A convenient, one-pot procedure for the preparation of acyl and sulfonyl fluorides using Cl3CCN, Ph3P, and TBAF(t -BuOH) 4

Article abstract of DOI:10.1055/s-0030-1259051

Various carboxylic acids were converted into acyl fluorides in excellent yields by treatment with trichloroacetonitrile, triphenylphosphine, and TBAF(t-BuOH)₄ at room temperature. The reaction was applicable to the preparation of acid-sensitive amino acid fluorides without deprotection or rearrangement

Full text of DOI:10.1055/s-0030-1259051

LETTER
3049
A Convenient, One-Pot Procedure for the Preparation of Acyl and Sulfonyl
Fluorides Using Cl3CCN, Ph3P, and TBAF(t-BuOH)4
P
reparatio
o
n of
A
cyl
a
n
o
d Sulfonyl Fl
n
uoride
s
g-Gon Kim,a Doo Ok Jang*b
a
Biotechnology Division, Hanwha Chemical R&D Center, Daejeon 305-345, South Korea
Department of Chemistry, Yonsei University, Wonju 220-710, South Korea
Fax +82(33)7602182; E-mail: dojang@yonsei.ac.kr
b
Received 29 September 2010
low solubility of metal fluorides in organic medium and
their hygroscopic nature. Recently, Kim et al. reported the
use of tetrabutylammonium tetra(tert-butyl alcohol) coor-
dinated fluoride [TBAF(t-BuOH)4] as a fluoride source,
which has low hygroscopicity for easy handling and has
good solubility in organic solvents.18 Herein, we report an
efficient and practical procedure for the synthesis of acyl
fluorides from carboxylic acids with trichloroacetonitrile,
triphenylphosphine, and TBAF(t-BuOH)4.
Abstract: Various carboxylic acids were converted into acyl fluo-
rides in excellent yields by treatment with trichloroacetonitrile,
triphenylphosphine, and TBAF(t-BuOH)4 at room temperature. The
reaction was applicable to the preparation of acid-sensitive amino
acid fluorides without deprotection or rearrangement.
Key words: carboxylic acid, acyl fluoride, sulfonyl fluoride, amino
acid fluoride, trichloroacetonitrile
Acyl fluorides have been used as valuable synthetic inter-
mediates for pharmaceuticals and other organic products.1
For instance, benzoyl fluoride has been used in the synthe-
ses of antibiotics,2 antitumor agents,3 and enzyme inhibi-
tors.4 Acyl fluorides have also been widely employed for
peptide bond formation since they are stable to moisture
and are easy to handle.5 Several approaches for preparing
acyl fluorides are available in the literature; these can be
classified by the use of either carboxylic acid or acyl chlo-
ride as the starting material. Acyl fluorides have been pre-
pared by treatment of carboxylic acids with fluorinating
agents such as sulfur tetrafluoride,6 selenium tetrafluo-
ride,7 cyanuric fluoride,8 (diethylamino)sulfur trifluo-
ride,9 tetramethylfluoroformamidinium hexafluoro-
phosphate,10 hydrogen fluoride–pyridine/1,3-dicyclohexyl-
carbodiimide,11 or aminodifluorosulfinium tetrafluorobo-
rate salts.12 Acyl fluorides have also been prepared from
acyl chlorides by halogen exchange reactions with a fluo-
ride source such as potassium fluoride,13 potassium hy-
drogen difluoride,14 hydrogen fluoride,15 zinc fluoride,16
or bromine trifluoride.17 However, these methods have
some drawbacks to practical use because they employ
highly toxic, gaseous, thermally unstable, expensive, cor-
rosive and/or highly moisture-sensitive reagents. Some of
these methods require low temperature, long reaction
times, hazardous solvents, and afford mixtures of prod-
ucts. Therefore, it would be highly desirable to have an ef-
ficient and practical method for the synthesis of acyl
fluorides.
We postulated that carboxylic acid chlorides, prepared in
situ from carboxylic acids with a combination of trichlo-
roacetonitrile and triphenylphosphine, might be trans-
formed into the corresponding acyl fluorides by treatment
with a fluoride source.19 We chose benzoic acid as a mod-
el compound to establish optimal reaction conditions.
When benzoic acid was treated with Cl3CCN (1 equiv),
Ph3P (1 equiv), and then TBAF(t-BuOH)4 (2 equiv) in ac-
etonitrile at room temperature for two hours, the desired
benzoyl fluoride was obtained in 42% yield along with
unreacted benzoic acid (Table 1, entry 1). However, when
the amounts of Cl3CCN and Ph3P were increased, benzoic
acid was completely converted into benzoyl fluoride with-
in one hour in 91% yield (entry 2). The reaction proceeded
efficiently even at 0 °C (entry 3). Further increases in the
amounts of Ph3P, CCl3CN and TBAF(t-BuOH)4 did not
affect the yield of benzoyl fluoride (entries 4 and 5), while
a decrease in the amount of TBAF(t-BuOH)4 significantly
decreased the yield of benzoyl fluoride (entry 6). Various
organic solvents were screened to find suitable solvents
for the reaction (entries 7–11), and acetonitrile and N,N-
dimethylformamide (DMF) were found to give the best
results. Other fluoride sources, such as TBAF, CsF, and
KF, were also examined for the reaction. With TBAF, the
reaction afforded a moderate yield of benzoyl fluoride
(entry 12); however, the reaction did not take place with
CsF or KF even in the presence of 18-crown-6 for pro-
longed reaction times (entries 13–15). This may be attrib-
utable to the low solubility of these metal fluorides. The
efficiency of various chlorinating reagents was investigat-
ed, and CCl3CN was found to be the reagent of choice (en-
tries 16–19).
Reactions that are available for the preparation of acyl
fluorides that use metal fluorides as the fluoride source
typically require high temperatures and long reaction
times and generate mixtures of products because of the
To investigate the scope and limitations of the reaction, a
wide range of aryl and alkyl carboxylic acids were sub-
jected to the reaction conditions. The results are summa-
rized in Table 2. Aryl carboxylic acids with either
electron-donating or electron-withdrawing groups were
SYNLETT 2010, No. 20, pp 3049–3052
x
x
.x
x
.2
0
1
0
Advanced online publication: 17.11.2010
DOI: 10.1055/s-0030-1259051; Art ID: U08710ST
© Georg Thieme Verlag Stuttgart · New York

