Orthogonal synthesis of fluorinated acridones and acridines from perfluorobenzophenone

Article abstract of DOI:10.1002/ejoc.201001647

The reaction between perfluorobenzophenone and aromatic amines proceeds with the substitution of one or more fluorine atoms. The regiochemistry of this substitution is controlled by solvent polarity, temperature, and nucleophilic character of the amine. o

Full text of DOI:10.1002/ejoc.201001647

FULL PAPER
DOI: 10.1002/ejoc.201001647
Orthogonal Synthesis of Fluorinated Acridones and Acridines from
Perfluorobenzophenone
Paola Del Buttero,[b] Ramona Gironda,[a] Massimo Moret,[a] Antonio Papagni,[a]
Matteo Parravicini,[a] Silvia Rizzato,[c] and Luciano Miozzo*[a,d]
Keywords: Nucleophilic substitution / Pericyclic reactions / Fluorine / Nitrogen heterocycles / Solvent effects
The reaction between perfluorobenzophenone and aromatic
amines proceeds with the substitution of one or more fluorine
atoms. The regiochemistry of this substitution is controlled
by solvent polarity, temperature, and nucleophilic character
of the amine. o-Anilinononafluorobenzophenone can be se-
lectively transformed into acridines or acridones by using
acid or base catalysis through electrocyclization or aromatic
nucleophilic substitution.
Pfitzinger reaction used for quinoline synthesis.[12] Recently,
a benzannulation reaction was used to prepare substituted
acridines through a 6-endo-dig cyclization process catalyzed
by a RhI complex.[13] Acridones are often prepared by some
of the aforementioned methods or others, such as the acid-
induced ring closure of N-phenylanthranilic acids, which
can be obtained from Ullmann condensation of anilines
with ortho-halogen-substituted benzoic acids. Recently, a
new approach based on an annulation reaction utilizing sa-
licylates and silylaryl triflates plus CsF has been pre-
sented.[14] However, harsh reaction conditions and
multistep procedures are generally required.[15] Within this
frame, fluorinated acridines and acridones form an interest-
ing group of compounds with applications as fluorophores
for biological probes and in materials science.[16] Among
different synthetic approaches, the reaction of anilines with
pentafluorobenzaldehyde has proven to be one of more sim-
ple methods to access fluorinated acridines.[17] While the
reaction of aromatic amines with pentafluorobenzaldehyde
to afford tetrafluoroacridines has been thoroughly ana-
lyzed, the same reaction on decafluorobenzophenone (1)
has received less attention. Decafluorobenzophenone (1)
shows different reactivity from that of pentafluorobenzalde-
hyde: for instance whereas that latter produces the corre-
sponding imines with anilines at room temperature without
an acid catalyst, the formation of the corresponding imines
of 1 requires the presence of AlCl3 and forced conditions.[18]
Because the formation of the corresponding imines is the
first step in the well-established synthesis of tetrafluoroacri-
dines from pentafluorobenzaldehyde,[17] that protocol can-
not be extended to the synthesis of fluorinated acridines
starting from 1. On the contrary, when 1 is treated with
anilines, fluorine aromatic nucleophilic substitution is al-
ways observed. On the other side, ortho-substituted nona-
fluorobenzophenones obtained in that way could be useful
reagents, for instance, for the synthesis of N-arylocta-
Introduction
Known since the 19th century, acridines and acridones
are versatile heteroaromatic compounds. Acridine deriva-
tives show broad biological activities and have been exten-
sively used for their chemotherapeutic properties, having a
wide range of applications against bacteria[1] and proto-
zoa.[2] In the 1970s, the antitumoral effects of acridines was
discovered.[3] Because of their high DNA binding affinity,
acridines have been used also as vectors to direct different
drugs (e.g., cis-platinum, aziridin) to specific DNA sites.[4]
Acridones as well form a well-known class of drugs with
antileishmanial, antifungal, antitumor, and anticancer
properties.[5] Beyond these classical applications as drugs
and as ligands (both η4 and η6 ligands[6] or through aza
coordination[7]), they have also been used as fluorescent
probes and chemosensors.[8] Common methods for the syn-
thesis of acridines are based on the substitution of o-halo-
genobenzoic acid derivatives with functionalized anilines
through reduction of acridone intermediates,[9] the
Bernthsen reaction (condensation of a diarylamine heated
with a carboxylic acid or an acid anhydride),[10] the cycliza-
tion of diphenylamine-2-carboxaldehyde,[11] or a modified
[a] Dipartimento di Scienza dei Materiali,
Università di Milano Bicocca,
Via R.Cozzi, 53 Milano, Italy
Fax: +39-0264485400
E-mail: luciano.miozzo@mater.unimib.it
[b] Dipartimento di Chimica Organica e Industriale,
Università degli Studi di Milano,
Via Venezian, 21 Milano, Italy
[c] Dipartimento di Chimica Strutturale e Stereochimica
Inorganica and Facoltà di Farmacia,
Università degli Studi di Milano,
Via Venezian, 21Milano, Italy
[d] ITODYS, Université Paris Diderot,
15, Jean Antoine de Baïf, 75205 Paris, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001647.
