Preparation of acyl fluorides with hydrogen fluoride-pyridine and 1,3-dicyclohexylcarbodiimide

Article abstract of DOI:10.1016/S0022-1139(02)00004-0

This work presents an efficient procedure for preparing acyl fluorides by simply reacting carboxylic acid with hydrogen fluoride-pyridine and 1,3-dicyclohexylcarbodiimide (DCC) in dichloromethane. The acyl fluorides were converted in situ to the corresponding benzyl carboxylic esters by adding benzyl alcohol and triethylamine to the reaction mixture.

Full text of DOI:10.1016/S0022-1139(02)00004-0

Journal of Fluorine Chemistry 115 (2002) 75–77
Preparation of acyl fluorides with hydrogen fluoride-pyridine
and 1,3-dicyclohexylcarbodiimide
Chinpiao Chen*, Chin-Tzu Chien, Chu-Hsiang Su
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan, ROC
Received 17 September 2001; received in revised form 7 January 2002; accepted 10 January 2002
Abstract
This work presents an efficient procedure for preparing acyl fluorides by simply reacting carboxylic acid with hydrogen fluoride-pyridine
and 1,3-dicyclohexylcarbodiimide (DCC) in dichloromethane. The acyl fluorides were converted in situ to the corresponding benzyl
carboxylic esters by adding benzyl alcohol and triethylamine to the reaction mixture. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Acyl fluoride; Hydrogen fluoride-pyridine; 1,3-Dicyclohexylcarbodiimide
1. Introduction
acyl fluorides were not purified and in situ reacted with
benzyl alcohol. To acquire the pure acyl fluorides, a varied
procedure was filtrated the reaction mixture, concentrated
the filtrate, and finally distilled the concentrated solution. To
our knowledge, the fluorination of carboxylic acids has not
been reported under these conditions until now (Scheme 1).
Acyl fluorides are generally prepared by halogen
exchange from the corresponding acyl chlorides with potas-
sium fluoride [1], potassium hydrogen difluoride [2], hydro-
gen fluoride [3], antimony trifluoride [4], zinc fluoride [5],
etc. [6]. Sulfur tetrafluoride [7], selenium tetrafluoride [8],
cyanuric fluoride [9], (diethylamino)sulfur trifluoride
(DAST) [10], tetramethylfluoroformamidinium hexafluoro-
phosphate [11], benzyl fluoride [12], etc. [13] have also been
used for fluorination of carboxylic acids. Halogen exchange
reactions with fluorides generally require a high reaction
temperature and direct fluorinations are inappropriate for
acid derivatives containing multifunctional groups. Cyanu-
ric fluoride is an extremely mild reagent, particularly when
used in the fluorination of amino acids to amino acid
fluorides [9b,9c] for peptide synthesis. However, this reagent
is too expensive.
This work presents an economical, mild and convenient
synthetic method for the fluorination of carboxylic acids to
acyl fluorides using hydrogen fluoride-pyridine and 1,3-
dicyclohexylcarbodiimide (DCC), in situ converted to
carboxylic acid esters by adding benzyl alcohol and triethyla-
mine to the reaction mixture. The C–F bond of acyl fluorides
has a greater stability than the corresponding acyl chlorides
toward neutral oxygen nucleophiles such as water or metha-
nol. However, the acyl fluorides can still not withstand the
moisture for an extended period. Therefore, the obtained
2. Results and discussion
Table 1 summarizes the yield of the fluorination of
carboxylic acids in situ converted to the corresponding
benzyl carboxylic esters, and the yield of acyl fluorides in
50 mmol scale purified by distilling. The fluorination of
trans-cinnamic acid (Entry 6) indicates that hydrogen fluor-
ide-pyridine and DCC is a feasible means of preparing acyl
fluorides containing unsaturated double bonds.
Experimental results indicated not only that pyridine
increases the solubility of carboxylic acid in dichloro-
methane, but also promotes the fluorination of carboxylic
acid with hydrogen fluoride-pyridine and DCC. The amount
of hydrogen fluoride-pyridine in excess of 2 eq., a side
reaction was occurred, and a cyclohexylisocyanate and
the corresponding N-cyclohexylalkanoylamides were pro-
duced (Scheme 2). When the amount of hydrogen fluoride-
pyridine is in large excess (12 eq.), the carboxylic acids with
an a-hydrogen leads to an unexpected dehydration reac-
tion, subsequently producing the corresponding ketones
(Scheme 3).
* Corresponding author. Tel.: þ886-38-663875; fax: þ886-38-661487.
E-mail address: chinpiao@mail.ndhu.edu.tw (C. Chen).
In the syntheses of natural and non-natural products, the
mild reaction conditions are always preferred in key bond-
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 0 4 - 0

76
C. Chen et al. / Journal of Fluorine Chemistry 115 (2002) 75–77
The general procedure is illustrated as follows to
synthesize benzyl benzoate. To a solution of 1,3-dicyclo-
hexylcarbodiimide(1.13 g, 5.5 mmol)andhydrogenfluoride-
pyridine (ꢀ70% HF, 143 ml, 5.5 mmol) in dichloromethane
(10 ml) was added using cannula at room temperature for a
solution of benzoic acid (0.66 g, 5 mmol) and pyridine
(1 ml) in dichloromethane (40 ml). The reaction mixture
was then stirred for 2 h. After the reaction was completed (as
monitored by GC-MS, HP 5973) and when the benzoic acid
was consumed entirely, benzyl alcohol (1.04 ml, 10 mmol)
and triethylamine (0.79 ml, 20 mmol) were added to the
reaction mixture, and at room temperature stirred for over-
night. The reaction mixture was filtered through celite, and
the filtrate was washed with 1N hydrochloric acid. The
organic phase was then dried over anhydrous magnesium
sulfate and concentrated. Finally, the crude product was
purified by column chromatography (ethyl acetate–hexane,
1:50) lead to benzyl benzoate (0.90 g, 85% yield).
Scheme 1.
Table 1
Fluorination of carboxylic acids with HF-pyridine and DCC in situ
converted to the corresponding benzyl carboxylic esters
a
Entry
yield (%)
yield (%)
1
2
3
4
5
6
7
8
Benzoic acid
98
100
84
85
88
84
88
88
99
84
93
p-Anisic acid
p-Nitrobenzoic acid
Phenylacetic acid
Diphenylacetic acid
trans-Cinnamic acid
Cyclohexanecarboxylic acid
Stearic acid
82
60
75
97
89
a The acyl fluorides were prepared in 50 mmol scale and purified by
distillation.
Acknowledgements
The authors would like to thank the National Science
Council of the Republic of China and Tzu Chi University for
financially supporting this research under Contract No. NSC
89-2113-M-320-001.
Scheme 2.
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