3050
J.-G. Kim, D. O. Jang
LETTER
Table 1 Fluorination of Benzoic Acid under Various Reaction Conditions
O
O
1) Cl3CCN, Ph3P, 1 h, r.t.
2) TBAF(t-BuOH)4, time, r.t.
Ph
F
Ph
OH
Entry
1
Ph3P (equiv) Halogenating agent (equiv) Fluorinating agent (equiv)
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
(ClCH2)2
toluene
Et2O
Time (h)
Yield (%)a
1
2
2
2.5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CCl3CN (1)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2.5)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl3CN (2)
CCl4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (3)
TBAF(t-BuOH)4 (1)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF (2)
2
1
42
91
89
88
91
65
0
2
3b
4
1
1
5
2
6
2
7
12
12
12
12
1
8
0
9
0
10
11
12
13
14
15
16
17
18
19
THF
12
89
68
29
0
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3
CsF (2)
12
24
24
10
10
10
10
KF (2)
KF (2)/18-crown-6 (0.1)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
TBAF(t-BuOH)4 (2)
5
0
Cl3CCOCCl3 (2)
Cl3CCO2Et (2)
Cl3CCONH2 (2)
29
16
38
a The yield was measured by GC.
b The reaction was carried out at 0 °C.
Table 2 Synthesis of Acyl Fluorides from Carboxylic Acidsa,b
Table 3 Synthesis of Sulfonyl Fluorides from Sulfonic Acids
Entry Acid
Time (h) Yield (%) Ref.
Entry Acid
Time Yield Ref.
(h) (%)
1
2
p-methoxybenzoic
1
89
90
95
85
83
79
81
78
77
80
80
11
1
2
3
4
5
methanesulfonic
1
1
1
2
2
87
93
94
91
89
21
21
21
21
21
p-bromobenzoic
p-nitrobenzoic
phenylacetic
1
13f
11
benzenesulfonic
3
0.5
1
4-methylbenzenesulfonic
4-bromobenzenesulfonic
5-(dimethylamino)naphthalene-1-sulfonic
4
13f
11
5
cyclohexanecarboxylic
propionic
1
6
1
13f
17
readily converted into the corresponding acyl fluorides in
high yields (entries 1–3). Compared to aryl carboxylic
acids, alkyl carboxylic acids afforded somewhat lower
yields of acyl fluorides (entries 4–7). trans-Cinnamic acid
was transformed into the corresponding acyl fluoride with
the carbon–carbon double bond intact (entry 8). Sterically
hindered substrates and dicarboxylic acids such as trime-
thylacetic acid and 5-methoxy-5-oxopentanoic acid re-
quired longer reaction times (entries 9–11). This method
of transforming carboxylic acids into the corresponding
7
octanoic
1
8
trans-cinnamic
2,2-diphenylacetic
trimethylacetic
5-methoxy-5-oxopentanoic
1
11
9
2
11
10
11
2
13d
17
2
a See the typical experimental procedure for reaction conditions.20
b Spectroscopic data of the products were consistent with literature
values.
Synlett 2010, No. 20, 3049–3052 © Thieme Stuttgart · New York