Eur. J. Org. Chem. 2011, 2265–2271
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Miozzo et al.
FULL PAPER
Scheme 1. Synthetic pathway to acridone and acridine starting from decafluorobenzophenone. The imine can be prepared only in the
presence of an acid catalyst (AlCl3).
fluoroacridones by an intramolecular aromatic nucleophilic of ortho-2 and para-5 isomers, and we found also that poly-
reaction; unfortunately, that approach is strongly hindered substitution products can sometimes contaminate para sub-
by haloform-type degradation that this ketone undergoes stitution products. We found that the yield of isomer 2 has
under basic conditions, producing pentafluorobenzene and a good correlation with donor number (DN)[20a] (Table 1).
pentafluorobenzoic acid.[19] Here we have investigated in Because Lewis basicity (expressed by DN) of the solvent
more detail the reactivity of 1 with aromatic amines and plays an important role in determining the yield of 2, this
we report on the possibility to exploit o-anilino-substituted fact indicates that the formation of isomer 2 is favored by
nonafluorobenzophenones 2 as starting materials for the the formation of a hydrogen bond between the amine hy-
orthogonal synthesis of 9-pentafluorophenyl-1,2,3,4-tetra- drogen atoms of the incoming aniline and the carbonyl unit
fluoroacridines (3) and octafluoroacridones (4) just acting of 1. In fact, when carrying out the reaction in decaline
on experimental conditions (Scheme 1).
or toluene (at 87 °C), with a DN similar to that of 1,2-
dichloroethane, the yield of isomer 2 was approximately the
same (Table 1). Solvents able to form H-bonds with the
amino group of the amine perturb or hinder the C=O···H–
N interaction, decreasing the yield of isomer 2.[21] This is
Results and Discussion
The reaction of decafluorobenzophenone with anilines particularly evident in the case of 1,4-dioxane, which shows
produces mainly two isomers, that is, ortho- and para-anil- the highest DN value between the solvent used, even
ino-substituted derivatives 2 and 5 (Scheme 2). We found though it has a dielectric constant similar to that of decaline
that the regiochemistry and the yield of this reaction are or toluene. When we carried out the reaction in DMSO,
strongly dependent on the nature of the solvent, the tem- which has an even higher DN, the yield of 2 fell to zero
perature, and the nucleophilic character of the aniline. and other substitution products were obtained. Also, high
Using p-anisidine as a reference aniline, we carried out a temperatures negatively affected the formation of isomer 2,
detailed study on the solvent effects of the aromatic nucleo- and this is reasonable due destabilization of the C=O···H–
philic substitution reaction, focusing our attention on or- N interaction, as shown in the test carried out in toluene
tho-substituted isomer 2. We always observed the formation and 1,4-dioxane at reflux.
Table 1. Solvent effects on the yield of 2.
Solvent
DN[a] (ε)
Time
[h]
Temp.
[°C]
Yield of 2
[%]
Decaline
1,2-Dichloroethane
Toluene
0 (2.2)
0 (10.4)
0.1 (2.38)
0.1 (2.38)
14 (2.3)
22
14
22
10
11
2
87
87
87
111
87
101
87
76
76
61
51
42
25
0
Toluene
1,4-Dioxane
1,4-Dioxane
DMSO
14 (2.3)
29.8 (46.7)
4
Scheme 2. Synthesis of anilino-substituted benzophenones.
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[a] See ref.[20b]
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Orthogonal Synthesis of Fluorinated Acridones and Acridines
Under optimized experimental conditions (1,2-dichloroe-
thane) the reaction was extended to other anilines with the
aim of comparing their reactivity and to prepare a pool of
compounds. As expected, the highest yield in substitution
products was obtained with electron-rich anilines (Table 2).
Reaction with p-(N,N)-dimethylaminoaniline afforded iso-
mer 2 in a lower yield, but the reaction was also much more
rapid, as the reagent was completely consumed after 4 h of
heating. At the basis of higher reactivity and lower selectiv-
ity is the higher nucleophilicity of incoming NH2, pre-
venting effective stereocontrol through the formation of the
C=O···H–N hydrogen bond.
Table 2. Substituent effects on the yield of 2.
