A new and practical grignard-coupling-fluorination sequence: Synthesis of 2-aryl fluoroarenes

Article abstract of DOI:10.1002/asia.201000288

A new strategy for the synthesis of 2-aryl-and 2-heteroaryl fluoroarenes has been developed. An intermolecular domino Grignard-coupling-fluorination sequence affords a range of 2-fluorobiaryls from aryl bromides under mild conditions. This methodology can be further extended to the synthesis of 2′-aryl-2-fluorobiphenyls.

Full text of DOI:10.1002/asia.201000288

DOI: 10.1002/asia.201000288
A New and Practical Grignard-Coupling–Fluorination Sequence: Synthesis of
2-Aryl Fluoroarenes
Pazhamalai Anbarasan, Helfried Neumann, and Matthias Beller*[a]
The introduction of fluorine atoms into therapeutically
important molecules increases the bioavailability, solubility,
and metabolic stability compared with their non-fluorinated
analogues.[1–2] As a result, numerous efforts have been di-
rected to the efficient fluorination of organic molecules in
recent years. In particular, aryl fluorides attracted significant
attention because of their presence in a number of pharma-
ceuticals and agrochemicals. Among the different aryl fluo-
rides, 2-fluorobiaryls constitute an interesting sub-class,
which is found in current drugs, such as Flurbiprofen and
Diflunisal (Scheme 1).
Traditionally known aromatic fluorination methods, such as
the direct fluorination of arenes,[3] the Balz–Schiemann reac-
tion of aryldiazonium salts with HBF4,[4] and Halex ex-
change reactions of activated aryl halides with metal fluo-
rides[5] require harsh reaction conditions and/or toxic re-
agents.
More recently, palladium-catalyzed fluorination of specific
[6]
À
substrates by C H activation as well as fluorination of aryl
boronic acids employing stoichiometric amounts of palladi-
um[7] and silver salts[8] have been accomplished with the aid
of electrophilic fluorination reagents, such as N-fluoropyridi-
nium salts and Selectfluor. Similarly, silver-mediated electro-
philic fluorinations of aryl stannanes were described.[9] How-
ever, the use of stoichiometric amounts of expensive metals
is a drawback of these strategies. In this respect, the recent
palladium-catalyzed fluorination of aryl triflates with AgF/
CsF is remarkable.[10]
On the other hand, electrophilic fluorination of easily ac-
cessible aryl nucleophiles, such as aryl lithium and aryl
Grignard reagents, have been scarcely studied before.[11–13]
Most recently, Knochel and co-workers as well as our group
have independently developed a general methodology for
the electrophilic fluorination of aryl and heteroaryl
Grignard reagents using NFSI (N-fluorobenzenesulfoni-
mide) and N-fluoropyridinium salts, respectively.[14] Based
on these results, herein we describe the first synthesis of 2-
fluorobiaryls starting from simple aryl bromides.
Scheme 1. Selected examples of 2-fluorobiaryl-containing pharmaceuti-
cals.
No convenient and general synthesis for this class of com-
pounds has so far been reported. Clearly, modern palladi-
um-catalyzed coupling reactions can be used for this trans-
formation; however, substrates such as 2-fluorobromoben-
zenes and 2-chlorofluorobenzenes often react sluggishly.
As 2-bromobiaryls are not readily available, we envi-
sioned a synthesis of 2-fluorobiaryls through an intermolecu-
lar domino reaction,[15–16] starting from aryl bromides and
1,2-dihaloarenes. Formation of the corresponding Grignard
reagent, followed by coupling with an in-situ-generated ben-
zyne[17] and subsequent electrophilic fluorination was ex-
pected to yield the desired 2-fluorobiaryl products
(Scheme 2). To the best of our knowledge, such a strategy
has not been applied for this class of compounds.
At the start of our investigation, we studied the electro-
philic fluorination of 4; thus, 4-bromotoluene 1 was convert-
ed into Grignard reagent 2 as described by Knochel and co-
workers.[18] Unfortunately, reaction of 2 with magnesium and
[a] Dr. P. Anbarasan, Dr. H. Neumann, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000288.
