1
44 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
On the Synthesis of 2-Amino-4,6-di¯uorobenzonitrile:
Highly Selective Formation of 5-Fluoro-3-nitro-1,2-
benzoquinone 2-Diazide in the Attempted Sandmeyer
Cyanation of 2,4-Di¯uoro-6-nitrobenzenediazonium
Cation$
1998, 144±145$
Pelayo Camps,* Jordi Morral and Diego Munoz-Torrero
Ä
Laboratori de Qu õÂ mica Farmaceutica, Facultat de Farmacia, Universitat de Barcelona,
Á Á
Av. Diagonal s/n, E-08028 Barcelona, Spain
Attempted cyanation of a diazonium salt derived from 2,4-di¯uoro-6-nitroaniline gives 5-¯uoro-3-nitro-1,2-benzo-
quinone 2-diazide% in good yield by selective nucleophilic substitution of the 2-¯uoride group by hydroxide, instead of
the desired 2-amino-4,6-di¯uorobenzonitrile, which can be obtained by the reaction of 2,4,6-tri¯uorobenzonitrile with
ammonia.
In connection with the preparation of tacrine related com-
pounds of potential interest for the treatment of Alzheimer's
disease, we required 2-amino-4,6-di¯uorobenzonitrile 4,
a compound which has been used for the synthesis of
4
-aminoquinoline derivatives but for which a preparation
has not been described. A general procedure to prepare
-aminobenzonitriles from the corresponding 2-nitroanilines
2
involves the amino group being replaced by cyanide via the
corresponding diazonium salt followed by reduction of the
Scheme 2 Synthesis of isomeric aminodifluorobenzonitriles 4
and 5
2
nitro groups which yields the amine function. It is known
that diazonium salts having leaving groups at the ortho or
para position can give products derived from nucleophilic
substitution of these groups by nucleophiles present in
the reaction medium, in competition with nucleophilic
¯uoride vs. a nitrite group but also the selective substitution
of the o- vs. the p-¯uoride.
Aminobenzonitrile 4 could be obtained by the reaction
of 2,4,6-tri¯uorobenzonitrile with an ethanolic solution of
ammonia at room temperature following a modi®cation of
3,5
3
substitution of the diazo group. When the attacking nucleo-
phile in these reactions is hydroxide, the substitution
the method described for the preparation of 2-amino-6-
¯
4
product is a 1,2- or 1,4-benzoquinone diazide.
When we attempted the preparation of 4 from 1 by the
6
uorobenzonitrile. In this reaction, a mixture of the two
possible monosubstitution products 4 and 5 in a ratio
close to the statistical one was obtained. This mixture was
easily separated by column chromatography, isolating both
products in 60 and 37% yield, respectively. Aminonitrile 4 is
being used for the preparation of tacrine-related products
above cited general procedure, we obtained a brown solid in
7
6% yield which was characterized as 5-¯uoro-3-nitro-1,2-
benzoquinone 2-diazide 2.% Especially signi®cant were its IR
�
1
[
1
ꢀ/cm 2149 (diazo group st), 1641 (C1O st), 1519 and
13
2
350 (NO st)] and C NMR spectra [two quaternary
È
through Friedlander reactions.
carbon atoms (d 175.6 and 79.4) and only one C-F carbon
atom (d 167.0, J 267.3 Hz)], which suggested the presence
of benzoquinone diazide and nitro functions and only one
Experimental
General.ÐMelting points were determined on a MFB 595010 M
Gallenkamp melting point apparatus, 500 MHz. H NMR spectra
¯
uorine atom. The value of the JH,F and JC,F coupling
constants were only compatible with the 1,2-benzoquinone
-diazide structure. The rest of the spectroscopic data and
1
13
were performed on a Varian VXR 500 spectrometer, 75.4 MHz,
C
1
2
NMR spectra on a Varian Gemini 300 and 200 MHz H and
13
elemental analysis were also concordant with the proposed
structure. Worthy of note is the highly selective formation
of 2, which implies not only the selective substitution of a
50.3 C NMR spectra on a Varian Gemini 200. Chemical shifts
ꢁ) are reported in ppm related to internal tetramethylsilane. IR
spectra were recorded on a FTIR Perkin-Elmer spectrometer, model
600. Silica gel SDS 60 (60±200 ꢂm) was used for the column
(
1
chromatography. Commercial solvents for column chromatography
were puri®ed by distillation at atmospheric pressure. Elemental
analyses were carried out at the Microanalysis Service of the Centro
de Investigacio
5
Â
n y Desarrollo (C.I.D.), Barcelona, Spain.
-Fluoro-3-nitro-1,2-benzoquinone 2-Diazide 2.ÐTo a solution of
sodium nitrite (150 mg, 2.2 mmol) and conc. sulfuric acid (1.10 ml),
a cold solution of 2,4-di¯uoro-6-nitroaniline 1 (340 mg, 1.95 mmol)
in acetic acid (2.2 mL) was added. The solution was stirred at 0 8C
for 30 min and then poured onto a cold (ice bath) solution of
NiCl
15 mL). The mixture was heated at 70 8C for 30 min and extracted
with CH Cl
(4Â 20 mL). The combined organic extracts were
washed with water, dried (Na SO ) and concentrated in vacuo to
2
Á 6H
2 2 3
O (600 mg), KCN (700 mg) and Na CO (1.85 g) in water
Scheme 1 Selective formation of 1,2-benzoquinone 2-diazide 2
from a diazonium salt derived from 1 under Sandmeyer reaction
conditions
(
2
2
2
4
give 2 as a brown solid (270 mg, 76%). The analytical sample was
obtained by crystallization from hexane, mp 74±75 8C; ꢀmax (KBr)
cm 2149 (s), 1641 (s), 1585 (s), 1519 (s), 1350 (s), 1325 (s), 1211
*
To receive any correspondence (e-mail: camps@farmacia.far.
ub.es).
This is a Short Paper as de®ned in the Instructions for Authors,
�
1
$
(s), 1160 (m), 1114 (s), 1008 (m), 943 (m), 891 (m), 854 (s), 774 (m)
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
and 739 (m); ꢁ
6-H), 7.19 (dd, J 7.8, J' 2.2 Hz, 1 H, 4-H); ꢁ
79.4 (C, br s, C-2), 107.7 (CH, d J 35.6 Hz, C-6), 114.1 (CH, d,
H
(200 MHz, CDCl
3
) 6.70 (dd, J 10.7, J' 2.2 Hz, 1 H,
C
(50.3 MHz, CDCl
3
)
%Systematic name: 6-diazo-3-¯uoro-5-nitrocyclohexa-2,4-dien-1-one.
Camps, Pelayo
