Convenient electrophilic fluorination of functionalized aryl and heteroaryl magnesium reagents

Article abstract of DOI:10.1002/anie.200905052

"Chemical Equation Presented" Cive me an "F": Electrophilic fluorination of various aromatic and heteroaromatic Grignard reagents is smoothly performed with (PhSO₂)₂NF as fluorinating agent in a 4:1 mixture of CH₂Cl₂/ perfluorodecalin (see scheme). This solvent system allows minimization of most side reactions.

Full text of DOI:10.1002/anie.200905052

Angewandte
Chemie
DOI: 10.1002/anie.200905052
Electrophilic Fluorination
Convenient Electrophilic Fluorination of Functionalized Aryl and
Heteroaryl Magnesium Reagents**
Shigeyuki Yamada, Andrei Gavryushin, and Paul Knochel*
Dedicated to Professor Hiroki Yamanaka on the occasion of his 70th birthday
Fluorine-substituted aromatic and heterocyclic compounds
are important target molecules due their useful physical and
biological properties.[1] Fluorinated arenes and especially
heteroarenes are prepared mostly starting from precursors
already bearing fluorine substituents[2] or in the case of
heterocycles from acyclic precursors.[3] Methods of direct
fluorination of aromatic compounds, for example using
electrolysis,[4] are usually not highly selective, and nucleo-
philic substitution of an aromatic halogen by fluorine is
mostly limited to electron-poor aromatics.[5] However, very
recently, Buchwald and co-workers[6] reported a general Pd-
catalyzed conversion of aryl triflates into fluorides. In the field
of electrophilic fluorination, major progress has been made by
Ritter and co-workers, who have reported a fluorination of
boronic acids[7] and stannanes[8] using palladium or silver
catalysis. Olah and co-workers[9] and very recently the
Lemaire group[10] published a direct conversion of electron-
rich arylboronic acids and aryl trifluoroborates into fluoroar-
enes. Sanford and co-workers[11] described an electrophilic
Scheme 1. One-pot method for converting aryl or heteroaryl bromides into the
corresponding fluorides by Hal–Mg exchange and electrophilic fluorination of
organomagnesium reagents with NFSI.
(3) using a Br–Mg or I–Mg exchange and a subsequent new
convenient electrophilic fluorination procedure (Scheme 1).
After the screening of commercially available fluorinating
reagents, we found that N-fluorobenzenesulfonimide (NFSI)
is the most suitable reagent for the fluorination of organo-
magnesium compounds.[15] 3,5-Dibromopyridine (1a) was
used as a test substrate for the one-pot Br–Mg exchange-
fluorination sequence optimization. Its treatment with
iPrMgCl·LiCl (THF, 08C, 1 h) afforded the corresponding
Grignard reagent 2a. However, the reaction with NFSI in
THF led to 3-bromo-5-fluoropyridine (3a) in only 19% yield,
as determined by GC. Altering the relative amounts of
reagents and the reaction temperature did not lead to a
significant improvement. However, the substitution of THF
by other solvents dramatically influenced the reaction out-
come (Table 1). Of various ethereal solvents tested, only
diethyl ether gave satisfactory results (Table 1, entries 1–4).
Because of solubility problems, further solvents were tested.
Halogenated solvents proved to give the best results. While
PhCF3 led to a very low yield, both CH2Cl2 and 1,2-dichloro-
ethane gave improved yields (60–68%; Table 1, entries 5, 6,
À
fluorination by palladium-mediated C H activation. How-
ever, a general method for a direct conversion of organome-
tallic reagents into the corresponding fluoroarenes is still
highly desirable. Readily available bromo- or iodoarenes and
heteroarenes of type 1 (Scheme 1) are attractive starting
materials for the preparation of the corresponding fluorine
analogues. Recently, we have developed general methods for
preparing functionalized unsaturated Grignard reagents
either using a halogen–magnesium exchange reaction[12] or
by a direct insertion of Mg in the presence of LiCl.[13] The
electrophilic fluorination of aryl magnesium compounds has
been reported for simple Grignard reagents; however, it
proceeds with moderate to poor yields.[14] Herein, we report
an efficient conversion of aryl and heteroaryl Grignard
reagents of type 2 into the corresponding fluorinated products
Table 1: Solvent optimization of the fluorination with NFSI.
[*] Dr. S. Yamada, Dr. A. Gavryushin, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen
Department Chemie & Biochemie
Entry
Solvent
Yield of 3a [%][a]
1
2
3
4
5
6
7
8
THF
19
54
<10
28
<10
60
68
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Et2O
DME[b]
1,4-dioxane
PhCF3
ClCH2CH2Cl
CH2Cl2
CH2Cl2/perfluorodecalin (4:1)
[**] S.Y. thanks the Humboldt Foundation for financial support. We
thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank
Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen) for the
generous gift of chemicals.