Chem. Asian J. 2010, 5, 1775 – 1778
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1775

COMMUNICATION
After having found suitable reaction conditions for this in-
termolecular fluorination sequence, we explored the sub-
strate scope in more detail. Inexpensive aryl bromides, such
as para-tolyl and para-anisyl bromides, are readily converted
into their corresponding 2-fluorobiaryls in 73% and 59%
yield, respectively (Table 2, entries 1 and 2).
Scheme 2. Approach to the synthesis of 2-fluorobiaryls.
Table 2. Domino Grignard-coupling–fluorination: Synthesis of 2-(hetero-
aryl)arylfluorobenzenes.[a]
1-bromo-2-chlorobenzene 3 at 608C,[17] followed by direct
fluorination of the resultant Grignard 4 gave a mixture of
products, which was difficult to purify. As shown in Table 1,
fluorination of 4 with N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate in tetrahydrofuran at 08C afforded the re-
duced product 5a, the brominated product 5b, and the ex-
pected fluorinated product 2-fluoro-4’-methylbiphenyl 5c.[19]
The ratio of these three products was found to be 5a/5b/
5c=1:3:6 (Table 1, entry 1).[20]
Entry
1
Aryl bromide
Product
Yield [%][b]
73
Table 1. Domino Grignard-coupling–fluorination: Variation of solvents
and fluorination reagents.[a]
2
59
3
4
61
67
Source of F+
Solvent
Ratio of
Yield [%][c]
5
6
7
8
56
63
88
68
Entry
5a/5b/5c[b]
1
2
3
THF
heptane
CH3OC4F9
1:3:6
1:0:15
1:0:16
66
73
71
6
4
5
7
8
heptane
heptane
6:3:1
1:5:6
61
65
6
9
heptane
28:1:5
59
À
[a] Reaction conditions: Grignard reagent (0.5 mmol), N F reagent
(0.75 mmol), solvent (2 mL), 08C, 2 h. Grignard reagent was added
slowly over 1 h; [b] Ratio of the products was estimated by 1H NMR
analysis; [c] Combined yield of the isolated mixture of 5a, 5b, and 5c.
THF=tetrahydrofuran.
9
54
49
10
To improve the selectivity, we varied both solvent and flu-
orination reagent. Heptane and methoxyperfluorobutane
(CH3OC4F9) as solvents gave improved product ratios of
1:0:15 and 1:0:16, respectively (Table 1, entries 2 and 3).
[a] All reaction were carried out with 1.2 equiv of aryl bromide, 1 equiv
of 3, and 1.5 equiv of 6. [b] Combined yield of the isolated mixture of flu-
orinated and reduced product in a ca. 15:1 ratio.
À
However, fluorination with other N F reagents, such as Se-
Reaction with mesityl bromide, a more hindered sub-
strate, provided 2-fluorophenyl mesitylene in excellent yield
(Table 2, entry 7). Similarly, less hindered (ortho-tolyl and 1-
naphthyl) and non-hindered (3-xylyl) aryl bromides were
also transformed into the desired products in good yield
lectfluor 7, NFSI 8, and N-fluoropyridinium tetrafluorobo-
rate 9 were not as effective as N-fluoro-2,4,6-trimethylpyri-
dinium tetrafluoroborate 6, yielding 5a and 5b as the major
products (Table 1, entries 4–6).[21]
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Coupling Reactions
(Table 2, entries 3, 6, and 8). Moreover, electron-rich 2-fluo-
robiaryl compounds were obtained in moderate to good
yield (Table 2, entries 4, 5, and 9). Finally, a heteroaryl bro-
mide (3-bromobenzothiophene) was also an effective sub-
strate for this domino reaction, producing 2-fluorophenyl-3-
benzothiophene in moderate yield (Table 2, entry 10).
into their corresponding 2-fluorobiaryls in good yield
(Table 3, entries 3–5).
