2-(Fluorophenyl)pyridines by the Suzuki-Miyaura method: Ag2O accelerates coupling over undesired ipso substitution (SNAr) of fluorine

Article abstract of DOI:10.1016/S0040-4039(02)02793-4

Problematic ipso substitution was observed in the Suzuki-Miyaura coupling of pentafluorophenylboronic acid to make 2-pentafluorophenylpyridine. Strong bases favored coupling, but under these conditions fluorine in the product tended to undergo nucleophili

Full text of DOI:10.1016/S0040-4039(02)02793-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1503–1506
2
-(Fluorophenyl)pyridines by the Suzuki–Miyaura method:
Ag O accelerates coupling over undesired ipso substitution
2
(SNAr) of fluorine
Jing Chen and Arthur Cammers-Goodwin*
University of Kentucky, Department of Chemistry, Lexington, KY 40506-0055, USA
Received 4 November 2002; revised 9 December 2002; accepted 9 December 2002
Abstract—Problematic ipso substitution was observed in the Suzuki–Miyaura coupling of pentafluorophenylboronic acid to make
2
-pentafluorophenylpyridine. Strong bases favored coupling, but under these conditions fluorine in the product tended to undergo
nucleophilic substitution. Inclusion of Ag O accelerated coupling over ipso substitution. © 2003 Elsevier Science Ltd. All rights
2
reserved.
Recently, we needed to access a variety of 2-arylpyridi-
nes. Two general structural families presented problem-
atic Suzuki–Miyaura coupling reactions: fluorinated
Fluorinated aryl groups at the 2-position on the pyri-
dine ring should be susceptible to ipso substitution
4
1
under most conditions of Suzuki-type aryl coupling
reactions because a nucleophile is usually necessary to
aromatic rings (1 and 2) and a derivative capable of
chelation 3 (Fig. 1). The versatility of Suzuki-type
couplings was manifest in the optimization of the reac-
tion conditions to access these desired pyridine deriva-
tives. The synthesis of 4 succeeded under conditions in
which the synthesis of 3 failed. However, inclusion of
CuI in the recipe to chelate 3 and liberate the Pd
catalyst brought the isolated yield of 3 up to that of 4.
The synthetic details of 3 and 4 have been reported
1
a
induce transmetallation from boron to palladium via
2
elsewhere. This letter focuses on the development of
Suzuki–Miyaura coupling reactions for the construction
of 2-(fluoroaryl)pyridine derivatives 1 and 2 and may
have general significance for Pd-catalyzed aryl cross
coupling in which the products are sensitive to Lewis
basic conditions. The difficulties encountered when try-
ing to couple pentafluorophenyl boronic acid 5 are
exemplified by the failure of 5 to couple to 6 under
conditions favorable for the cross coupling of a variety
of arylboronic acids possessing electron-withdrawing or
3
-
donating groups. Furthermore literature searches for
the reactions of 5 and its 2,5,6-trifluoro analogue
revealed no Suzuki-type couplings. The reactions
reported herein are the first for these readily available
boronic acid derivatives.
Keywords: Suzuki coupling; aryl cross coupling; transmetallation; Pd
catalyst.
Figure 1. 2-Fluoroarylpyridine derivatives via Suzuki cou-
*
Corresponding author. E-mail: acgood1@uky.edu
pling.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02793-4

