Efficient synthesis of aryl fluorides

Article abstract of DOI:10.1002/anie.200905855

Chemical Equation Presented Creating C-F bonds: A novel electrophilic fluorination of aryl and heteroaryl Crignard reagents has been discovered and was used for the efficient synthesis of various aryl fluoride derivatives (see picture; THF = tetrahydrofuran).

Full text of DOI:10.1002/anie.200905855

Angewandte
Chemie
DOI: 10.1002/anie.200905855
Selective Fluorination
Efficient Synthesis of Aryl Fluorides**
Pazhamalai Anbarasan, Helfried Neumann, and Matthias Beller*
Dedicated to Professor Michael Drꢀscher on the occasion of his 60th birthday
Selective functionalization reactions of aromatic and hetero-
aromatic halides with carbon, oxygen, and nitrogen nucleo-
[
1]
philes have attracted much attention in the last decades. In
addition to typical metal-catalyzed coupling reactions, direct
functionalization of aryl halides through the formation of
Grignard reagents offer new ways for the efficient construc-
[
2,3]
tion of biologically interesting carbo- and heterocycles.
Recent elegant examples include the development of LiCl-
mediated preparation of Grignard reagents by Knochel and
[4]
co-workers. Inspired by their work and our interest in
[
5]
functionalization reactions of aryl halides, we have been
fascinated in the direct synthesis of aryl fluoride compounds
from aryl Grignard reagents.
Although a large number of known pharmaceutical and
agrochemical
Scheme 1), which enhance solubility, bioavailability, and
metabolic stability compared with non-fluorinated ana-
products
contain
fluorinated
arenes
(
[
6,7]
logues,
there is no convenient and general synthetic
method available for their synthesis. Commonly known
methods for the introduction of a fluorine atom to arenes
require relatively harsh reaction conditions.
Typical examples include the direct fluorination of
[
8]
arenes, the Balz–Schiemann reaction of aryldiazonium
[
9]
salts with HBF4, and the so-called Halex exchange reaction
Scheme 1. Selected examples of therapeutically important aryl fluoride
compounds.
[10]
of activated aryl halides with metal fluorides. In addition,
transition-metal-promoted fluorinations have been achieved
through the use of electrophilic NÀF reagents such as
[
11]
Selectfluor or N-fluoropyridinium salts. Unfortunately, in
most of these reactions stoichiometric amounts of the
transition metal must be used or specific directing groups
Table 1: Fluorination of 4-MeOC H MgBr·LiCl: Variation of temperature
6
4
[a]
and additives.
[
12]
on the substrate are required. Most recently, Buchwald and
co-workers developed an elegant palladium-catalyzed fluori-
nation of aryl triflates using AgF or CsF.
[13,14]
Our initial investigations aimed at the fluorination of 4-
bromoanisole (1), which is a particularly challenging substrate
for nucleophilic fluorination, to give 4-fluoroanisole (2;
Table 1).
[b]
[b]
Entry NÀF reagent T [8C] Additive Yield of 2 [%]
Anisole [%]
[
c]
[d]
1
2
3
4
5
6
7
8
9
Selectfluor
F-TMP-BF4
Selectfluor
F-TMP-BF4
F-TMP-BF4
F-TMP-BF4
Selectfluor
0
0
0
–
–
–
–
–
–
0
0
–
–
[
c]
[d]
In our model reaction we converted 1 into the corre-
sponding aryl Grignard 3 mediated by LiCl, according to the
[e]
[e]
[f]
32
51
13
40
9
4
19
16
21
12
10
39
0
[
4a]
procedure developed by Krasovskiy and Knochel.
We
RT
À25
0
[
g]
g]
[h]
[h]
pyridine
[*] Dr. P. Anbarasan, Dr. H. Neumann, Prof. M. Beller
[
F-TMP-BF4
0
0
pyridine
18
47
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
g]
F-TMP-BF4
PBu3[
[
(
a] Reaction conditions: 3 (0.5 mmol), NÀF reagent (0.75 mmol), THF
2 mL), 1.5 h. [b] Determined by GC analysis with hexadecane as the
internal standard; the yield is based on Grignard reagent. [c] Fluoronium
source was added to the Grignard reagent. [d] Yield was not calculated.