92
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905052.
[a] Yield of hydrolyzed reaction aliquots as determined by GC using an
internal standard. [b] DME=dimethoxyethane.
Angew. Chem. Int. Ed. 2010, 49, 2215 –2218
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and 7). Unfortunately, the Grignard reagent (2a) undergoes a
1b, 1c, 1d, 1 f (entries 1–3 and 5 of Table 2) and electron-poor
bromoarenes 1h, 1i, 1k (entries 7, 8, and 10) can be readily
converted into the corresponding fluorides of type 3 using this
new protocol. Highly sterically hindered substrates such as
2,4,6-trimethylphenylmagnesium bromide (2b) or even 2,4,6-
triisopropylphenylmagnesium bromide (2d; Table 2, entries 1
and 3) react especially smoothly and afford the best yields of
the fluorinated products. Functional groups like an ester
(Table 2, entry 2) or an amide (entry 4) are well-tolerated.
Noticeably, o-fluoro-N,N-dimethylaniline (3 f), prone to rad-
ical oxidation, was obtained in 64% yield (Table 2, entry 5).
Also, halogenated aryl bromides 1g–k were converted into
the corresponding Grignard reagents using iPrMgCl·LiCl in
THF and led to the fluorinated products (3g–k) in 34–55%
yield of isolated product (Table 2, entries 6–10).
fast decomposition in 1,2-dichloroethane, precluding the use
of this solvent. Dichloromethane was found to be the solvent
of choice, as it leads to almost homogeneous reaction
mixtures and provides the best reaction yields. The only
side reaction in the fluorination step is the formation of
protonated product.
The electrophilic fluorination[16] of Grignard reagents is
believed to proceed by a nucleophilic substitution on the
fluorine atom of NFSI (SN2 mechanism), which competes with
a single electron transfer, leading to radical intermediates
(Scheme 2).[17] Thus, the formation of the protonated arene as
a side product can be attributed to the formation of a radical
intermediate, which abstracts a hydrogen atom from the
solvent.
An especially interesting and challenging problem is the
synthesis of fluorinated heterocycles. Such compounds are
quite important for modern medicinal and materials chemis-
try.[18] Our new procedure allows the preparation of various
fluorinated derivatives of most important classes of hetero-
cycles. Halogenated pyridines (1a, 1l, 1m), an isoquinoline
(1n), a pyrrole (1o), a benzo[b]thiophene (1p), thiophenes
(1q and 1r), and furan (1s) afford satisfactory yields of the
corresponding fluorinated derivatives by this simple one-pot
procedure (Table 3).
Scheme 2. Reaction pathways of unsaturated magnesium reagents
with NFSI.
Thus, the substituted pyridines (1a, 1l, 1m) are readily
converted to the corresponding magnesium reagents of type 2
We presumed that the introduction of a
Table 2: Preparation of fluoroarenes by the reaction of Grignard reagents with NFSI in 4:1
fluorinated cosolvent may improve the
reaction outcome, since the formed aryl
radical may be able to abstract a fluorine
atom from this cosolvent. Indeed, addition
of hexafluorobenzene (20 vol%) increased
the yield of 3a from 68% to 84%. After the
screening of various fluorinated additives,
we found that perfluorodecalin gives the
best results, leading to the minimum
amount of the side product (arene). In a
4:1 mixture of CH2Cl2/perfluorodecalin, 3-
bromo-5-fluoropyridine (3a) was obtained
in 92% yield (determined by GC; Table 1,
entry 8).
CH2Cl2/perfluorodecalin.
Entry
Grignard reagent
Method of mag-
nesiation[a]
Product
Yield [%][b]
1
2
2b B, 258C, 15 h
2c B, 258C, 15 h
3b 74 (91)
3c 91[c]
3
2d B, 258C, 15 h
3d 90
Using the new fluorination protocol, we
have prepared, starting from aryl bromides
(1b–k) and heteroaryl bromides and
iodides (1a, 1l–s), various fluorinated
arenes and heteroarenes (Table 2 and
Table 3). The Grignard reagents were
obtained either a by Br–Mg exchange
reaction (method A)[12a] or by the direct
insertion of Mg into an aromatic bromide in
the presence of LiCl (method B).[13] The
solvent was then removed in vacuo and
replaced by a 4:1 CH2Cl2/perfluorodecalin
mixture. Addition of NFSI and reaction for
2 h at room temperature gave the corre-
sponding aryl fluorides of type 3 in satis-
factory yields. Electron-rich bromoarenes
4
5
2e B, 258C, 2 h
2 f B, 258C, 15 h
3e 94[c]
3 f 64
6
2g A, 258C, 1 h
3g 55
7
8
2h A, 08C, 1 h
3h 53
2i A, 08C, 0.5 h
3i 52 (88)
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Chemie
Table 2: (Continued)
reagents are converted to the fluorinated
5-membered heterocycles 3o–s in 43–60%
yield of isolated product.