1
504
J. Chen, A. Cammers-Goodwin / Tetrahedron Letters 44 (2003) 1503–1506
ate complex, 8—a mechanistically related process to
duce 1 and 2. In the current study, Ag O was the key
2
ipso substitution (S Ar, 1 to 9 to 7) (Scheme 1). Even
ingredient that accelerated the overall rate of coupling
over the rate of ipso substitution, allowing the isolation
of compounds 1 (76%) and 2 (32%). The conditions
attempted in the optimization of 1 are summarized in
N
the hindered t-butoxide anion added in this fashion
resulting in the isolation of 7. Nucleophilic aromatic
substitution of F by OtBu might have transformed 5 to
10–13
10 which could have gone on to produce 7. However,
the next section.
the rate of coupling of compound 5 with 2-iodopyridine
to produce 1 and subsequent ipso substitution of 1 to
produce 7 must have been faster than the hypothetical
conversion of 5 to 10 because the concentration of 1
increased as the reaction ran and subsequently dimin-
ished with the appearance of 7. In reality, dynamic
exchange between multiple species related to 5 and 8
was certainly more complex than Scheme 1 indicates
because arylboronic acids accompany arylboronic
anhydrides and triarylboroxine under these conditions.
Experimental
1
13
The H and C NMR spectra were referenced to
residual CHCl3 in the deuterated solvent (7.27 and
19
77.23 ppm, respectively). The F NMR spectra were
referenced to CFCl (0 ppm). The procedures below
used pentafluorophenylboronic acid (CAS 1582-24-7)
and trifluorophenylboronic acid (CAS 182482-25-3)
purchased from Aldrich Chem. Co. without further
purification. All solvents used were dried and distilled.
3
General procedure for coupling reactions
2
2
-2,4,6-Trifluorophenylpyridine (2): The preparation of
-2,4,6-trifluorophenylpyridine is representative. All
operations were performed under a nitrogen atmo-
sphere. An oven-dried, 50 mL flask, fitted with a con-
denser was charged with iodopyridine (0.73 g, 3.56
mmol), Pd(PPh3)4 (0.29 g, 0.25 mmol), and 1,2-
dimethoxyethane (DME, 20 mL). The bright yellow
solution was stirred at room temperature for 20 min.
Sequential addition of 1,3,5-trifluorophenyl boronic
acid (0.72 g, 4.09 mmol), t-BuOK (0.80 g, 7.11 mmol),
Scheme 1. Hypothetical intermediates in the coupling of 5
and 2-iodopyridine. Conceptually, 7 could have come from 8
via 9 or 10. This work indicated that 9 was the intermediate
that led to 7.
t-BuOH (3.6 mL) and Ag O (1.64 g, 7.08 mmol)
2
resulted in a dark solution and the formation of a dark
precipitate. The mixture refluxed under nitrogen at
8
5°C for 17 h. The mixture was cooled, concentrated in
vacuum, and partitioned between EtOAc:H O (1:1, 120
2
Compounds 1 and 2 remained elusive until known
Suzuki-type reaction conditions were surveyed. Study-
ing the chemical literature on Suzuki coupling sug-
gested two possible ways around the undesired ipso
substitution: (1) use fluoride as the nucleophile to
expand the valence of the boron atom or (2) optimize
reagents and reaction conditions to increase the rate of
coupling relative to the rate of ipso substitution. Fluo-
ride-induced Suzuki coupling to yield biaryl products
mL). The layers were separated and the aqueous layer
was washed with two additional 60 mL portions of
EtOAc. The combined organic layers were dried over
MgSO and concentrated in vacuum. Silica gel column
4
chromatography (hexane/EtOAc=90:10) gave 2,4,6-
trifluorophenylpyridine as a light yellow solid that crys-
1
tallized from hexanes (32%); mp 54–56°C; H NMR
(400 MHz, CDCl ): l 8.77 (ddd, J=4.9, 1.8, 1.0 Hz,
3
1H), 7.81 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.47 (dtdd,
J=7.7, ꢀ1.2, ꢀ1.2, ꢀ1.2 Hz, 1H), 7.31 (ddd, J=7.7,
5
,6
has been reported. However, in our hands fluoride
failed to induce Suzuki coupling in the attempted syn-
thesis of 1 and 2. Even though trifluoroborate salts7
have been used to perform Suzuki coupling reactions,
this avenue was not taken for two reasons. Among the
many successful examples, heavily fluorinated aryl rings
were not reported. Furthermore there is much evidence
that the fluorine atoms of aryltrifluoroborate starting
materials exchange with oxygen-atom nucleophiles
13
4.9, 1.2 Hz, 1H), 6.79 (m, 2H); C NMR (100 MHz,
CDCl ): l 162.8 (dt, J=251, 15.2 Hz), 160.9 (ddd,
3
J=252, 15.2, 9.8 Hz), 150.0, 148.9, 136.7, 126.1, 123.3,
19
114.8 (m), 100.89 (m); F NMR (377 MHz, CDCl ): l
3
158.3 (m, 1F), 154.0 (t, J=7.7 Hz, 2F); MS (IE) m/z
209 [M], 190 [M−F]. X-Ray diffraction confirmed con-
nectivity, see supplemental section for structural details.
8
before coupling occurs. Recently silver oxide was
2-Pentafluorophenylpyridine (1): Using 5 in analogous
conditions to those above, 1 is the major product after
30 min. Products 1 and 7 had similar retention times on
reported to induce Suzuki–Miyaura cross coupling of
n-alkylboronic acids presumably by accelerating the
9
B-to-Pd alkyl transfer step of the catalytic cycle. We
SiO under a variety of elution conditions; however, 1
2
reasoned that Ag O might also accelerate B-to-Pd aryl
was efficiently separated from 7 by crystallization from
2
1
transfers crucial to the catalytic cycles that would pro-
hexanes (76%), mp 63–65°C; H NMR (400 MHz,

