Regioselectivity of fluorine substitution by alkoxides on unsymmetrical difluoroarenes

Article abstract of DOI:10.1016/j.tetlet.2008.05.091

An efficient approach to unsymmetrical halogenated resorcinol diethers has been developed. This synthesis consists of two subsequent nucleophilic aromatic substitutions (S_NAr) of unsymmetrical difluoroarenes by alkoxides. The novelty of this ap

Full text of DOI:10.1016/j.tetlet.2008.05.091

Tetrahedron Letters 49 (2008) 4588–4590
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselectivity of fluorine substitution by alkoxides
on unsymmetrical difluoroarenes
*
Ronan Dirr, Cyril Anthaume, Laurent Désaubry
UMR 7175-LC1, Université Louis Pasteur, CNRS, Faculté de Pharmacie, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach to unsymmetrical halogenated resorcinol diethers has been developed. This synthe-
sis consists of two subsequent nucleophilic aromatic substitutions (SNAr) of unsymmetrical difluoro-
arenes by alkoxides. The novelty of this approach is its control of regioselectivity during the first SNAr,
which occurs at room temperature. Interestingly, the reactivity of competing fluorines was correlated
to their chemical shift in 19F NMR.
Received 21 April 2008
Revised 19 May 2008
Accepted 20 May 2008
Available online 24 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
SNAr
Fluorine substitution
19F NMR
The synthesis of unsymmetrical resorcinol diethers by sequ-
ential alkylation of resorcinol is tedious and low yielding. Very
recently, Toczko and co-workers developed a short and efficient
route to these compounds by performing two successive nucleo-
philic aromatic substitutions (SNAr) of 1,3-difluorobenzene by alk-
oxides (Scheme 1).1 The second fluoride displacement requires
more vigorous conditions than the first one due to the deactivation
by the first alkoxy substituent.
During our synthesis of benzofurans by double lithiation of 2-
bromophenyl ethers according to Sanz’ methodology,2 we needed
an easy and efficient access to differently substituted bromoresor-
cinol diethers. Towards this end, we aimed at modifying Toczko’s
method using a bromo (or iodo) difluorobenzene as a substrate.
In the course of their studies, Toczko and co-workers examined
only the reactivity of unsubstituted difluorobenzenes.1 Thus,
although much work in SNAr of fluoroarenes has been done, as
far as we know, the regioselectivity of this reaction on unsymmet-
rically substituted difluoroarenes remained unexplored.3 To ad-
dress this issue, we surveyed a broad spectrum of parameters
such as the nature of the difluoroarene and of the alkoxide count-
eranion, the temperature, and solvent. The goal of this study was to
establish procedures to control the selectivity of the SNAr on vari-
ously substituted difluoroarenes.
Preliminary studies on the SNAr were conducted with 1 and
benzyl alcohol as substrates to investigate the effects of the reac-
tion conditions on the yield and the regioselectivity (Table 1). Per-
forming this reaction at r.t. with t-BuOK as a base afforded the
products 2 and 3 with a 4:1 selectivity, albeit in low yield (entry
1). Replacing t-BuOK by n-BuLi did not change significantly the
yield or the regioselectivity (entry 2). Gratifyingly, the use of
NaH as a base improved the yield to 80% without altering the
regioselectivity (entry 3). Replacing DMF by THF slightly lowered
the yield but further increased the regioselectivity (9:1 ratio)
(entry 4). Lowering the reaction temperature did not improve
the regioselectivity further but diminished the yield to 30%
(entry 5).
Table 1
Optimization conditions for the regioselective SNAr on difluoroarene 1
Entry
Base
Solvent
Temperature
2:3
Yield (%)
1
2
3
4
5
t-BuOK
n-BuLi
NaH
NaH
NaH
DMF
DMF
DMF
THF
rt
rt
rt
rt
80:20
83:17
77:23
90:10
90:10
25
20
80
70
30
Scheme 1. Double SNAr on 1,3-difluorobenzene.1
* Corresponding author. Tel.: +33 90 244 141; fax: +33 390 244 310.
E-mail address: desaubry@chimie.u-strasbg.fr (L. Désaubry).
THF
4 °C
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.091