R
Time [h]
Yield of 2 [%]
Figure 1. Molecular structure of 3a.[23] Selected bond lengths [pm]
and angles [°]: O–C9 135.3(4), O–C14 142.7(4), C9–O–C14
118.0(3), O–C9–C8 125.7(3), O–C9–C10 113.9(3), C5–C6–C15–
C16 110.0(4), C5–C6–C15–C20 –69.5(4).
2a: OCH3
2b: N(CH3)2
2c: Br
14
4
25
22
18
76
52
31
43
43
2d: H
2e: NH–Ph
The formation of an intramolecular hydrogen bond be-
tween the C=O and N–H moieties in the ortho derivatives
1
is clearly evident in both the H NMR and IR spectra. In
1
fact, in the H NMR spectra, the N–H resonances in the
ortho derivatives fall in the 8–9 ppm region. The presence
of hydrogen bonding is also confirmed by IR spectroscopy
(see the Supporting Information). The strongest hydrogen
bond is present in 2b, where the electron-donating dimeth-
ylamino fragment causes the highest low-field shift of the
1
N–H H NMR signal and the highest low-frequency shift
of the stretching signal of the N–H bond. In analogy with
the reaction of anilines with pentafluorobenzaldehyde, or-
tho-substituted nonafluorobenzophenones allow access to
the corresponding 9-pentafluorophenyltetrafluoroacridines.
Indeed, during purification by column chromatography of
compound 2a over Al2O3, we noticed the formation of a
fluorescent compound, which was found to be the corre-
Figure 2. Molecular structure of 3b.[23] Selected bond lengths [pm]
and angles [°]: N2–C9 137.2(7), N2–C14 143.7(8), N2–C15
sponding 9-pentafluorophenyltetrafluoroacridine. The 146.5(6), C9–N2–C14 122.7(4), C9–N2–C15 118.2(5), C14–N2–
C15 117.9(4), N2–C9–C8 123.3(4), N2–C9–C10 118.9(5), C5–C6–
C16–C17 79.9(4), C5–C6–C16–C21 –98.4(4).
Lewis acid properties of Al2O3 suggest that the transforma-
tion of 2 into 3 requires acid catalysis. This is also con-
firmed by reports in the literature,[19] where concentrated
H2SO4 is used for the transformation of 2-aminobenzophe-
than sulfuric acid (Table 3). We did not observe any reac-
tion of 2b [R = N(CH3)2] even after 22 h of heating at reflux
in TFA. The use of concentrated H2SO4, which has better
dehydrating properties than TFA, could be important in the
evolution of 2 in 3 by shifting all the equilibria towards the
nones into the corresponding acridines. Thus, ortho-substi-
tuted derivatives 2a–e were firstly treated with concentrated
H2SO4. As expected, these where transformed into the cor-
responding acridines in excellent or nearly quantitative
yield by stirring a H2SO4 solution of 2a–e at room tempera-
ture. The structures of compounds 3a and 3b were also con-
firmed by single-crystal X-ray diffraction. Figures 1 and 2
show the molecular structure of 3a and 3b together with
selected bond parameters.
It is reasonable that the cyclization of 2 to acridine 3
proceeds by 6π-electrocyclization involving the enolic form
of the carbonyl group favored by protonation of the car-
bonyl in the strong acid media, followed by H2O elimi-
nation.[22] We have also tried another strong acid such as
trifluoroacetic acid (TFA), but it proved to be less effective
Table 3. Substituent effects on the yield of 3.
R
H2SO4
Time
[h]
CF3COOH
Yield
[%]
T
[°C]
Yield
Time
[h]
T
[°C]
[%]
3a:OCH3
3b: N(CH3)2
3c: Br
89
90
93
90
43
24
88
64
80
80
25
25
25
25
25
99
0
93
–
72
72
72
–
25
25
25
–
3d: H
3e: NH-Ph
–
–
–
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L. Miozzo et al.
FULL PAPER
formation of acridine. This could be particularly true in the octafluoroacridone. Starting from 2a, the p-methoxyphenyl
case of 2b, considering the fact that in this case the reaction group was removed by oxidation with CeNH4(NO3)4 to ob-
occurs on its the protonated form (Scheme 3).
tain the corresponding 2-aminononafluorobenzophenone 7
in 70% chemical yield and 40% from the starting decafluo-
robenzophenone (Scheme 4). The obtained overall yield is
ten times better than that reported in the literature, where
the synthesis of 7 was carried out from 3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-
nonafluorobenzophenone by a multistep procedure. We
transformed compound 7 into the corresponding octafluo-
roacridone 8 by treating it with tetrabutylammonium fluo-
ride in DMF at 120 °C (51% yield, comparable to that re-
ported in the literature;[23] Scheme 4).