During our studies on the model reaction, we observed
the formation of 11 in small quantities (8–10%). It appears
that 4-tolylmagnesium bromide 2 reacts with two equiva-
lents of benzyne, followed by fluorination (Scheme 3). To
Next, to expand the scope of the aryne, various 1,2-diha-
loarenes were examined. Therefore, para-tolylmagnesium
bromide was coupled with different 1,2-dihaloarenes and
the resultant Grignard reagent was fluorinated with 6 to
obtain diverse 2-fluorobiaryls. 1-Bromo-2-fluorobenzene, a
complementary dihaloarene to 1-bromo-2-chlorobenzene 3,
smoothly afforded the 2-fluorobiaryl in good yield (Table 3,
Table 3. Domino Grignard-coupling–fluorination: Synthesis of 2-(para-
tolyl)fluoroarenes.[a]
Scheme 3. Domino Grignard-double-coupling–fluorination sequence for
the synthesis of 2-(4-methylbiphenyl)-fluorobenzene.
obtain 11 as the predominant product, we simply increased
the amount of 1-bromo-2-chlorobenzene 3 to two equiva-
lents and obtained 11 in 61% yield. Obviously, other aryl
Grignard reagents could be also used for this domino
Grignard-double coupling–fluorination reaction.
Entry
1
1,2-Dihaloarene
Product
Yield [%][b]
78[c]
In conclusion, the synthesis of 2-(heteroaryl)aryl-fluoroar-
enes was accomplished using a novel domino Grignard-cou-
pling–fluorination sequence. This reaction utilizes simple
Grignard reagents as effective nucleophiles and as a cou-
pling partner.
2
3
4
5
52
65
59
64
Experimental Section
Synthesis of 2-arylfluoroarenes: In the glove box, a 25 mL Schlenk tube
flushed with argon was charged with LiCl (2.2 mmol), a magnetic stir
bar, and sealed with a septum. Mg (2.5 mmol) and 0.5 mL of THF were
added under argon. To this slurry, 0.2 mL of a solution of aryl bromide in
THF (2 mmol was dissolved in 1.5 mL) was added and stirred vigorously.
The formation of Grignard reagents began very rapidly (1 minute; realiz-
ed by the generation of heat), then the remaining aryl bromide was
added slowly by maintaining the temperature around RT. After the addi-
tion of aryl bromide, the reaction mixture was stirred for 15–30 min at
RT. GC analysis with hexadecane as the internal standard revealed the
formation of Grignard reagent in 90–95% yield. Another 25 mL Schlenk
tube flushed with argon was charged with Mg (2.2 mmol), a magnetic stir
bar, and sealed with a septum, followed by THF (1 mL) and ArMgBr·-
LiCl (2.2 mmol, prepared as mentioned above) at room temperature. To
the slurry, 0.1 mL of a solution of 1-bromo-2-chlorobenzene in THF
(2 mmol dissolved in 1 mL) was added and the solution was stirred vigo-
rously at room temperature. After the formation of the Grignard reagent
was initiated, the reaction mixture was kept at 608C and the remaining
aryl bromide was added slowly over 30 min. After the addition of aryl
bromide, the reaction mixture was stirred for 1 h at the same temperature
and was used for the subsequent fluorination step. To the another dry
10 mL Schlenk tube flushed with argon was added N-fluoro-2,4,6-trime-
thylpyridinium tetrafluoroborate (1.5 mmol), and a magnetic stir bar.
After sealing the Schlenk tube with a septum, heptane (4 mL) was added
and the mixture was cooled to 08C. A solution of Grignard reagent in
THF (ca. 1 mmol, prepared as mentioned above) was added slowly over
[a] All reaction were carried out with 1.2 equiv of 4-bromotoluene,
1 equiv of 1,2-dihaloarene, and 1.5 equiv of 6. [b] Combined yield of the
isolated mixture of fluorinated and reduced product in a ca. 15:1 ratio.
[c] 608C.
entry 1). Reaction with the substituted aryne that was gener-
ated from 4,5-dibromo-ortho-xylene underwent efficient
coupling, followed by fluorination with 6 (Table 3, entry 2).