J. Chen, A. Cammers-Goodwin / Tetrahedron Letters 44 (2003) 1503–1506
1505
Table 1.
CDCl ): l 8.78 (ddd, J=4.9, 1.8, 1.1 Hz, 1H), 7.85
2-2,3,5,6-Tetrafluoro-4-t-Butoxylphenylpyridine
(7):
3
(
1
ddd, J=7.8, 7.8, 1.8 Hz, 1H), 7.49 (dm, J=7.8 Hz,
H), 7.40 (ddd, J=7.8, 4.9, 1.1 Hz, 1H); C NMR (100
Running the reaction above for 24 h. gave 7 as the
1
3
major product that crystallized from hexanes (60%), mp
1
MHz, CDCl ): l 150.4, 147.1, 144.8 (dm, J=250 Hz),
58–60°C; H NMR (400 MHz, CDCl ): l 8.77 (ddd,
3
3
1
1
41.4 (dm, J=255 Hz), 138.0 (dm, J=252 Hz), 136.9,
26.1, 124.0, 115.6 (m); F NMR (377 MHz, CDCl3):
J=5.0, 1.8, 1.0 Hz, 1H), 7.83 (ddd, J=7.8, 7.8, 1.8 Hz,
1H), 7.51 (dm, J=7.8 Hz, 1H), 7.37 (ddd, J=7.8, 5.0,
1.0 Hz, 1H), 1.45 (s, 9H); C NMR (100 MHz,
1
9
13
l 122.2 (m, 2F), 111.6 (t, J=21.4 Hz, 1F), 103.6 (m,
2
F); MS (IE) m/z 245 [M], 226 [M−F]. X-Ray diffrac-
CDCl ): l 150.3, 148.1, 144.8 (dm, J=249 Hz), 143.9
3
tion confirmed connectivity, see supplemental section
for structural details.
(dm, J=245 Hz), 136.8, 134.7 (m), 126.2, 123.7, 115.3
19
(m), 85.6, 28.6; F NMR (377 MHz, CDCl ): l 119.7
3

1
506
J. Chen, A. Cammers-Goodwin / Tetrahedron Letters 44 (2003) 1503–1506
(
m, 2F), 113.9 (m, 2F); MS (IE) m/z 299 [M], 284
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. This reaction has been extensively reviewed. See: (a)
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The authors thank the NSF (0111578) for financial
support.