scheme 1 Preparation of indoles 2 and 3
In contrast to the fluorinated derivative, 7-phenyl-1H-in-
dole (3) was easily obtained in 47% by Suzuki–Miyaura
coupling as described before.16 The difference in the
availability of the fluorinated or nonfluorinated com-
pounds 2 and 3 by cross-coupling reaction can be assigned
to the ‘electronic character’ (electron-deficient vs. elec-
tron-rich) of the aromatic coupling partner.
Figure 2 Molecular structures of 2 and 4 as observed in the crystal.
Black: C, grey: H, green: F, blue: N, red: O.21
The compounds 2–6 were used for anion binding studies
with tetrabutylammonium chloride in acetonitrile. The
nonfluorinated derivatives 3 and 5 did not show specific
binding of the anion. Addition of the chloride salt to the
compounds in acetonitrile-d3 resulted in a more or less lin-
ear shifting of the resonance of the NH protons. No con-
vergence could be observed.
The acetamides 4–6 were prepared by reduction of the ni-
tro group of the corresponding biaryls15 12–14 and subse-
quent reaction of the obtained amines 15 and 16 with
acetyl chloride in the presence of pyridine in dichloro-
methane (yield over two steps: 83% 4, 79% 5, 83% 6;
Scheme 2).
For 2 and 4 a 1:1 interaction can be shown by Job plots
and association constants of 46 M–1 (2) or 52 M–1 (4) are
determined by 1H NMR titrations (19F NMR: 50 M–1 for 2
and 55 M–1 for 4). Most probably the electron-deficient ar-
omatic units of 2 and 4 allow the binding of the halide to
the NH by utilization of attractive anion–π interactions. In
addition, enhanced acidity of the indolyl NH due to the in-
fluence of the electron-deficient C6F5 group may lead to
the stronger binding. Perhaps both effects contribute to
the increased anion binding affinity. In compounds 3 and
5 this interaction is repulsive and no specific binding oc-
curs.
The compounds 2–6 were characterized by mass spec-
1
trometry, elemental analysis, H NMR, 13C NMR, 19F
NMR, and IR spectroscopy. The single-crystal structures
of fluorinated receptors 2 and 4 were characterized by sin-
gle-crystal X-ray crystallography.
1
The key compound 2 shows characteristic signals by H
NMR in CD3CN at δ = 9.32 (br s, 1 H), 7.77 (dd, J = 2.4,
6.4 Hz, 1 H), 7.31 (m, 1 H), 7.20 (m, 2 H), 6.60 (dd, J =
19
2.0, 3.2 Hz, 1 H). By F NMR (CD3CN) corresponding
Synlett 2014, 25, 2075–2077
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 7-Pentafluorophenyl-1H-indole
2077
(3) (a) Quiñonero, D.; Garau, C.; Rotger, C.; Frontera, A.;
The ‘para’-acetamide 6 behaves in a different fashion as
Ballester, P.; Costa, A.; Deyà, P. M. Angew. Chem. Int. Ed.
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anion binder. Relatively ‘high’ chloride binding constants
of 92 M–1 (following NH) or 128 M–1 (following CHortho
)
are determined. Based on the strong effect of anion addi-
tion on the resonances of the protons ortho to the acet-
amide of 6, participation of this proton as extra
complexation site is expected.6 The 2D NOESY cross-
peak intensities between N–H and its ortho proton in-
crease with the addition of chloride anions. This indicates
a coplanar conformation of the amide, and the aryl ring
which is enforced by anion binding as shown in Figure 3.
There is no indication that similar binding occurs with re-
ceptors 2 or 4.
(4) (a) Schottel, B. L.; Chifotides, H. T.; Dunbar, K. R. Chem.
Soc. Rev. 2008, 37, 68. (b) Estarellas, C.; Frontera, A.;
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(5) Ballester, P. Acc. Chem. Res. 2013, 46, 874.
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F
F
F
F
H
H
H
N
O
F
Figure 3 Proposed receptor 6–chloride interaction
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(b) Albrecht, M.; Müller, M.; Mergel, O.; Rissanen, K.;
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In this report we presented a facile synthesis for 7-penta-
fluorophenyl-1H-indole (2). This key compound could
not be obtained by metal-catalyzed aryl–aryl coupling re-
action but finally was built up by classical Bartoli indole
synthesis. Comparison of 2 with the nonfluorinated 3 as
well as 4 and 5 in chloride binding studies shows the abil-
ity of the fluorinated receptors 2 and 4 to interact with an-
ions in a specific manner. For the nonfluorinated
derivatives no specific interaction is observed. This can be
assigned to attraction between the anion and the electron-
deficient pentafluorophenyl groups in 2 and 4 and repul-
sion in case of 3 and 5. For compound 6 chelated binding
of the anion by NH and an ortho aryl proton is observed
by NMR spectroscopy.
(18) Pummer, W. J.; Wall, L. A. Science 1958, 127, 643.
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(21) CCDC 1001536 (2) and 955438 (4) contain the
supplementary crystallographic data for 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.
Acknowledgment
Z.-H. Sun and F. Pan are thankful to the China Scholarship Council
for scholarship assistance. K.R. thanks the Academy of Finland for
financial support (project no. 263256 and 265328).
References and Notes
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Soc. 2002, 124, 6274.
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