[e] Inverse addition of reagents. [f] Formation of 4,4’-dimethoxybiphenyl
and 1 was observed. [g] 1 equivalent of additive was used. [h] 1 was the
major product.
[**] This work was funded by the Alexander-von-Humboldt-Stiftung, the
State of Mecklenburg-Western Pomerania, the BMBF, and the DFG
(
Leibniz Prize). We thank S. Leiminger (LIKAT) for analytical
support.
Angew. Chem. Int. Ed. 2010, 49, 2219 –2222
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2219

Communications
envisioned that subsequent addition of electrophilic fluorina-
tion reagents should result in the desired fluorinated product
. Initially both Selectfluor and N-fluoro-2,4,6-trimethylpyr-
idinium tetrafluoroborate (F-TMP-BF ) were tested as fluo-
2
4
[
15]
rinating reagents. As shown in Table 1, the addition of the
fluoronium source to 3 at 08C gave no fluorination, but 4,4’-
dimethoxybiphenyl and other side products were observed
(
Table 1, entries 1 and 2). On the other hand, slow introduc-
tion of the Grignard reagent 3 to the fluorinating reagent at
the same temperature smoothly produced the desired fluori-
nated arene 2 (Table 1, entries 3 and 4). In addition to the
desired product, hydrolysis to the dehalogenated arene was
observed. The best result (51% yield) was obtained at 08C
with F-TMP-BF . Variation of the temperature did not
4
improve the fluorination, instead the yield decreased
(
Table 1, entries 5 and 6). Likewise, additives were not
effective (Table 1, entries 7–9).
Next, the influence of various cosolvents was investigated
in more detail. For this purpose the Grignard reagent was
added to a solution of fluorination reagent in various solvents
(
Table 2). Notably, the cosolvent had a significant effect on
Scheme 2. Fluorination of 4-MeOC H MgBr·LiCl using various fluorina-
6
4
tion reagents. Yield of fluorination in designated solvents and yield of
anisole is in parenthesis. Tf=trifluoromethanesulfonyl.
[
a]
Table 2: Fluorination of 4-MeOC H MgBr·LiCl: Variation of solvent.
6
4
[
b]
[b]
Entry
Solvent
Yield of 2 [%]
Anisole [%]
1
2
3
4
5
6
7
8
THF
51
24
35
63
59
30
81
79
19
15
24
19
23
19
17
20
smoothly and provided the corresponding aryl fluorides in
high yield (Table 3, entries 2 and 4).
Et O
2
dioxane
C H CH
3
Notably, unhindered substrates such as 4-methyl- and 4-
fluoro phenyl magnesium bromides are also efficiently
converted into the fluorinated products without increased
hydrolysis (Table 3, entries 3 and 13). What is important from
a synthetic standpoint is that various functional groups such as
methylthio, vinyl, and heteroarenes such as pyridines were
also successfully fluorinated by using these reaction condi-
tions (Table 3, entries 5, 6, 17, and 18). Besides being tolerant
of many functional groups, this reaction accommodated
sterically crowded and electron-rich Grignard reagents that
were efficiently fluorinated in good yield (Table 3, entries 7–
6
5
C H CF
3
6
5
CH Cl2
2
heptane
CH OC F
4 9
3
[
(
a] Reaction conditions: 3 (0.5 mmol), F-TMP-BF (0.75 mmol), solvent
2 mL), 08C, 1.5 h. [b] Determined by GC analysis with hexadecane as the
internal standard; the yield is based on Grignard reagent. THF=tetra-
hydrofuran.
4
1
1). Moderate to good yields of fluorinated arene compounds
the conversion and selectivity of the electrophilic fluorina-
tion. Improved yields of up to 81% and good selectivities
were obtained with heptane or commercially available
methoxyperfluorobutane (CH OC F ) as solvents (Table 2,
entries 7 and 8). To the best of our knowledge such high yields
for selective fluorination of electron-rich arenes have not
been reported before.
were obtained with the electron-deficient Grignard reagents,
which are substrates that react slowly (Table 3, entries 12–16).