Conclusions
In conclusion, we explored the reactivity of perfluo-
robenzophenone with aromatic amines, showing how the
reaction yield depends on the nature of the amine and on
the reaction conditions. ortho-Derivatives are interesting in-
termediates for the synthesis of N-aryloctafluoroacridones
and fluorinated acridines. Whereas the formation of acri-
dines proceeds very well in pure H2SO4, the optimization
of the synthesis of octafluoroacridones proved to be more
difficult. Finally, o-aminononafluorobenzophenone can be
readily prepared by an original approach. This latter com-
pound allow access to another compound, namely, oc-
tafluoroacridone, but other transformations of this group
can be also envisaged.
Scheme 3. Mechanism of acridine formation.
Later on, our attention was focused on the conversion of
ortho derivatives 2 into N-aryloctafluoroacridones 4, be-
cause in principle this could be possible by deprotonation
of the NH group by a base, followed by intramolecular nu-
cleophilic aromatic substitution of fluorine. However, the
selection of the base and the experimental conditions were
not trivial, given that nucleophilic attack to the carbonyl
function by the base catalyst is in competition with the de-
protonation at nitrogen. Indeed it is reported that nucleo-
philic attack to the carbonyl function causes haloform-type
degradation of the ketone, affording pentafluorobenzene
and perfluorinated aromatic carboxylic acids.[19] We per-
formed a detailed study on 2a to optimize the experimental
conditions for its transformation into the corresponding ac-
ridone. We obtained the best results when using 1 equiv. of
pyridine in DMSO, allowing 4a (64% yield) to be collected
after 19 h at room temperature (Scheme 4). It is noteworthy
that, when R = N(CH3)2, owing to the strong nucleophilic
character of the amino group, the cyclization to the corre-
sponding octafluoroacridone partially occurs during the
synthesis of 2b. Finally, we undertook the synthesis of N-H-
Experimental Section
General Experimental Procedures: Solvents of analytical grade were
used without further purification. Reagents were purchased from
Sigma–Aldrich and used without further purification. Melting
points were measured with an Electrothermal 9100 melting point
instrument. UV spectra were recorded with a Perkin–Elmer
Lambda 900 spectrophotometer. Fluorescence spectra were mea-
sured with an Aminco Bowman AB2 spectrofluorimeter. IR spectra
were obtained with a Spectrum 100, FTIR Spectrometer Perkin–
Elmer. NMR spectra were recorded in CDCl3 with a Varian Mer-
cury 400 Spectrometer (1H 400 MHz, 13C 100 MHz, 19F 376 MHz).
Molecular structures and purity were analyzed by GC–MS (GCD
1800C; Hewlett–Packard) with a 50-m DB-5MS column (J&W Sci-
entific, Folsom, Calif.). Silica gel (230–400 mesh) was used for col-
umn chromatography.
General Procedure for the Synthesis of o-Anilinononafluorobenzo-
phenones 2a–e: To a solution of decafluorobenzophenone (1:
250 mg, 0.691 mmol) in the appropriate solvent (30 mL, see
Table 1) was added the appropriate aniline (2 equiv.), and the solu-
tion was heated at 87 °C (or at reflux temperature, depending of
the experimental conditions; see Table 1 for details). The reaction
was monitored by TLC (SiO2; n-hexane/CH2Cl2, 7:3). Then the sol-
vent was removed under reduced pressure. The crude was purified
by silica gel column chromatography, affording the desired product.
2-(4-Methoxyanilino)-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzophenone
(2a): The crude was purified by column chromatography (silica gel;
1
n-hexane/CH2Cl2, 1:1). Yield: 76%. Orange solid. M.p. 92 °C. H
NMR (CDCl3): δ = 9.48 (s, 1 H, NH), 6.99–7.02 (d, J = 8.7 Hz, 2
Scheme 4. Synthesis of octafluoroacridones.
H), 6.85–6.87 (d, J = 8.8 Hz, 2 H), 3.81 (s, 3 H) ppm. 19F NMR
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Orthogonal Synthesis of Fluorinated Acridones and Acridines
(CDCl3): δ = –137.77 (m, 1 F), –142.80/–142.85 (d, J = 17.2 Hz, 2
F), –144.13 (m,1 F), –145.80 (m, 1 F), –149.7 (t, J = 22, 44 Hz, 1 F),
(t, J = 35, 17.5 Hz, 1 F), –151.62 (t, J = 44.4, 22 Hz, 1 F), –154.44
(t, J = 36.8, 18.4 Hz, 1 F), –155.22 (t, J = 18.4, 36.8 Hz, 1 F),
–160.38 (m, 2 F), –169.92 (t, J = 46, 23 Hz, 1 F) ppm. C20H8F9NO2 –161.01 (m, 2 F) ppm. C20H6F9NO (447.03): calcd. C 53.71, H
(465.04): calcd. C 51.63, H 1.73, N 3.01; found C 51.21, H 1.70, N
2.95.