Additionally, an electron rich aryne (generated from 4,5-di-
bromoveratrole and 4,5-(methylenedioxy)-1,2-dibromoben-
zene) as well as an electron poor aryne (generated from 1,2-
dibromo-4,5-difluorobenzene) were also readily converted
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1777

M. Beller et al.
COMMUNICATION
1.5 h using a syringe pump. After the addition, the reaction mixture was
stirred for 1 h at same temperature before being quenched by addition of
saturated aqueous NH4Cl and extracted with diethyl ether. Evaporation
of the solvent, followed by column chromatography of the crude product
using pentane/diethyl ether as eluent yielded the corresponding 2-(heter-
oaryl)arylfluorobenzene.
c) R. E. Banks, R. A. Du Boisson, E. Tsiliopoulos, J. Fluorine Chem.
1986, 32, 461–466; d) R. E. Banks, I. Sharif, J. Fluorine Chem. 1991,
55, 207–214; e) F. A. Davis, W. Han, Tetrahedron Lett. 1991, 32,
1631–1634; f) G. S. Lal, J. Org. Chem. 1993, 58, 2791–2796.
[12] For electrophilic fluorination of selected aryl trifluoroborates and
boronic acids, see: C. Cazorla, E. Mꢄtay, B. Andrioletti, M. Lemaire,
Tetrahedron Lett. 2009, 50, 3936–3938.
[13] For electrophilic fluorination of electron-rich arenes, see: a) G.
Stavber, M. Zupan, S. Stavber, Tetrahedron Lett. 2007, 48, 2671–
2673; b) K. K. Laali, G. I. Borodkin, J. Chem. Soc. Perkin Trans. 2
2002, 953–957; c) T. B. Patrick, D. L. Darling, J. Org. Chem. 1986,
51, 3242–3244.
[14] a) P. Anbarasan, H. Neumann, M. Beller, Angew. Chem. 2010, 122,
2265-2268; Angew. Chem. Int. Ed. 2010, 49, 2219–2222; b) S.
Yamada, A. Gavryushin, P. Knochel, Angew. Chem. 2010, 122, 2261-
2264; Angew. Chem. Int. Ed. 2010, 49, 2215–2218; c) for a related
cyanation reaction, see: P. Anbarasan, H. Neumann, M. Beller,
Chem. Eur. J. 2010, 16, 4725–4728.
Acknowledgements
This work has been funded by the Alexander-von-Humboldt-Stiftung, the
State of Mecklenburg-Western Pomerania, the BMBF, and the DFG
(Leibniz Prize). We thank Mrs. S. Leiminger, Drs. W. Baumann, C.
Fisher, and Mrs. S. Buchholz (all LIKAT) for analytical support.
Keywords: arylfluorides
· arynes · domino reactions ·
fluorination · Grignard reaction
[15] Domino Reactions in Organic Synthesis (Eds.: L. F. Tietze, G. Bra-
sche, K. Gericke), Wiley-VCH, Weinheim, 2006.
[16] For the use of Grignard reagents in domino reactions, see: a) P. He,
C.-G. Dong, Q.-S. Hu, Tetrahedron Lett. 2008, 49, 1906–1909; b) Q.-
S. Hu, Synlett 2007, 1331–1345 and references cited therein; c) C.-G.
Dong, P. Yeung, Q.-S. Hu, Org. Lett. 2007, 9, 363–366; d) F. Grelle-
pois, V. M. Timoshenko, Y. G. Shermolovich, C. Portella, Org. Lett.
2006, 8, 4323–4326; e) S. M. Sheehan, G. Lalic, J. S. Chen. M. D.
Shair, Angew. Chem. 2000, 112, 2826–2827; Angew. Chem. Int. Ed.
2000, 39, 2714–2715.
[1] a) Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applica-
tions (Ed.: P. Kirsch), Wiley-VCH, Weinheim, 2004; b) Fluorine and
Health: Molecular Imaging, Biomedical Materials and Pharmaceuti-
cals (Eds.: A. Tressaud, G. Haufe), Elsevier, Amsterdam, 2008;
c) Fluorinated Heterocyclic Compounds: Synthesis Chemistry and
Applications (Ed.: V. A. Petrov), John-Wiley, Hoboken, 2009.
[2] a) G. Gerebtzoff, X. Li-Blatter, H. Fischer, A. Frentzel, A. Seelig,
ChemBioChem 2004, 5, 676–684; b) P. Jeschke, ChemBioChem
2004, 5, 570–589; c) M. E. Phelps, Proc. Natl. Acad. Sci. USA 2000,
97, 9226–9233; d) C. Pesenti, F. Viani, ChemBioChem 2004, 5, 590–
613.