In summary, a general and convenient protocol for the
electrophilic fluorination of aryl and heteroaryl Grignard
reagents has been developed. Various aryl fluoride deriva-
tives were synthesized in a straightforward manner in only
two steps from readily available aryl bromides. Notable
features of this novel fluorination procedure are easy
handling and mild reaction conditions.
3
4
9
As shown in Scheme 2, the fluorination reagent also
showed a major influence on the model system. As a result, N-
fluoro-2,4,6-trimethylpyridinium salt is superior to Selectfluor
in both heptane and CH OC F . Interestingly, examination of
3
4 9
various fluoropyridinium salts revealed the importance of the Experimental Section
2
,4,6-trimethylpyridinium motif and showed no influence of
General procedure for the preparation of Grignard reagents with
direct Mg insertion in the presence of LiCl: To a Schlenk tube flushed
with argon was added Mg (5.5 mmol), LiCl (5 mmol), and then THF
the counter ion belonging to the fluorination reagent.
Finally, we were interested in the scope and limitations of
the procedure using different aryl Grignard reagents. As seen
in Table 3, the fluorination of aryl Grignard reagents has
substantial scope. Simple aromatic substrates, such as 2-
methoxy- and 2-methylphenyl magnesium bromides, reacted
(
(
1.5 mL). To the slurry 0.2 mL of a solution of aryl bromide in THF
5 mmol was dissolved in 3.5 mL) was added and stirred vigorously.
The formation of Grignard reagents was initiated in one minute
which was realized by the generation of heat), then remaining aryl
bromide was added slowly by maintaining the same temperature.
(
2
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Angewandte
Chemie
Table 3: Fluorination of ArMgX·LiCl with F-TMP-BF : Scope and limitation.
4
[
a]
[b]
[a]
[b]
Entry
ArMgX·LiCl
Product
Yield [%]
Entry
ArMgX·LiCl
Product
Yield [%]
heptane
CH OC F
heptane
CH OC F
3 4 9
3
4
9
1
2
81
79
10
11
71
79
69
78
73
62
[
c]
3
4
5
6
73
70
61
61
83
80
73
69
12
13
–
57
76
30
66
57
33
48
[
d]
14
15
[
d]
7
68
71
16
40
37
8
9
44
59
48
80
17
18
60
61
78
48
[
a] Grignard reagents were prepared in two ways, Method A: Direct insertion of Mg into the CÀBr bond in the presence of LiCl; Method B: Br/Mg
exchange with iPrMgCl·LiCl. [b] Determined by GC analysis with hexadecane as the internal standard; the yield is based on Grignard reagent.
c] Solvent and product had same retention time. [d] Grignard reagent was prepared by using Method B.
[
After the addition of aryl bromide the reaction mixture was stirred for
Keywords: aryl fluorides · aryl halides · electrophilic fluorination ·
.
1
5–30 min at RT. The quantitative estimation of Grignard was carried
À
Grignard reagents · N F reagents
out by GC analysis with hexadecane as THE internal standard.
General procedure for the preparation of Grignard reagents via
Br/Mg exchange with iPrMgCl·LiCl: To a Schlenk tube flushed with
argon was added iPrMgCl·LiCl (5.5 mmol, 1.3m solution in THF).
Neat aryl bromide (5 mmol) was added in portions over 20–30 min at
[
1] For selected reviews and books, see: a) F. Monnier, M. Taillefer,
Angew. Chem. 2009, 121, 7088 – 7105; Angew. Chem. Int. Ed.
0
8C. The reaction mixture was stirred for 1–3 h. Quantitative
2009, 48, 6954 – 6971; b) I. P. Beletskaya, A. V. Cheprakov,
estimation of formed Grignard reaction was achieved by GC analysis
with hexadecane as the internal standard.
Coord. Chem. Rev. 2004, 248, 2337 – 2364; c) A. R. Muci, S. L.
Buchwald, Top. Curr. Chem. 2002, 219, 131 – 209; d) J. F.
Hartwig, Angew. Chem. 1998, 110, 2154 – 2177; Angew. Chem.
Int. Ed. 1998, 37, 2046 – 2067; e) Metal-Catalyzed Cross-Cou-
pling Reactions, 2nd ed. (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, Weinheim, 2004; f) K. C. Nicolaou, P. G. Bulger, D.
