One-pot fluoro-de-diazoniation of anilines in organic medium

Article abstract of DOI:10.1016/j.tetlet.2006.06.024

Treatment of anilines with tert-butyl nitrite in the presence of boron trifluoride in ortho-dichlorobenzene leads to in situ fluoro-de-diazoniation and affords the corresponding fluoroaromatics with fair yields. This process, conducted in organic medium without Broensted acids, does not require isolation of hazardous diazonium salts and reduces the amounts of wastes. The results of the first screening are given.

Full text of DOI:10.1016/j.tetlet.2006.06.024

Tetrahedron Letters 47 (2006) 5705–5708
One-pot fluoro-de-diazoniation of anilines in organic medium
Laurent Garel and Laurent Saint-Jalmes*
Rhodia Recherches et Technologies, Centre de Recherches de Lyon, 85 rue des fr e` res Perret, 69192 Saint-Fons cedex, France
Received 3 April 2006; revised 23 May 2006; accepted 2 June 2006
Available online 23 June 2006
Abstract—Treatment of anilines with tert-butyl nitrite in the presence of boron trifluoride in ortho-dichlorobenzene leads to in situ
fluoro-de-diazoniation and affords the corresponding fluoroaromatics with fair yields. This process, conducted in organic medium
without Broensted acids, does not require isolation of hazardous diazonium salts and reduces the amounts of wastes. The results of
the first screening are given.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
conditions5 increase the scope of functions in the
aromatic ring but require isolation of the diazonium
tetrafluoroborates, which are hazardous intermediates.
Dryness of diazonium tetrafluoroborates is mandatory
to avoid side formations of phenols and biaryl ethers,
but this step can be dangerous because of weak
thermal stability of these salts. In some cases, diazo-
nium tetrafluoroborate salts are harmful and act as
sensitizers.
Fluoroaromatics Ar–F form one of the most important
classes of fluorinated compounds used in pharmaceuti-
cals, agrochemicals and performances markets such as
liquid crystals. Fluoro-de-diazoniation of anilines is
one of the classical routes to fluoroaromatics. It consists
1
2
of a first step of diazotation of an aniline, followed by
the introduction of the fluorine atom directly from the
3
4
diazonium salt in HF or HF-base media or via thermal
decomposition of diazonium tetrafluoroborate salts
Previous works describe transformations of anilines into
5
known as the Balz–Schiemann procedure (Scheme 1).
fluoroaromatics in non-aqueous medium. NOBF was
4
often used to form a diazonium tetrafluoroborate in
6
7
Fluoro-de-diazoniation in anhydrous HF is limited to
non-acid sensitive compounds. The Balz–Schiemann
organic solvents or in ionic liquids, followed by ther-
mal decomposition into fluoroaromatics. This approach
1
is not easily scalable because NOBF is expensive and
4
not available in large quantities.
N
N, F-
Heterocycles bearing an amino group have been trans-
formed into the corresponding fluoroderivatives with
tert-butyl-thionitrite as the nitrosing agent and sodium
Rx
NaNO , HF
2
Δ
8
NH2
tetrafluoroborate as the fluoride source.
F
tert-Butyl nitrite was used as the nitrosing agent with
Rx
9
Rx
SiF as the fluoride source to transform various ani-
4
N N, BF4-
lines, but these conditions are limited by the toxicity
Δ
10
of SiF4.
NaNO , HBF
2
4
Rx
H O
2
Our goals were, first to synthesize fluoroaromatics Ar–F
from anilines without the isolation and the accumula-
tion of diazonium salts due to their toxicity and their
potential explosivity and second to work in complete
organic medium without acids to minimize aqueous
wastes.
Scheme 1.
*
Corresponding author. Tel.: +33472736648; e-mail: laurent.
saint-jalmes@eu.rhodia.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.024