[17] a) C. H. Burgos, T. E. Barder, X. Huang, S. L. Buchwald, Angew.
Chem. 2006, 118, 4427–4432; Angew. Chem. Int. Ed. 2006, 45, 4321–
4326; b) C. C. Mauger, G. A. Mignani, Org. Process Res. Dev. 2004,
8, 1065–1071; c) S. Kaye, J. M. Fox, F. A. Hicks, S. L. Buchwald,
Adv. Synth. Catal. 2001, 343, 789–794; d) H. Tomori, J. M. Fox, S. L.
Buchwald, J. Org. Chem. 2000, 65, 5334–5341 and reference cited
therein; e) R. Huisgen, J. Sauer, Angew. Chem. 1960, 72, 91–108.
[18] a) F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryush-
in, P. Knochel, Chem. Eur. J. 2009, 15, 7192–7202; b) L. Shi, Y. Chu,
P. Knochel, H. Mayr, Angew. Chem. 2008, 120, 208–210; Angew.
Chem. Int. Ed. 2008, 47, 202–204; c) A. Krasovskiy, B. F. Straub, P.
Knochel, Angew. Chem. 2006, 118, 165–169; Angew. Chem. Int. Ed.
2006, 45, 159–162; d) A. Krasovskiy, P. Knochel, Angew. Chem.
2004, 116, 3396–3399; Angew. Chem. Int. Ed. 2004, 43, 3333–3336.
[19] Products 5a and 5b were expected to be formed from a radical pro-
cess: a) P. T. Nyffeler, S. G. Duron, M. D. Burkart, S. P. Vincent, C.-
H. Wong, Angew. Chem. 2005, 117, 196–217; Angew. Chem. Int. Ed.
2005, 44, 192–212 and references cited therein; b) E. Differring, M.
Wehrli, Tetrahedron Lett. 1991, 32, 3819–3822.
[3] G. Sandford, J. Fluorine Chem. 2007, 128, 90–104.
[4] G. Balz, G. Schiemann, Ber. Dtsch. Chem. Ges. 1927, 60, 1186–1190.
[5] a) H. Sun, S. G. DiMagno, Angew. Chem. 2006, 118, 2786–2791;
Angew. Chem. Int. Ed. 2006, 45, 2720–2725; b) A. Pleschke, A. Mar-
hold, M. Schneider, A. Kolomeitsev, G.-V. Rçschenthaler, J. Fluo-
rine Chem. 2004, 125, 1031–1038; c) G. C. Finger, C. W. Kruse, J.
Am. Chem. Soc. 1956, 78, 6034–6037.
[6] a) X. Wang, T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 7520–
7521; b) N. D. Ball, M. S. Sanford, J. Am. Chem. Soc. 2009, 131,
3796–3797; c) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem.
Soc. 2006, 128, 7134–7135.
[7] 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, T. Ritter, J. Am. Chem. Soc. 2008, 130, 10060–10061.
[8] T. Furuya, T. Ritter, Org. Lett. 2009, 11, 2860–2863.
[9] T. Furuya, A. E. Strom, T. Ritter, J. Am. Chem. Soc. 2009, 131,
1662–1663.
[20] Ratio of products was determined by 1H NMR with respect to the
methyl protons.
[21] Formation of the reduced product as the major product can be ac-
[10] D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢃa-Fortanet,
T. Kinzel, S. L. Buchwald, Science 2009, 325, 1661–1664.
[11] For preliminary investigations on the electrophilic fluorination of
phenylmagnesium bromide/chloride and phenyl lithium, see:
a) W. E. Barnette, J. Am. Chem. Soc. 1984, 106, 452–454; b) F. A.
Davis, W. Han, C. K. Murphy, J. Org. Chem. 1995, 60, 4730–4737;
counted for by a radical process as well as the presence of acidic
À
protons (ortho C H proton on pyridinium ring). T. Umemoto, G.
Tomizawa, J. Org. Chem. 1989, 54, 1726–1731.
Received: April 21, 2010
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Chem. Asian J. 2010, 5, 1775 – 1778