1.35, N 3.13; found C 53.56, H 1.23, N 3.16.
1,2,3,4-Tetrafluoro-7-N,N-dimethylamino-9-pentafluorophenyl-
acridine (3b): The reaction was monitored by TLC (silica gel; n-
hexane/CH2Cl2, 1:1). Yield: 90%. Red purple solid. M.p. 246 °C.
1H NMR (CDCl3): δ = 8.21–8.24 (d, J = 9.8 Hz, 1 H), 7.64–7.65/
2-(4-N,N-Dimethylamino)-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzo-
phenone (2b): The crude was purified by column chromatography
(silica gel, CH2Cl2). Yield: 52%. Red solid. M.p. 120 °C. 1H NMR
(CDCl3): δ = 9.61 (s, 1 H, NH), 6.99–6.97 (d, J = 8 Hz, 2 H), 6.69– 7.67–7.68 (dd, J = 9.7, 2.7 Hz, 1 H), 6.14 (s, 1 H), 3.07 (s, 6 H)
6.67 (d, J = 8 Hz, 2 H), 3.95 (s, 6 H) ppm. 19F NMR (CDCl3): δ ppm. 19F NMR (CDCl3): δ = –139.66 (dd, J = 23.6, 8 Hz, 2 F),
= –138.16 (s, 1 F), –142.90/–142.95 (d, J = 18.4 Hz, 2 F), –144.53
(s, 1 F), –147.02 (s, 1 F), –150.25 (s, 1 F), –160.57 (s, 2 F), –171.23
–149.47 (t, J = 34.4, 17.2 Hz, 1 F), –151.27 (t, J = 34.4, 17.2 Hz, 1
F), –152.72 (t, J = 44, 22 Hz, 1 F), –156.71 (t, J = 37.2, 18.4 Hz, 1
(s, 1 F) ppm. C21H11F9N2O (478.07): calcd. C 52.73, H 2.32, N F), –157.36 (t, J = 40, 20 Hz, 1 F), –161.66 (m, 2 F) ppm.
5.86; found C 52.44, H 2.20, N 5.77.
C21H9F9N2 (460.06): calcd. C 54.80, H 1.97, N 6.09; found C 54.55,
H 1.81, N 6.15.
2-(4-Bromoanilino)-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzophenone
(2c): The crude was purified by column chromatography (silica gel;
n-hexane/CH2Cl2, 3:7). Yield: 31%. White solid. M.p. 90 °C. 1H
NMR (CDCl3): δ = 9.09 (s, 1 H, NH), 7.41–7.43 (d, J = 8.7 Hz, 2
1,2,3,4-Tetrafluoro-7-bromo-9-pentafluorophenylacridine (3c): The
reaction was monitored by TLC (silica gel; n-hexane/CH2Cl2, 7:3).
Yield: 93%. White solid. M.p. 191 °C. 1H NMR (CDCl3): δ = 8.28–
H), 6.88–6.85 (dd, J = 8.8, 2.5 Hz, 2 H) ppm. 19F NMR (CDCl3): 8.3 (d, J = 9.2 Hz, 1 H), 7.96–7.99 (dd, J = 9.2, 1.4 Hz, 1 H), 7.68
δ = –137.11/–137.22 (m, 1 F), –142.40/–142.44 (d, J = 18.4 Hz, 3
F), –143.68/–143.82 (m, 1 F), –148.45/–148.56 (t, J = 44.4, 22.4 Hz,
(s, 1 H) ppm. 19F NMR (CDCl3): δ = –139.23 (dd, J = 20, 4 Hz, 2
F), –147.04 (t, J = 36, 16 Hz, 1 F), –149.25 (t, J = 36, 16 Hz, 1 F),
1 F), –160.01 (m, 1 F), –166.50/–166.67 (m, 1 F) ppm. –150.57 (t, J = 44, 24 Hz, 1 F), –151.11 (t, J = 36, 16 Hz, 1 F),
C19H5BrF9NO (512.94): calcd. C 44.39, H 0.98, N 2.72; found C
44.22, H 0.85, N 2.65.
–153.43 (t, J = 36, 16 Hz, 1 F), –160.37 (m, 2 F) ppm. C19H3BrF9N
(494.93): calcd. C 46.00, H 0.61, N 2.82; found C 45.78, H 0.59, N
2.91.
2-Anilino-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzophenone (2d): The
crude was purified by column chromatography (silica gel; n-hexane/
1,2,3,4-Tetrafluoro-9-pentafluorophenylacridine (3d): The reaction
CH2Cl2, 3:7). Yield: 43%. Yellow solid. M.p. 124 °C. 1H NMR was monitored by TLC (silica gel; n-hexane/CH2Cl2, 7:3). Yield:
(CDCl3): δ = 9.17 (s, 1 H, NH), 7.30–7.34 (dd, J = 7.5, 8.1 Hz, 2
H), 7.09–7.13 (dd, J = 7.9, 7.3 Hz, 1 H), 6.99–7.00 (d, J = 7.5 Hz,
90%. Bright yellow solid. M.p. 156 °C. 1H NMR (CDCl3): δ =
8.44–8.41 (d, J = 9.2 Hz, 1 H), 7.96–7.92 (dd, J = 8, 16 Hz, 1 H),
2 H) ppm. 19F NMR (CDCl3): δ = –137.67 (m, 1 F), –142.48/ 7.68–7.65 (dd, J = 15, 8.4 Hz, 1 H), 7.57–7.55 (d, J = 8.8 Hz, 1 H)
–142.55 (m, 2 F), –142.89 (m, 1 F), –144.29 (m, 1 F), –148.98 (t, J ppm. 19F NMR (CDCl3): δ = –139.36/–139.39 (dd, J = 24, 8 Hz, 2
= 44, 22 Hz, 1 F), –160.22 (m, 2 F), –167.61 (t, J = 48.4, 24 Hz, 1 F)
F), –147.25 (t, J = 36, 20 Hz, 1 F), –149.82 (t, J = 36, 20 Hz, 1 F),
ppm. C19H6F9NO (435.03): calcd. C 52.43, H 1.39, N 3.22; found C –151.48 (t, J = 48, 24 Hz, 1 F), –152.01 (t, J = 40, 20 Hz, 1 F),
52.30, H 1.22, N 3.25.
–154.88 (t, J = 40, 20 Hz, 1 F), –160.940/–161.094 (m, 1 F) ppm.
C19H4F9N (417.02): calcd. C 54.70, H 0.97, N 3.36; found C 54.65,
H 0.92, N 3.39.
2-(4-Phenylamino-anilino)-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzo-
phenone (2e): The crude was purified by column chromatography
(silica gel; n-hexane/CH2Cl2, 1:1). Yield: 43%. Red solid. M.p.
159 °C. H NMR (CDCl3): δ = 9.41 (s, 1 H), 7.24–6.93 (m, 9 H) The reaction was monitored by TLC (silica gel; n-hexane/CH2Cl2,
1,2,3,4-Tetrafluoro-7-phenylamino-9-pentafluorophenylacridine (3e):
1
ppm. 19F NMR (CDCl3): δ = –137.5/–137.7 (m, 1 F), –142.6/–142.7
(d, J = 26 Hz, 2 F), –144.1 (m, 1 F), –145.0 (m, 1 F), –149.4 (t, J
= 49, 25 Hz, 1 F), –160.2/–160.3 (m, 2 F), –169.5 (m, 1 F) ppm.
C25H11F9N2O (526.07): calcd. C 57.05, H 2.11, N 5.32; found C
56.90, H 2.15, N 5.20.
7:3). Yield: 43%. Red solid. M.p. 192 °C. H NMR (CDCl3): δ =
8.26–8.24 (d, J = 9.2 Hz, 1 H), 7.63–7.60 (dd, J = 9.2, 2.0 Hz, 1
H), 7.34 (m, 2 H, arom.), 7.17 (m, 2 H, arom.), 7.11 (m, 1 H,
arom.), 6.81 (d, J = 2.0 Hz, 1 H), 6.34 (br. s, 1 H, NH) ppm. 19F
NMR (CDCl3): δ = –139.4 (dd, J = 24, 8 Hz, 2 F), –148.5 (t, J =
40, 20 Hz, 1 F), –150.5 (t, J = 36, 16 Hz, 1 F), –152.2 (t, J = 48,
24 Hz, 1 F), –155.6 (t, J = 40, 20 Hz, 1 F), –161.6 (m, 2 F) ppm.
C25H9F9N2 (508.06): calcd. C 59.07, H 1.78, N 5.51; found C 59.01,
H 1.66, N 5.53.