Entry
Grignard reagent
Method of mag-
nesiation[a]
Product
Yield [%][b]
In summary, we developed a simple,
convenient, and highly versatile one-pot
method for converting aromatic and heter-
oaromatic bromides or iodides into the
corresponding fluorides by choosing an
optimized solvent mixture (4:1 CH2Cl2/
perfluorodecalin). This procedure allows a
direct access to fluorinated pyridines, thio-
phenes, pyrroles and isoquinolines as well
as to sterically congested fluorine-substi-
tuted benzenes, which are otherwise diffi-
cult to prepare. Further investiga-
9
2j A, 258C, 1 h
2k A, 258C, 1 h
3j (66)
10
3k 34 (62)
[a] Method A: Br/Mg exchange using iPrMgCl·LiCl. Method B: Mg insertion in the presence of
LiCl. [b] Yields of isolated products more than 95% pure as determined by NMR spectroscopy.
Yields in parentheses are determined by GC (comparison with an authentic sample). [c] The
remaining starting material (1) was removed by performing a Negishi cross-coupling with 4-
methoxyphenylzinc bromide on the reaction mixture.
Table 3: Fluorine-substituted heterocyclic products of type 3 obtained by electrophilic fluorination using
NFSI.
tions of this potentially practical
synthetic method are currently
underway.
Entry
Grignard reagent
Method of magnesia-
tion[a]
Product
Yield [%][b]
1
2
3
2a A, 08C, 1 h
3a 58 (92)
Experimental Section
Typical procedure (synthesis of 3a): A
50 mL Schlenk flask under N2 was
charged with 3,5-dibromopyridine (1a,
1.21 g, 5 mmol) in THF (5.0 mL).
iPrMgCl·LiCl (5.5 mmol) in THF
(1.16m, 4.7 mL) was added at 08C and
the mixture was stirred at this temper-
ature for 1 h. Then the solvent was
removed in vacuo (0.5 mbar, 408C,
0.5 h). CH2Cl2 (5 mL) was added, and
NFSI (1.95 g, 6 mmol) in CH2Cl2
(15 mL) and perfluorodecalin (5 mL)
was slowly added at À788C. The reac-
tion mixture was stirred at 08C for
30 min, then at 258C for 2 h, and was
poured into ice-cooled saturated aque-
ous NH4Cl (50 mL). After extraction
with CH2Cl2 (3 ꢀ 50 mL), the organic
layers were dried (Na2SO4), filtered,
and concentrated in vacuo. The crude
residue was purified by column chro-
matography (SiO2) using pentane/Et2O
(20:1) as an eluent, affording 3a
(574 mg, 58% yield). The analytical
data for 3a are in accordance with
those of the commercially available
compound.
2l A, 08C, 1 h
2m A, 258C, 1 h
3l 75[c] (97)
3m 65
4
2n A, 08C, 1 h
3n 63
5
6
2o B, 258C, 24 h
2p B, 258C, 15 h
3o 43[d]
3p 60[d]
7
8
9
2q A, 258C, 1 h
2r A, 258C, 1 h
2s A, 258C, 1 h
3q 57[e]
3r 56
3s 49
[a] Method A: Br/Mg exchange using iPrMgCl·LiCl. Method B: Mg insertion in the presence of LiCl.
[b] Yields of isolated products more than 95% pure as determined by NMR spectroscopy. Yields in
parentheses are determined by GC (comparison with an authentic sample). [c] 2.4 equiv NFSI was used.
[d] The remaining starting material (1) was removed by performing a Negishi cross-coupling with 4-
methoxyphenylzinc bromide on the reaction mixture. [e] PhOCF3 was used as a cosolvent instead of
perfluorodecalin.
Received: September 9, 2009
Revised: November 3, 2009
Published online: February 16, 2010
by a Br–Mg exchange.[12] After the replacement of THF by a
4:1 mixture of CH2Cl2/perfluorodecalin and treatment with
NFSI (1.2 equiv), the expected fluorinated pyridines 3a, 3l
and 3m are obtained in 58–75% yields (Table 3, entries 1–3).
Interestingly, the magnesiated isoquinoline (2n) obtained by
I–Mg exchange is smoothly fluorinated, leading to 1-fluoro-
isoquinoline (3n) in 63% yield of isolated product (Table 3,
entry 4). Sensitive electron-rich pyrroles, thiophenes, and
furans are readily magnesiated either by direct Mg inser-
tion[13] (leading to 2o, 2p) or Br–Mg exchange[12] (leading to
2q–s). Using the same procedure, those heterocyclic Grignard
Keywords: arenes · electrophilic substitution · fluorination ·
Grignard reaction · nitrogen heterocycles
.
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