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L. Garel, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 5705–5708
To reach these goals, our strategy was to introduce the
nitrosing agent to the reaction medium composed of
the aniline, the fluoride source in the solvent at the
decomposition temperature of the diazonium salt. In
Table 1. Diazonium tetrafluoroborates from anilines with t-BuONO
a
and BF
3
ÆOEt
2
in 1,2-dichlorobenzene
þ
ꢀ
Entry
Aniline
ArN2 , BF4
Isolated yield (%)
1
1
our works, alkyl nitrites (and more specifically tert-
NH
2
2
1
2
butyl nitrite stable until 110 °C ) and a complex of
BF were chosen as nitrosing agents and the fluoride
3
1
80
source, respectively.
CH3
The first step of the study was to quantify the efficiency
of the diazotation of anilines and to determine the tem-
perature of decomposition of the diazonium salts. In the
second step, the one-pot transformation of anilines into
fluoroaromatics (i.e., diazotation followed by fluoro-
de-diazoniation) was studied.
NH
2
3
4
5
70
80
65
80
CF
3
NH2
2. Results
Doyle’s procedure13 seems particularly relevant to syn-
thesize diazonium salts in organic medium. tert-butyl
nitrite and boron trifluoride etherate were used in this
procedure to obtain tetrafluoroborate diazonium salts
with good yields in solvents like dichloromethane and
ethers. We have extended the scope of this method by
using solvents having higher boiling point solvents than
dichloromethane or THF. Various solvents were tried
in the diazotation reaction of meta-toluidine with
Br
NH2
Cl
NH2
t-BuONO in the presence of BF ÆOEt: glyme, and 1,2-
3
dichlorobenzene gave good yields, comparable with
the ones obtained in CH Cl . 1,2-dichlorobenzene was
2
2
NO
2
preferred as a scalable solvent since it has a high boiling
point (180 °C) consistent with temperatures of decom-
position of various tetrafluoroborate salts and it is
chemically inert. Thus, several anilines were treated with
boron trifluoride etherate and tert-butyl nitrite at tem-
peratures between ꢀ5 °C and 5 °C to obtain diazonium
tetrafluoroborate salts (Table 1).
NH
2
6
7
55
60
O
N
NH2
Satisfactory yields were obtained in our conditions.
Temperatures of decomposition of these tetrafluoro-
borate diazonium salts in 1,2-dichlorobenzene were
performed by DSC: globally, they are completely
decomposed above 90–100 °C.
a
Anilines (5 g) were dissolved in 1,2-dichlorobenzene (30 ml), boron
trifluoride etherate (1.5 M equiv) was added at ꢀ5 °C, then tert-butyl
nitrite (1.2 M equiv) was slowly added via a syringe pump main-
taining the temperature below 5 °C. The solid was isolated by fil-
tration, washed with pentane and analyzed by NMR ( H and
with internal standard) to measure the yield of formation of diazo-
nium tetrafluoroborate salt.
In situ fluoro-de-diazoniation was performed by adding
tert-butyl nitrite to a mixture of aniline and boron triflu-
oride etherate at a temperature above the measured
temperature of decomposition of the intermediate diazo-
nium salt in 1,2-dichlorobenzene. We think that, in these
conditions, diazotation of anilines is very fast and that
the concentration of diazonium derivative should be
very low. The reaction mixture was maintained at ele-
vated temperature until complete transformation of
starting anilines. Table 2 summarizes the performances
of fluoro-de-diazoniation.
1
19
F
63% from diazonium intermediate of 3-trifluoromethyl-
aniline. The same orders of fluorination efficiency were
obtained on 4-bromoaniline (67%, entry 3), 2-chloroan-
iline (60%, entry 4) and 3-aminoquinoline (67%, entry
7). These yields obtained for the one-pot procedure, that
is, the direct transformation of the anilines into the flu-
oroaromatics Ar–F, are very similar to the ones ob-
tained for the reactions carried out in water and with
isolation of the diazonium salts followed by the Balz–
Yields are satisfactory for 3-toluidine and 3-trifluoro-
methylaniline (entries 1, 2). Since yields of diazotation
have been determined before (80% for 3-toluidine and
5
Schiemann step.
7
0% for 3-trifluoromethylaniline, see Table 1), it is pos-
sible to estimate the efficiency of the fluorination step:
5% from diazonium intermediate of 3-toluidine and
Concerning 4-nitroaniline (entry 5), yield in 4-nitro-
fluorobenzene is low (25%). This can come from the
7

