A mild and efficient method for nucleophilic aromatic fluorination using tetrabutylammonium fluoride as fluorinating reagent

Article abstract of DOI:10.1016/j.cclet.2009.10.014

Anhydrous tetrabutylammonium fluoride (TBAF_anh.) has been found to be a highly efficient fluorinating reagent for nucleophilic aromatic fluorinations such as fluorodenitration or halogen exchange (Halex) reaction. The products were formed in high to excellent yields under surprisingly mild reaction conditions and no phenol or ether side-products were detected in these reactions.

Full text of DOI:10.1016/j.cclet.2009.10.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 151–154
www.elsevier.com/locate/cclet
A mild and efficient method for nucleophilic aromatic
fluorination using tetrabutylammonium fluoride as
fluorinating reagent
*
¨
Yu Feng Hu, Jun Luo, Chun Xu Lu
School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing 210094, China
Received 15 June 2009
Abstract
Anhydrous tetrabutylammonium fluoride (TBAFanh.) has been found to be a highly efficient fluorinating reagent for
nucleophilic aromatic fluorinations such as fluorodenitration or halogen exchange (Halex) reaction. The products were formed
in high to excellent yields under surprisingly mild reaction conditions and no phenol or ether side-products were detected in these
reactions.
# 2009 Chun Xu Lu¨. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: TBAFanh.; Fluoroaromatics; Fluorodenitration; Halex
Fluoroaromatics have applications in many sectors, including the pharmaceutical and agrochemical industries due
to the unusual properties of the C–F bond [1–4]. Because of the industrial importance of fluoroaromatics, mild and
selective methods for their preparation are desirable, thus an expansive set of nucleophilic reagents has been developed
to replace various C–X functional groups with C–F via nucleophilic aromatic fluorination. Alkali metal fluoride such
as potassium fluoride is the traditional reagent for nucleophilic aromatic fluorination. However, its limited solubility in
organic solvent and low nucleophilicity require generally vigorous conditions [5]. CsF being both more reactive and
more expensive and LiF and NaF being completely unreactive. Thus, a number of metal fluoride reagents such as KF/
18-crown-6, ‘‘freeze-dried’’ KF and ‘‘spray-dried’’ KF have been reported to solve these problems [6]. However, these
above-mentioned processes are generally less efficient than those using tetraalkylammonium fluorides [7–10].
TBAFanh. was found to be an efficient fluorinating reagent for the nucleophilic fluorination [11–14]. TBAFanh. is a
soluble, highly nucleophilic fluoride-ion source. It can be dissolved in dimethyl sulfoxide (DMSO), CH3CN and THF,
and it can fluorinate primary alkyl halides and tosylates rapidly at low temperature (ꢀ35 8C) for 5 min in THF [12].
The rapid rate observed for SN2 reactions that feature TBAFanh. prompted us to investigate nucleophilic aromatic
substitution (SNAr) reactions with this reagent. Below we describe variants of fluorodenitration and Halex processes
for aromatic fluorination. The results show that TBAFanh. permits these reactions to be performed under surprisingly
mild conditions.
* Corresponding author.
E-mail address: lucx@mail.njust.edu.cn (C.X. Lu¨).
1001-8417/$ – see front matter # 2009 Chun Xu Lu¨. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.10.014