LETTER
Preparation of Acyl and Sulfonyl Fluorides
3051
Table 4 Synthesis of Amino Acid Fluorides
22
Entry
1
Amino acid
Yield (%)a
[a]D
Lit. [a]D
N-Fmoc-L-Gly-OH
N-Fmoc-L-Ala-OH
N-Fmoc-L-Val-OH
N-Fmoc-L-Ile-OH
N-Fmoc-L-Met-OH
N-Fmoc-L-Asp(t-BuO)OH
N-t-Boc-L-Ala-OH
N-t-Boc-L-Leu-OH
N-t-Boc-L-Met-OH
N-t-Boc-L-Asp(OBn)-OH
N-Cbz-L-Ala-OH
88
83
75
80
76
73
78
81
71
87
81
79
–
–
2
+ 3.8 (c 1, EtOAc)
+11.0 (c 1, CH2Cl2)
+15.9 (c 1, EtOAc)
–13.3 (c 1, EtOAc)
+ 4.1 (c 1, EtOAc)
–17.1 (c 1, EtOAc)
–17.7 (c 1, EtOAc)
–23.3 (c 1, EtOAc)
–13.9 (c 1, EtOAc)
– 8.0 (c 1, EtOAc)
–36.9 (c 1, EtOAc)
+ 3.6 (c 0.5, EtOAc)5b
+10.7 (c 1, CH2Cl2)5b
+15.0 (c 0.5, EtOAc)5b
–12.9 (c 0.55, EtOAc)5b
+ 4.0 (c 0.5, EtOAc)5b
–17.2 (c 1, EtOAc)5c
–17.4 (c 1, EtOAc)5c
–23.5 (c 1, EtOAc)5c
–13.2 (c 1, EtOAc)5c
– 7.8 (c 1, EtOAc)5c
–36.4 (c 1, EtOAc)5c
3
4
5
6
7
8
9
10
11
12
N-Cbz-L-Phe-OH
a Isolated yield after silica gel column chromatography.
Soc. 1990, 112, 9651. (c) Carpino, L. A.; Mansour, E.-S. M.
E.; Sadat-Aalaee, D. J. Org. Chem. 1991, 56, 2611.
(6) (a) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am.
Chem. Soc. 1960, 82, 543. (b) Bloshchitsa, F. A.;
Burmakov, A. I.; Kunshenko, B. V.; Alekseeva, L. A.;
Yagupol’skii, L. M. J. Org. Chem. USSR (Engl. Transl.)
1985, 21, 1286. (c) Ritter, S. K.; Hill, B. K.; Odian, M. A.;
Dai, J.; Noftle, R. E.; Gard, G. L. J. Fluorine Chem. 1999,
93, 73.
acyl fluorides was found to be very mild, efficient, and
general. The reaction was also applicable to the synthesis
of sulfonyl fluorides from sulfonic acids (Table 3).
Next, we applied our method to the synthesis of amino
acid fluorides, which are frequently used in peptide syn-
thesis (Table 4). Treatment of Fmoc, Boc, and Cbz pro-
tected amino acids with Cl3CCN, Ph3P, and TBAF(t-
BuOH)4 in acetonitrile for two hours gave the correspond-
ing amino acid fluorides in 71–88% yields without any in-
dication of deprotection or rearrangement.
(7) Olah, G. A.; Nojima, M.; Kerekes, I. J. Am. Chem. Soc.
1974, 96, 925.
(8) (a) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973,
487. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.;
Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am.
Chem. Soc. 1999, 121, 11953. (c) Schkeryantz, J. M.; Woo,
J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J.
J. Am. Chem. Soc. 1999, 121, 11964. (d) Grugier, J.; Xie, J.;
Duarte, I.; Valery, J.-M. J. Org. Chem. 2000, 65, 979.
(9) (a) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V.
Synthesis 1973, 787. (b) O’Sullivan, A. C.; Struber, F.; Ley,
S. V. J. Org. Chem. 1999, 64, 6252.
(10) (a) Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995,
117, 5041. (b) Nicolaou, K. C.; Mitchell, H. J.; Suzuki, H.;
Rodriguez, R. M.; Baudoin, O.; Fylaktakidou, K. C. Angew.
Chem. Int. Ed. 1999, 38, 3334. (c) Nicolaou, K. C.;
Rodriguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell,
H. J. Angew. Chem. Int. Ed. 1999, 38, 3340.
In summary, we have developed a mild and convenient
synthesis of acyl fluorides from carboxylic acids with
Cl3CCN, Ph3P, and TBAF(t-BuOH)4.21 The process is
general for the preparation of acyl fluorides and sulfonyl
fluorides from a variety of carboxylic acids and sulfonic
acids. The reaction is applicable to the preparation of acid-
sensitive amino acid fluorides without deprotection or re-
arrangement.
Acknowledgment
This work was supported by the Center for Bioactive Molecular
Hybrids.
(11) Chen, C.; Chien, C.-T.; Su, C.-H. J. Fluorine Chem. 2002,
115, 75.
References and Notes
(12) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier,
M.; LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050.
(13) (a) Saunders, S. J. Chem. Soc. 1948, 1778. (b) Haszeldine,
N. J. Chem. Soc. 1959, 1084. (c) Ishikawa, N.; Kitazume,
T.; Yamazaki, T.; Mochida, Y.; Tatsuno, T. Chem. Lett.
1981, 761. (d) Tordeux, M.; Wakselman, C. Synth.
Commun. 1982, 12, 513. (e) Clark, J. H.; Hyde, A. J.; Smith,
D. K. J. Chem. Soc., Chem. Commun. 1986, 791. (f) Liu,
H.; Wang, P.; Sun, P. J. Fluorine Chem. 1989, 43, 429.
(g) Krespan, C. G.; Dixon, D. A. J. Org. Chem. 1991, 56,
3915.
(1) Tayer, A. M. Chem. Eng. News 2006, 84 (23), 15.
(2) Turks, M.; Huang, X.; Vogel, P. Chem. Eur. J. 2005, 11,
465.
(3) Rajeswari, S.; Jones, R. J.; Cava, M. P. Tetrahedron Lett.
1987, 28, 5099.
(4) Dabkowski, W.; Cramer, F.; Michalski, J. Tetrahedron Lett.
1987, 23, 3561.
(5) (a) Carpino, L. A.; Bayermann, M.; Wenschuh, H.; Bienert,
M. Acc. Chem. Res. 1996, 29, 268. (b) Carpino, L. A.;
Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J. Am. Chem.
Synlett 2010, No. 20, 3049–3052 © Thieme Stuttgart · New York