Sarlah, Angew. Chem. 2005, 117, 4516 – 4563; Angew. Chem. Int.
Ed. 2005, 44, 4442 – 4489.
General procedure for the fluorination of Grignard reagents with
NÀF reagent: To a dry Schlenk tube flushed with argon was added the
NÀF reagent (0.75 mmol) followed by the respective solvent (2 mL)
and cooled to 08C (Table 3). A solution of Grignard reagent in THF
(
ꢀ0.5 mmol in 0.5 mL of THF) was added very slowly over 45–50 min
using the syringe pump technique. After the addition, the reaction
mixture was stirred for 45 min at the same temperature and quenched
[
2] For excellent reviews, see: a) W. M. Czaplik, M. Mayer, J.
Cvengros, A. Jacobi von Wangelin, ChemSusChem 2009, 2, 396 –
by addition of saturated aq NH Cl. The yield of fluorinated product
4
was determined by GC analysis of the organic phase with hexadecane
as the internal standard.
4
1
17; b) J. Terao, N. Kambe, Acc. Chem. Res. 2008, 41, 1545 –
554; c) H. Ila, O. Baron, A. J. Wagner, P. Knochel, Chem.
Commun. 2008, 583 – 593; d) B. D. Sherry, A. Fꢀrstner, Acc.
Chem. Res. 2008, 41, 1500 – 1511; e) P. Knochel, W. Dohle, N.
Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis,
Received: October 19, 2009
Published online: December 10, 2009
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2221

Communications
V. A. Vu, Angew. Chem. 2003, 115, 4438 – 4456; Angew. Chem.
Int. Ed. 2003, 42, 4302 – 4320.
3] a) W. M. Czaplik, M. Mayer, A. Jacobi von Wangelin, Angew.
Chem. 2009, 121, 616 – 620; Angew. Chem. Int. Ed. 2009, 48, 607 –
[6] a) Modern Fluoroorganic Chemistry: Synthesis Reactivity, Ap-
plications (Ed.: P. Kirsch), Wiley-VCH, Weinheim, 2004;
b) Fluorine and Health: Molecular Imaging, Biomedical Materi-
als and Pharmaceuticals (Eds.: A. Tressaud, G. Haufe), Elsevier,
Amsterdam, 2008.
[
610; b) T. Hatakeyama, S. Hashimoto, K. Ishizuka, M. Naka-
mura, J. Am. Chem. Soc. 2009, 131, 11949 – 11963; c) O.
Vechorkin, V. Proust, X. Hu, J. Am. Chem. Soc. 2009, 131,
[7] a) G. Gerebtzoff, X. Li-Blatter, H. Fischer, A. Frentzel, A.
Seelig, ChemBioChem 2004, 5, 676 – 684; b) P. Jeschke, Chem-
BioChem 2004, 5, 570 – 589; c) M. E. Phelps, Proc. Natl. Acad.
Sci. USA 2000, 97, 9226 – 9233; d) C. Pesenti, F. Viani, Chem-
BioChem 2004, 5, 590 – 613.
[8] G. Sandford, J. Fluorine Chem. 2007, 128, 90 – 104.
[9] G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60, 1186 –
1190.
[10] a) G. C. Finger, C. W. Kruse, J. Am. Chem. Soc. 1956, 78, 6034 –
6037; b) A. Pleschke, A. Marhold, M. Schneider, A. Kolomeit-
sev, G.-V. Rꢄschenthaler, J. Fluorine Chem. 2004, 125, 1031 –
1038; c) H. Sun, S. G. DiMagno, Angew. Chem. 2006, 118, 2786 –
2791; Angew. Chem. Int. Ed. 2006, 45, 2720 – 2725.
[11] a) T. Furuya, H. M. Kaiser, T. Ritter, Angew. Chem. 2008, 120,
6082 – 6085; Angew. Chem. Int. Ed. 2008, 47, 5993 – 5996; b) T.
Furuya, A. E. Strom, T. Ritter, J. Am. Chem. Soc. 2009, 131,
1662 – 1663; c) A. W. Kaspi, A. Yahav-Levi, I. Goldberg, A.