R. Dirr et al. / Tetrahedron Letters 49 (2008) 4588–4590
4589
Table 2
SNAr of unsymmetrical difluoroarenes with benzyl alcohol, and 19F NMR chemical shifts of these difluoroarenes
Entry
1
ArF2
Yield (%)
95
Products
dFa (ppm)*
À103.1
dFb (ppm)*
À111.1
dFa À dFb
8
2
3
61
À134.4
À139.1
4.7
40
À130.9
À113.8
À134.8
À114.9
3.9
1.1
4
0 (68)**
*
19F NMR (CDCl3, 200 MHz).
Solvent: DMSO instead of THF.
**
With conditions for regioselective SNAr in hand, we undertook a
Table 3
SNAr of various alcohols with difluoroarene 44
study of substrate generality with a series of unsymmetrical diflu-
oroarenes (Table 2).4 Reactions occurred with an excellent regio-
selectivity ranging from 90:10 to 100:0 in a 40–95% yield. It is
generally accepted that an electron-withdrawing substituent, such
as bromine, orientates the SNAr with the following regioselectivity:
ortho > para > meta, while the electron-donating character of the
methyl group favours the para over the ortho position.3 Surpris-
ingly, 4-bromo-1,2-difluorobenzene did not follow this general
trend (entry 2), as the substitution occurred in majority at the meta
position. The same regioselectivity had been described for the reac-
tion of this difluoroarene with N-hydroxyacetimidate as a nucleo-
phile.5 2,4-Difluorotoluene (entry 4) was unreactive in THF, but
shifting the solvent to DMSO allowed the reaction to be performed
in 68% yield with a 95:5 regioselectivity, which indicates that with
a poorly reactive substrate, the use of DMSO may allow the reac-
tion to be achieved with a good regioselectivity and in a reasonable
yield.
Entry
ROH
Yield (%)
Ratio 5:6
1
2
3
4
5
MeOH
n-BuOH
i-PrOH
Ph(CH2)3OH
CF3CH2OH
42
45
50
47
15
100:0
100:0
95:5
95:5
95:5
6
41
95:5
We also examined whether there is a relationship between the
reactivity and the chemical shift of the fluorides, as they are both
partially related to their electron density. Indeed, in each and every
case, the most reactive fluorine was the most deshielded (Table 2).
This observation suggests that it might be possible to predict the
reactivity pattern for other polyfluoroarenes from their 19F NMR
data.
As shown in Table 3, the SNAr reaction proceeded with a high
regioselectivity and reasonable yields with many primary and sec-
ondary alcohols. As expected, reactions with electron deficient tri-
fluoroethanol or sterically encumbered tert-butanol afforded lower
yields (entries 5 and 8).
7
8
62
22
91:9
95:5
t-BuOH
was performed in DMF at 80 °C, under milder conditions than
those described by Toczko, due to the activation effect of the addi-
tional bromine or iodide1,6 (Table 4).
In conclusion, we have demonstrated that the SNAr of unsym-
metrical difluoroarenes by alkoxides occurs with an unprece-
dented high level of regioselectivity at room temperature. We
have also shown that the most reactive position corresponds to
the most deshielded fluorine in 19F NMR. This method provides
an easy access to variously substituted halogenated resorcinol
diethers.
Next, with the appropriate reactants in hand, we performed a
second fluorine displacement to synthesize variously substituted
halogenated resorcinol diethers, which are important precursors
to benzofurans according to Sanz’s methodology.2 This second SNAr

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R. Dirr et al. / Tetrahedron Letters 49 (2008) 4588–4590
argon at 0 °C. The solution was stirred at 0 °C for 15 min. 1-Bromo-2,4-
Table 4
SNAr of various alcohols with benzyloxy-monofluoroarenes6
difluorobenzene (0.19 g, 1 mmol) was then added, and the solution was at room
temperature for 17 h before being quenched with a satd aqueous solution of
NH4Cl (3 ml). The mixture was extracted with EtOAc, washed with brine, dried
over MgSO4 and concentrated to dryness. Purification of the resulting oily
residue by chromatography (pentane–Et2O) afforded the desired product.
5. Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. Org. Prep. Proc. Int. 1997, 29, 594–600.
6. Typical procedure for the reaction of alkoxides with benzyloxy-mono-
fluoroarenes: preparation of 2-benzyloxy-4-butoxy-1-iodobenzene. n-BuOH
(0.84 ml, 9.12 mmol) was slowly added to a suspension of t-BuOK (743 mg,
6.08 mmol) in DMF (5 ml) under argon at 0 °C. The solution was stirred at 0 °C
Entry
X
ROH
Yield (%)
1
2
3
Br
I
I
MeOH
MeOH
n-BuOH
80
90
75
for 10 min and
a solution of 2-benzyloxy-4-fluoro-1-iodobenzene (500 mg,
1.52 mmol) in DMF (1 ml) was then added. The solution was heated at 80 °C for
20 h, cooled to room temperature and quenched with a satd aqueous solution of
NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over
MgSO4 and concentrated to dryness. Purification of the resulting oily residue by
chromatography (pentane–Et2O 7:3) afforded the desired product (435 mg, 75%)
as a colourless oil. 1H NMR (300 MHz, CDCl3): d 7.66 (1H, d, J = 8.6 Hz); 7.55 (2H,
d, J = 7.3 Hz); 7.30–7.44 (3H, m); 6.54 (1H, d, J = 2.6 Hz); 6.36 (1H, dd, J = 2.6,
8.6 Hz); 5.14 (2H, s); 3.92 (2H, t, J = 6.2 Hz); 1.64–1.67 (2H, m); 1.47 (2H, m);
0.95 (3H, t, J = 6.9 Hz).
References and notes
1. Kim, A.; Powers, J. D.; Toczko, J. F. J. Org. Chem. 2006, 71, 2170–2172.
2. Sanz, R.; Miguel, D.; Martinez, A.; Pérez, A. J. Org. Chem. 2006, 71, 4024–4027.
3. Vlasov, V. M. Russ. Chem. Rev. 2003, 72, 681–703.
4. Typical preparation of 1-bromo-4-fluoro-2-alkoxybenzenes: To a suspension of
NaH (71 mg, 3 mmol) in THF (3 ml) was slowly added alcohol (3 mmol) under