1
General Procedure for the Synthesis of 1,2,3,4-Tetrafluoro-9-penta-
fluorophenylacridines 3a–c: o-Anilinononafluorobenzophenone
(0.2 mmol) was dissolved in H2SO4 (4 mL) at room temperature
under a nitrogen atmosphere. The reaction was monitored by TLC
(see Table 3 for the total reaction time). The 1,2,3,4-tetrafluoroacri-
dines were easily detected, as they are fluorescent. The solution was
then poured into an excess amount of water and then neutralized;
the pH of the solution was initially increased with NaOH and then
adjusted to pH 7 with NaHCO3. The solution was then extracted
with CH2Cl2. The organic phase was washed with water and then
dried with Na2SO4; the solvent was removed under reduced pres-
sure, affording the expected product with the desired purity.
General Procedure for the Synthesis of 1,2,3,4,5,6,7,8-Octafluoro-N-
arylacridones: o-Anilinononafluorobenzophenone (0.5 mmol) was
dissolved in xylene (15 mL) at room temperature under a nitrogen
atmosphere. A solution of pyridine (0.093 mg) in xylene (7 mL) was
added. The reaction was stirred under reflux for 48 h under a nitro-
gen atmosphere. After evaporation of the solvent under reduced
pressure, the product was purified by silica gel chromatography (n-
hexane/CH2Cl2, 3:7), affording the desired product and unreacted
o-anilinononafluorobenzophenones.
1,2,3,4-Tetrafluoro-7-methoxy-9-pentafluorophenylacridine (3a):
The reaction was monitored by TLC (silica gel; n-hexane/CH2Cl2,
1:1). Yield: 89%. Yellow solid. M.p. 235 °C. H NMR (CDCl3): δ
1,2,3,4,5,6,7,8-Octafluoro-N-p-anisidinoacridone (4a): Yield: 66%.
Pale grey solid. M.p. 199 °C. H NMR (CDCl3): δ = 7.28–7.26 (d,
1
1
= 8.32–8.29 (d, J = 9.5 Hz, 1 H), 7.62–7.59 (dd, J = 9.5, 2.8 Hz, 1
J = 8.7 Hz, 2 H), 6.89–6.87 (d, J = 8.7 Hz, 2 H), 3.81 (s, 3 H) ppm.
H), 6.58 (s, 1 H), 3.85 (s, 3 H) ppm. 19F NMR (CDCl3): δ = –139.42 19F NMR (CDCl3): δ = –142.2 (m, 2 F), –143.4 (t, J = 36, 16 Hz,
(dd, J = 23, 7 Hz, 1 F), –148.44 (t, J = 35, 17.5 Hz, 1 F), –150.26
2 F), –145.7 (m, 2 F), –161.1 (t, J = 44, 20 Hz, 2 F) ppm.
Eur. J. Org. Chem. 2011, 2265–2271
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2269

L. Miozzo et al.
FULL PAPER
C20H7F8NO2 (445.03): calcd. C 53.95, H 1.58, N 3.15; found C
53.81, H 1.55, N 3.12.
intramolecular NH–CO hydrogen bond analysis of compounds 2a–
e by IR and NMR spectroscopy.
Synthesis of 2-Aminononafluorobenzophenone (7): 2-(4-Methoxy-
anilino)-3,4,5,6,2Ј,3Ј,4Ј,5Ј,6Ј-nonafluorobenzophenone (0.3 mmol)
was dissolved in CH3CN/H2O (9:1, 20 mL). The solution was co-
oled to 0 °C, and a solution of ammoniumcerium(IV) nitrate
(0.391 g) in CH3CN/H2O (9:1, 20 mL) was dropped under a nitro-
gen atmosphere. The mixture was warmed to room temperature.
The reaction was monitored by TLC (n-hexane/CH2Cl2, 7:3; silica
gel). After 48 h the solvent was removed under reduce pressure.
The solid was taken up with CH2Cl2, and the solution was washed
with water. The organic solution was dried with Na2SO4, and then
the solvent was removed under reduced pressure, affording the ex-
pected product with the desired purity.
Acknowledgments
The Authors wish to thank Massimiliano Labate, Franco Merletti,
and Francesca Bettinelli for experimental contributions.