3052
J.-G. Kim, D. O. Jang
LETTER
(14) Miller, J.; Ying, O.-L. J. Chem. Soc., Perkin Trans. 2 1985,
323.
(19) Jang, D. O.; Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 40,
5323.
(15) (a) Young, D. J. Org. Chem. 1959, 24, 1021. (b) Abe, T.;
Hayashi, E.; Baba, H.; Nagase, S. J. Fluorine Chem. 1984,
25, 419.
(16) (a) Swain, C. G.; Scott, C. B. J. Am. Chem. Soc. 1953, 75,
246. (b) Nenajdenko, V. G.; Lebedev, M. V.; Belenkova, E.
S. Tetrahedron Lett. 1995, 36, 6317.
(20) Typical experimental procedure: To a mixture of benzoic
acid (1.22 g, 10 mmol) and Ph3P (5.26 g, 20 mmol) in MeCN
(25 mL) under argon, was added Cl3CCN (2 mL, 20 mmol)
dropwise at r.t. The reaction mixture was stirred at r.t. for
1 h. TBAF(t-BuOH)4 (11.2 g, 20 mmol) was added to the
above solution, and stirring was continued for 1 h at r.t. After
concentration of the reaction mixture by using a rotary
evaporator, the residue was purified by distillation under
reduced pressure to give benzoyl fluoride (1.12 g, 91%;
bp 88–90 °C/100 mmHg (Lit.13c 84–86 °C/98 mmHg).
(21) Bianchi, T. A.; Cate, L. A. J. Org. Chem. 1977, 42, 2031.
(17) Cohen, O.; Sasson, R.; Rozen, S. J. Fluorine Chem. 2006,
127, 433.
(18) (a) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.
Angew. Chem. Int. Ed. 2008, 47, 8404. (b) Kim, D. W.;
Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen,
J. A.; Chi, D. Y. J. Org. Chem. 2008, 73, 957.
Synlett 2010, No. 20, 3049–3052 © Thieme Stuttgart · New York

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