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Y.F. Hu et al. / Chinese Chemical Letters 21 (2010) 151–154
1. Experimental
A mixture of TBAFanh. (30 mmol), dried THF (10 mL), nitroaromatics or chloroaromatics (25 mmol) were stirred
for certain time at room temperature or refluxed under nitrogen atmosphere. The reactions were trapped by GC. Side-
products were obtained by flash column chromatography. 4,40-Dinitrodiphenyl ether: 1H NMR (CDCl3): d 7.16–7.18
(d, 4 ꢁ CH, J = 7.5 Hz), 8.29–8.30 (d, 4 ꢁ CH, J = 7.5 Hz); 13C NMR (CDCl3): d 160.71, 144.19, 126.19, 119.31;
melting point: 145–146 8C; MS (m/z): 260, 138, 123, 95, 77; IR (KBr): 3099.91, 1582.87, 1464.64, 1321.93, 1308.05,
1
1281.75, 1146.28, 1088.96 cmꢀ1. p-Nitrophenyl methyl sulfide: H NMR (CDCl3): d 2.58 (s, CH3), 7.31–7.32 (d,
2 ꢁ CH, J = 8.9 Hz), 8.15–8.17 (d, 2 ꢁ CH, J = 8.9 Hz); 13C NMR (CDCl3): d 148.92, 144.74, 124.99, 123.85, 14.82;
melting point: 68–69 8C; MS (m/z): 169, 139, 111, 108, 77, 45; IR (KBr): 1530.34, 1359.32, 1334.26, 745.42 cmꢀ1
.
2. Results and discussion
The usual reagents employed to effect fluorodenitration or Halex are spray-dried KF (SD-KF); a high-boiling-point
polar aprotic solvent, such as sulfolane; and a phase-transfer catalyst to improve the solubility of the fluoride ion.
Prolonged and vigorous heating is often required. Such harsh conditions preclude syntheses in which the late
introduction of fluorine substituents is desired. In contrast, many aromatic compounds undergo fluorodenitration or
Halex reactions at room temperature in THF upon exposure to TBAFanh. (Scheme 1). Some examples are summarized
in Table 1.
As the data in Table 1 indicate, aromatics with electron-withdrawing groups at the 2- or 4-position (entries 2–4, 6, 7
and 9) underwent smooth denitration to afford the corresponding fluoroaromatics after a few hours either at room
temperature or at reflux. While aromatics with electron-withdrawing groups at the 3-position required prolong the
reaction time to drive completion (entries 1 and 8). A comparison of the meta- ortho- and para-dinitrobenzene
examples shows fluorination of meta-dinitrobenzene requires 40 h, whereas ortho- and para-dinitrobenzene are
exhaustively fluorinated in 1.5 h under identical conditions. Nitroaromatic substrates bearing more strongly electron-
withdrawing (cyano) substituents are also fluorinated rapidly. It is noteworthy that 2- and 4-nitrobenzonitriles are
fluorinated quantitatively within 1 h. In addition, TBAFanh. performs fluorinations even on relatively weakly activated
arenes, for example, nitrobenzaldehydes and chlorobenzaldehydes, fluorodenitration and Halex fluorinations of 2- and
4-nitrobenzaldehydes and 2- and 4-chlorobenzaldehydes require heating at reflux for ten or twenty hours to give more
than 80% yields. Adams and Clark reported that NO2ꢀ is superior to chloride as a leaving group in SNAr [15], as the
data in Table 1 confirmed the conclusion (entries 4, 6, 7, 9, 10 and 12–14). Entries 8 and 15 were chosen as examples of
meta-substituent, which are of interest due to the difficulty of forming such fluoroaromatics via Halex fluorination,
thus entries 1 and 8 are established industrial methods of forming such fluoroaromatics.
In order to compare the reaction efficiency for nucleophilic aromatic fluorination of various fluorinating reagents,
we chose the conversion of p-dinitrobenzene (PDNB) to p-fluoronitrobenzene (PFNB). Representative fluorinations
are shown in Table 2.
As the data in Table 2 indicate, the activity of KF is the weakest and it needs very high temperature to make the
reaction proceed successfully. Attempted displacement of 25 mmol of PDNB by 100 mmol of SD-KF in the presence
of 2.5 mmol of Ph4PBr, 1.25 mmol of TEG-Me2 and 25 mmol of PDC in 15 mL of DMSO at 189 8C for 1 h gave only
82.7% of PFNB. In the mean time, because of weak stability of NO2ꢀ, there will result some by-products, such as
phenols and ethers (we had isolated the 4,40-diꢀnitrodiphenyl ether from the reaction mixture). Generally, side reaction
can be controlled effectively by adding NO2 trapping agent, such as phthaloyl dichloride (PDC) [16]. The high
Scheme 1. Fluorodenitration and Halex reactions of nitro- and chloroaromatic compounds by TBAFanh. (a) TBAFanh., THF, in RT.

Y.F. Hu et al. / Chinese Chemical Letters 21 (2010) 151–154
153
Table 1
Fluorodenitration and Halex reactions of various nitro- and chloroaromatic compounds using TBAFanh.
a
.
Entry
1
Substrate
Product
T (8C)
Time (h)
40
Yield (%)
85.3
RT
2
3
RT
RT
1.5
1.5
98.5
97.4
4
5
Reflux
Reflux
10
48
82.1
<5
6
7
8
Reflux
RT
10
1
80.6
97.3
94.6
RT
36
9
10
11
RT
1
20
48
98.2
79.7
Trace
Reflux
Reflux
12
13
Reflux
RT
20
30
77.3
95.8
14
15
RT
40
48
92.5
Reflux
Trace
a
Yields based on GC area, corrected by the presence of an internal standard, and biphenyl as standard.

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Y.F. Hu et al. / Chinese Chemical Letters 21 (2010) 151–154
Table 2
Fluorodenitration reactions of PDNB using various fluorinating reagents.
Entry
Fluorinating reagent
Solvent
T (8C)
Time (h)
Yield (%)a
1
2
3
4
SD-KF (4 equiv)
CsF (4 equiv)
15 mL DMSO
15 mL DMSO
10 mL DMF
10 mL THF
189
120
80
1
82.7
91.4
95.6
98.5
1.5
1
TMAFanh. (1.4 equiv)
TBAFanh. (1.2 equiv)
RT
1.5
a
Yields calculated by GC area, corrected by the presence of an internal standard, and biphenyl as standard.
basicity of the fluoride can also result in the formation of by-products arising from reaction with the solvent. p-
Nitrophenyl methyl sulfide incorporated products (derived from DMSO) were also isolated. In contrast, the activity of
CsF is stronger than that of KF. So it can make the reaction temperature decrease evidently. TMAFanh. was observed to
be more efficient than SD-KF and CsF but was less efficient than TBAFanh. TMAFanh. gave 95.6% yield of PFNB after
1 h at 80 8C in DMF. No phenols or ethers were detected in either reaction and, unlike the method of fluorodenitration
with SD-KF no brown fumes were observed. Whereas TBAFanh. permits the reaction to be performed under
surprisingly mild reaction conditions. TBAFanh. gave 98.5% yield of PFNB after 1.5 h at only RT. No phenols or ethers
were detected in reaction. Tetraalkylammonium fluorides are known to be a particularly effective fluorodenitration
reagent partly because it forms a stable nitrite which is less likely to back-attack the fluoro product leading to a loss in
yield and the formation of phenol and ether side-products. This may indicate that the displaced NO2ꢀ can exist in this
system with not very high temperature as effectively stable R4NNO2 [10].
In conclusion, TBAFanh. is a highly efficient fluorinating reagent for selective nucleophilic aromatic fluorination of
a wide range of nitroaromatics and chloroaromatics. In addition, high yields of the products, surprisingly mild reaction
conditions, little side reactions and easy work-up are worthy advantages of this method.
Acknowledgment
We are grateful to the National Basic Research (973) Program of China (No. 613740101).
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