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67%. Yellow solid. 1H NMR (CDCl3): δ = 6.54 (s, 2 H) ppm. M.p.
and 19F NMR spectroscopy data in accordance with literature
data.[23]
Synthesis of N-H-Octafluoroacridone (8): To a solution of o-amino-
perfluorobenzophenone (0.3 mmol) in dry DMF (5 mL) was added
tetrabutylammonium fluoride trihydrate (315 mg), and the mixture
was heated for 3 h at 120 °C. The reaction was monitored by TLC
(CH2Cl2, silica gel). The formation of the product could be easily
detected by TLC, because of its fluorescence. The solution was
poured into water and then extracted with CH2Cl2. The red mix-
ture was sublimated at 120 °C to give octafluoroacridone, as a yel-
low solid. Yield: 51%. M.p. and NMR spectroscopy data in accord-
ance with literature data.[23]
Crystal Structure Analysis of 1,2,3,4-Tetrafluoro-7-methoxy-9-
pentafluorophenyl-acridine (3a):[24] C20H6F9NO, molecular weight
¯
447.26, crystal system triclinic, space group P1, a = 7.365(1) Å, b
= 10.021(1) Å, c = 12.574(2) Å, α = 105.986(2)°, β = 102.199(2)°, γ
= 102.818(2)°, V = 832.4(2) Å3, Z = 2, dcalcd. = 1.784 g/cm3, F(000)
=
444,
0.08ϫ0.08ϫ0.03 mm3, Bruker SMART-APEX CCD (area detec-
tor) diffractometer, T = 298(2) K, λ(Mo-Kα) = 0.71073 Å, θmin
μ =
0.180 mm–1, crystal color yellow, crystal size
=
2.21°, θmax = 25.66°, –8Յ h Յ8, –12Յ k Յ12, –15Յ l Յ15, empiri-
cal absorption correction (SADABS), 12486 reflections collected,
3138 unique reflections [R(int) = 0.0523], refinement program
SHELXL-97, refinement by full-matrix least-squares on F2, S =
0.983, R indices [IϾ2σ(I)]: R1 = 0.0488, wR2 = 0.1076, R indices
[all data]: R1 = 0.1172, wR2 = 0.1389, min./max. Residual electron
density: –0.180/0.239, completeness of data 99.9%.
Crystal Structure Analysis of 1,2,3,4-Tetrafluoro-7-N,N-dimeth-
ylamino-9-pentafluorophenylacridine (3b):[24] C21H9F9N2, molecular
weight 460.30, crystal system orthorhombic, space group P212121,
a = 7.235(1) Å, b = 12.028(2) Å, c = 20.281(2) Å, V = 1765.0(4) Å3,
Z = 4, dcalcd. = 1.732 g/cm3, F(000) = 920, μ = 0.170 mm–1, crystal
color orange, crystal size 0.22ϫ0.08ϫ0.04 mm3, Bruker SMART-
APEX CCD (area detector) diffractometer, T = 150(2) K, λ(Mo-
Kα) = 0.71073 Å, θmin = 2.63°, θmax = 24.47°, –2Յ h Յ8, –13Յ k
Յ9, –23Յ l Յ8, empirical absorption correction (SADABS), 2556
reflections collected, 1419 unique reflections [R(int) = 0.0518], re-
finement program SHELXL-97, refinement by full-matrix least-
squares on F2, S = 0.936, R indices [IϾ2σ(I)]: R1 = 0.0395, wR2 =
0.0922, R indices [all data]: R1 = 0.0506, wR2 = 0.0977, min./max.
Residual electron density: –0.347/0.307, completeness of data
83.0%.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 19F NMR spectra, GC–MS and MS spectra, UV/Vis
absorption and fluorescence spectra of selected compounds, and
2270
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2265–2271

Orthogonal Synthesis of Fluorinated Acridones and Acridines
P. Campiglio, M. Campione, P. Del Buttero, A. Mani, L.
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Gerasimova, E. P. Fokin, Russ. Chem. Bull. 1981, 29, 1149.
[19] T. N. Gerasimova, E. P. Fokin, Uspekhi Khim. 1980, 49, 1057;
T. N. Gerasimova, Russ. Chem. Rev. 1980, 49, 558.
[22] The synthesis of octafluorophenazine from pentafluoroaniline
by a similar electrocyclic ring closure was reported: J. J. Dead-
man, M. Jarman, R. McCague, R. McKenna, S. Neidle, J.
Chem. Soc. Perkin Trans. 2 1989, 971.
[23] D. M. Owen, A. E. Pedler, J. C. Tatlow, J. Chem. Soc. Perkin
Trans. 1 1975, 14, 1380.
[20] a) The donor number or DN is a qualitative measure of Lewis
basicity; see: W. B. Jansen, Chem. Rev. 1978, 78, 1; b) Y. Mar-
cus, The Properties of Solvent, Wiley, New York, 1999, p. 145.
[21] The existence of an intramolecular hydrogen bond between NH
and CO of isomers 2 is highlighted by analysis of the IR and
NMR spectra (see the Supporting Information).
[24] CCDC-799110 (for 3a) and -799111 (for 3b) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: December 8, 2010
Published Online: March 2, 2011
Eur. J. Org. Chem. 2011, 2265–2271
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2271