L. Garel, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 5705–5708
5707
Table 2. In situ fluoro-de-diazoniation of anilines with t-BuONO and
biaryl compounds coming from cationic or radical path-
ways, and tars when the yields are low. Arenes Ar–H or
phenols derivatives were detected only in very low
amount (<1%).
a
3 2
BF ÆOEt in 1,2-dichlorobenzene
Entry Aniline
T (°C), time
Yield Ar–F
%)
(
NH
2
2
If boron trifluoride etherate is changed for the complex
1
2
100 °C 20 min
60
44
of boron trifluoride with water (BF Æ2H O), the results
3
2
in terms of yields and profile of impurities are very sim-
CH3
ilar to the ones obtained with BF ÆEt O. It is worth not-
3
2
ing that no more phenol derivatives were detected by gas
chromatography and NMR.
NH
100 °C 40 min
These results are not optimized but correspond to the
first screening efficiency and scope of in situ organic
fluoro-de-diazoniation process. Optimizations of condi-
tions to increase the selectivity of fluorination are in
progress. We also assume that the amounts of diazo-
nium derivative of starting anilines are very low in
our conditions, because the reaction temperature is
above the decomposition of diazonium salt. In further
work, we will try to measure this amount of diazo-
nium derivatives to show that, in our conditions, we
could avoid the accumulation of hazardous diazonium
salts.
CF
3
NH2
3
4
5
100–110 °C 120 min 54
Br
NH2
Cl
110–120 °C 90 min
110–120 °C 60 min
39
25
In conclusion, we have found that it is possible to trans-
form anilines into the corresponding fluoroaromatics
with fair yields via in situ fluoro-de-diazoniation in
organic medium using tert-butylnitrite as the nitrosing
agent and a complex of boron trifluoride as the fluoride
source. No acid was used and the reaction was per-
formed in complete organic medium. No isolation of
intermediate diazonium salts is required and treatment
of the reaction medium is easy.
NH2
NO
2
NH2
6
7
90 °C 45 min
100 °C 60 min
25
40
References and notes
O
N
1
2
. Moilliet, J. S. In Industrial Routes to Ring-Fluorinated
Aromatic Compounds; Banks, R. E., Smart, B. E., Tatlow,
J. C., Eds.; Organofluorine Chemistry, Principles and
Commercial Applications; Plenum: New York, 1994; pp
NH2
1
95–219.
a
Anilines (5 g) were dissolved in 1,2-dichlorobenzene (30 ml), boron
trifluoride etherate (1.5 M equiv) was added at 20 °C, then the mix-
ture was warmed at the temperature mentioned and tert-butyl nitrite
1.2 M equiv) was slowly added in 15 min. The medium was main-
tained at reaction temperature for the time specified. After cooling at
room temperature, water (30 ml) was added. After classical work-up,
. (a) Zollinger, H. Diazo Chemistry I and II; VCH:
Weinheim, 1994; pp 228–230; (b) Langlois, B. In Intro-
duction of Fluorine via Diazonium Compounds; Baasner,
B., Hagemann, H., Tatlow, J. C., Eds.; Houben-Weyl,
Methods of Organic Chemistry, Vol. E10a, Organo-
Fluorine Compounds; Thieme: Stuttgart, 1999; pp 686–
(
1
19
organic phase was analyzed by GC and NMR ( H and F with
internal standard) to measure the yield of fluoroaromatics.
7
40.
3
. Osswald, P.; Scherer, O. German Patent (to I. G.
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at elevated temperature during the decomposition of the
diazonium intermediate.
5
1
3
2
-Fluoro-acetophenone (entry 6) is formed with only
5% yield from 3-aminoacetophenone. The literature14
6
7
gives a 65% yield for the Balz–Schiemann procedure
on 3-amino-acetophenone, but in our hands the yield
of this reaction was below 30%.
3
1–34.
. Kim, Y.-H.; Lee, C. H.; Chang, K. Y. Tetrahedron Lett.
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8
1
In all our trials, starting anilines were not detected in the
final reaction mixture and the only by-products were
9. Tamura, M.; Shibakami, M.; Sekiya, A. Eur. J. Org.
Chem. 1998, 725–727.

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L. Garel, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 5705–5708
3
1
1
1
0. SiF4 exposure limits: 2.5 mg/m (OSHA TWA, ACGIH
Oxford, 1995; p 571. Determination of decomposition
temperature of tert-butyl nitrite was performed by DSC.
13. Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572–
1574.
14. Zenitz, B. L.; Hartung, W. H. J. Org. Chem. 1946, 11,
444–453.
TWA, NIOSH recommended TWA 10 h).
1. Rhodia is supplier of alkyl nitrites such as n-BuONO, sec-
BuONO, t-BuONO at industrial scale.
2. Bretherick’s Handbook of Reactive Chemical Hazards;
Vol. 1, 5th ed.; Urben, P. G., Ed.; Butterworth-Heinemann: