4,5-Difluoro-1,2-dehydrobenzene: Generation and cycloaddition reactions

Article abstract of DOI:10.1070/MC2005v015n02ABEH002072

The oxidation of 1-amino-5,6-difluorobenzotriazole with Pb(OAc) ₄ in dry CH₂Cl₂ afforded 4,5-difluoro-1,2-dehydrobenzene, a new active intermediate, which can be used in situ for the synthesis of fluorinated carbo- and heterocyclic compounds via cycloaddition reactions.

Full text of DOI:10.1070/MC2005v015n02ABEH002072

, 2005, 15(2), 45–46
4,5-Difluoro-1,2-dehydrobenzene: generation and cycloaddition reactions
Valery N. Charushin,*a Svetlana K. Kotovskaya,b Svetlana A. Romanova,b Oleg N. Chupakhin,a Yury V. Tomilovc
and Oleg M. Nefedovc
a I. Ya. Postovsky Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg,
Russian Federation. Fax: +7 3433 74 5191; e-mail: charushin@ios.uran.ru
b Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.
Fax: +7 3433 74 0458; e-mail: charushin@htf.ustu.ru
c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: tom@ioc.ac.ru
DOI: 10.1070/MC2005v015n02ABEH002072
The oxidation of 1-amino-5,6-difluorobenzotriazole with Pb(OAc)4 in dry CH2Cl2 afforded 4,5-difluoro-1,2-dehydrobenzene, a new
active intermediate, which can be used in situ for the synthesis of fluorinated carbo- and heterocyclic compounds via cycloaddition
reactions.
Benzotriazoles are of continuing interest for chemists and
biologists as an important class of heterocyclic compounds.
F
F
NH2
NH2
F
F
N
NOH
Indeed, benzotriazole is a key structural fragment of a number
of natural compounds,1 vitamins (for example, B12)2 and bio-
logically active compounds exhibiting herbicidal,3 insecticidal,4
acaricidal5 and other activities. In particular, some benzotriazoles
are active towards G-serotonin receptors (5-HT1A),6 while others
are inhibitors of cytochromes P-450s.7 On the other hand,
N-substituted benzotriazoles are widely used in synthetic organic
chemistry as easily modified and good leaving groups, and also
as a source of iminium cations.8–10
It is well known that the incorporation of fluorine atoms into
organic molecules modifies their biological, chemical and physical
properties.11,12 In this respect, derivatives of 1-aminobenzotri-
azoles bearing fluorine atoms in the benzene ring might be of
interest as a source of fluorinated dehydrobenzene. However,
fluorinated benzotriazoles have not so far been described in the
literature. We have tried to generate 4,5-difluoro-1,2-dehydro-
benzene and to demonstrate that it is a useful intermediate for
the synthesis of fluorinated carbo- and heterocyclic compounds.
1,2-Dehydrobenzene (DHB) is an important and extremely
active intermediate, which is widely used in organic chemistry to
functionalise aromatic compounds and to study the mechanisms
of chemical and biochemical reactions.13,14 Both intra- and inter-
molecular cycloaddition reactions of DHB can be used for the
construction of a variety of natural compounds.15 4,5-Difluoro-
1,2-dehydrobenzene has been generated from 4,5-difluoro-
2-trimethylsilanylphenyl trifluoromethanesulfonate in order to
be involved in the reaction with alkynes.16 There are also pub-
lished data concerning the generation and reactions of tetra-
fluorodehydrobenzene.17–19
i
NH2
1
F
F
N
N
N
F
F
N
NH2
ii
N
3
N
H
F
F
N
N
NH2
2
N
4
Scheme 1 Reagents and conditions: i, NaNO2, AcOH, 5 °C; ii, aqueous
KOH, HASA, 30 °C.
n
at d 8.17 and 7.79 ppm due to coupling constants J(H,F), while
1
in the H NMR spectrum of symmetrical N-2 isomer 4 protons
H-4 and H-7 are chemically equal, thus, giving rise to a pseudo-
triplet at 7.93 ppm.
The 1H NMR spectra in [2H6]DMSO were recorded on a Bruker
WP-250 instrument (250 MHz). Mass spectra were recorded using a
Varian MAT 311A spectrometer.
†
5,6-Difluorobenzotriazole 2. 1,2-Diamino-3,4-difluorobenzene 122
(0.14 g, 1.00 mmol) was dissolved in AcOH (0.12 ml, 2.00 mmol) and
5 ml of water on heating. The reaction mixture was cooled, and a
solution of NaNO2 (0.08 g, 1.09 mmol) in 2 ml of water was added at
5 °C. The reaction mixture became immediately dark-green, and it was
stirred at room temperature for 1 h. The precipitate obtained after cooling
was filtered off, dried in air and recrystallised from water. Yield, 74%;
mp 183–184 °C. 1H NMR, d: 15.85 (br. s, 1H, NH), 7.90 (t, 2H, H-4,
H-7, JHF 9.0 Hz). MS, m/z (%): 155 (100) [M+], 127 (32), 100 (41), 75
(10), 50 (16). Found (%): C, 46.24; H, 1.89; N, 27.16. Calc. for
C6H3F2N3 (%): C, 46.46; H, 1.94; N, 27.09.
One of the well-known ways to generate DHB is the oxidative
degradation of 1-aminobenzotriazole, which can be derived
from ortho-nitroaniline through diazotation with sodium nitrite
followed by the interaction with diethyl malonate and subse-
quent chain of complicated catalytic reactions.20,21 However,
our attempts to obtain 1-amino-5,6-difluorobenzotriazole 3 from
2-nitro-3,4-difluoroaniline using the procedures described21 were
unsuccessful.
1-Amino-5,6-difluorobenzotriazole 3 and 2-amino-5,6-difluorobenzo-
triazole 4. 5,6-Difluorobenzotriazole (0.16 g, 10.00 mmol) 2 was dis-
solved in 3 ml of aqueous KOH (0.17 g, 30.00 mmol) at 30 °C. HASA
(0.20 g, 16.00 mmol) was added in portions at 70–75 °C for 1 h, and the
reaction mixture was cooled. The precipitate obtained was filtered off
and dried in air. A mixture of N-1 and N-2 isomers was separated by
column chromatography (silica gel 5–40 µm, petroleum ether–diethyl
ether, 1:2; Rf 0.50 (3) and 0.63 (4). Yields of 67% (3) and 27% (4).
We prepared aminotriazoles 3 and 4 through the N-amination
of 5,6-difluorobenzotriazole 2 with hydroxylaminosulfonic acid
(HASA). Starting 1,2-diamino-4,5-difluorobenzene 1 was con-
verted into corresponding benzotriazole 2 through nitrosation in
water/AcOH at 65–80 °C (Scheme 1).† The reaction of 2 with
HASA resulted in a mixture of N-1 and N-2 isomeric amino
compounds 3 and 4, which were separated by column chro-
matography (diethyl ether–petroleum ether, 2:1). The ratio
between isomers was found to depend on the reaction tem-
perature and solvents used. The best yield of N-1 isomer 3
(75%) was reached when the reaction was carried out in water
at 70–75 °C.
For 3: mp 157–159 °C. H NMR, d: 8.17 (dd, 1H, H-4, 3JHF 10.1 Hz,
1
4JHF 7.1 Hz), 7.79 (dd, 1H, H-7, JHF 10.1 Hz, JHF 7.0 Hz), 7.15 (br. s,
2H, NH2). MS, m/z (%): 170 (8) [M+], 155 (72), 142 (26), 141 (43), 127
(27), 126 (19), 114 (16), 113 (100), 100 (38), 99 (18), 88 (14), 81 (15),
76 (13), 75 (30), 63 (39), 62 (13), 56 (12), 50 (22). Found (%): C, 42.41;
H, 2.13; N, 33.04. Calc. for C6H4F2N4 (%): C, 42.36; H, 2.37; N, 32.93.
For 4: mp 144–146 °C. 1H NMR, d: 8.95 (br. s, 2H, NH2), 7.93 (t, 2H,
H-4, H-7, JHF 9.1 Hz).
3
4
1
In the H NMR spectrum of 1-amino compound 3, the reso-
nance signals of H-4 and H-7 protons appear as double doublets
Mendeleev Commun. 2005 45

, 2005, 15(2), 45–46
In order to generate 4,5-difluoro-1,2-dehydrobenzene 5,
1-amino-5,6-difluorobenzotriazole 3 was oxidised with Pb(OAc)4
in dry CH2Cl2 at room temperature (Scheme 2).‡
We found that oxidation is accompanied by the release of
nitrogen. In the absence of any ‘traps’ in the reaction mixture,
the dimerisation of dehydrobenzene 5 takes place to give
2,3,6,7-tetrafluorobiphenylene 6 in a nearly quantitative yield.
A very intense peak of the molecular ion [M+ = 224 (100%)]
and the 1H NMR data for biphenylene 6 are in a full agreement
with its aromatic structure.
biphenylene 6 increased up to 43%. In the 1H NMR spectra, the
resonance signal of the bridge head protons H-9 and H-10 of
adduct 7 can be easily distinguished as a singlet at 5.56 ppm,
thus enabling the ratio of compounds 6 and 7 to be determined
by measuring the integral intensities of corresponding signals.
The reaction of 3 with tetracyclone was carried out in a
minimal volume of dry CH2Cl2 to give 6,7-difluoro-1,2,3,4-
tetraphenylnaphthalene 8 in a very good yield (96%) after
several minutes of stirring at room temperature. The mass spec-
trum of fluorinated naphthalene 8 exhibits a very intense peak
of the molecular ion, which is in agreement with its aromatic
structure.
Interaction of 3 with furan was found to result in the forma-
tion of a mixture of 6 and 9. In order to obtain 9 in a good yield,
the reaction has to be carried out in furan as a solvent. In the
mass spectrum of cycloadduct 9, the molecular ion peak with
m/z 180 was observed. Some plausible ways for degradation of
the molecular ion of 9 are consistent with the structure.
In conclusion, note that we generated 4,5-difluoro-1,2-
dehydrobenzene from 1-amino-5,6-difluorobenzotriazole and
demonstrated its ability to undergo cycloaddition reactions,
which can be used for the synthesis of new fluorinated com-
pounds.
F
F
F
F
F
F
F
F
N
i
N
N
NH2
3
5
6
iv
ii
– CO iii
O
F
Ph
F
F
Ph
Ph
F
F
9
F
H
Ph
This study was supported by the Russian Foundation for
Basic Research (grant no. 04-03-96090) and the US Civilian
Research and Development Foundation (award no. REC-005,
EK-005-X1), and grant no. 1766.2003.3 ‘Leading Scientific
Schools’.
8
H
7
Scheme 2 Reagents and conditions: i, Pb(OAc)4, dry CH2Cl2, 20 °C;
ii, anthracene, dry CH2Cl2, Pb(OAc)4, 20 °C; iii, tetracyclone, dry CH2Cl2,
Pb(OAc)4, 20 °C; iv, furan, dry CH2Cl2, Pb(OAc)4, 20 °C.
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9
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·
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Received: 19th October 2004; Com. 04/2397
46 Mendeleev Commun. 2005