Vigalok, Inorg. Chem. 2008, 47, 5 – 7; d) D. C. Powers, T. Ritter,
Nat. Chem. 2009, 1, 302 – 309.
9756 – 9766; d) C. E. Hartmann, S. P. Nolan, C. S. J. Cazin,
Organometallics 2009, 28, 2915 – 2919; e) G. Cahiez, O. Gager,
F. Lecomte, Org. Lett. 2008, 10, 5255 – 5256; f) G. Cahiez, V.
Habiak, C. Duplias, A. Moyeux, Angew. Chem. 2007, 119, 4442 –
4444; Angew. Chem. Int. Ed. 2007, 46, 4364 – 4366; g) M. G.
Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J. Nasielski, C. J.
OꢁBrien, C. Valente, Chem. Eur. J. 2007, 13, 150 – 157.
[
4] a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396 –
3399; Angew. Chem. Int. Ed. 2004, 43, 3333 – 3336; b) A. E.
Jensen, W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P.
Knochel, Synthesis 2002, 565 – 569; c) M. Rottlꢂnder, L. Boy-
mond, L. Bꢃrillon, A. LeprÞtre, G. Varchi, S. Avolio, H. Laaziri,
P. Knochel, Chem. Eur. J. 2000, 6, 767 – 770; d) M. Abarbri, F.
Dehmel, P. Knochel, Tetrahedron Lett. 1999, 40, 7449 – 7453;
e) F. Trꢃcourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais, G.
Quꢃguiner, Tetrahedron 2000, 56, 1349 – 1360; f) K. Kitagawa, A.
Inoue, H. Shinokubo, K. Oshima, Angew. Chem. 2000, 112,
2
594 – 2596; Angew. Chem. Int. Ed. 2000, 39, 2481 – 2483; g) F.
Kopp, A. Krasovskiy, P. Knochel, Chem. Commun. 2004, 2288 –
289.
[12] a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc.
2006, 128, 7134 – 7135; b) N. D. Ball, M. S. Sanford, J. Am. Chem.
Soc. 2009, 131, 3796 – 3797; c) X. Wang, T.-S. Mei, J.-Q. Yu, J.
Am. Chem. Soc. 2009, 131, 7520 – 7521.
[13] a) D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢅa-
Fortanet, T. Kinzel, S. L. Buchwald, Science 2009, 325, 1661 –
1664.
2
[
5] For selected recent examples, see: a) A. G. Sergeev, T. Schulz, C.
Torborg, A. Spannenberg, H. Neumann, M. Beller, Angew.
Chem. 2009, 121, 7731 – 7735; Angew. Chem. Int. Ed. 2009, 48,
7
595 – 7599; b) T. Schulz, C. Torborg, S. Enthaler, B. Schꢂffner,
A. Spannenberg, H. Neumann, A. Bꢄrner, M. Beller, Chem. Eur.
J. 2009, 15, 4528 – 4533; c) C. Torborg, J. Huang, T. Schulz, B.
Schꢂffner, A. Zapf, A. Bꢄrner, M. Beller, Chem. Eur. J. 2009, 15,
[14] For earlier studies on the reductive elimination of aryl fluorides
from palladium complexes, see: a) V. V. Grushin, Chem. Eur. J.
2002, 8, 1006 – 1014; b) W. J. Marshall, V. V. Grushin, Organo-
metallics 2004, 23, 3343 – 3347.
[15] These electrophilic fluorination reagents are commercially
available: Selectfluor 2.7 E/mmol (TCI Europe 2009); N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate 2.9 E/mmol
(TCI Europe 2009).
1
329 – 1336; d) T. Schulz, C. Torborg, B. Schꢂffner, J. Huang, A.
Zapf, R. Kadyrov, A. Bꢄrner, M. Beller, Angew. Chem. 2009,
21, 936 – 939; Angew. Chem. Int. Ed. 2009, 48, 918 – 921; e) H.
Neumann, A. Brennfꢀhrer, M. Beller, Adv. Synth. Catal. 2008,
50, 2437 – 2442.
1
3
2
222
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Angew. Chem. Int. Ed. 2010, 49, 2219 –2222