Polyhalogenoheterocyclic compounds. Part 54: [1] Suzuki reactions of 2,4,6-tribromo-3,5-difluoropyridine

Article abstract of DOI:10.1016/j.jfluchem.2007.02.012

Palladium catalysed Suzuki cross-coupling reactions between 2,4,6-tribromo-3,5-difluoropyridine and a short series of aromatic boronic acid derivatives gave 4-bromo-3,5-difluoro-2,6-diphenylpyridine derivatives arising from displacement of bromine atoms a

Full text of DOI:10.1016/j.jfluchem.2007.02.012

Journal of Fluorine Chemistry 128 (2007) 718–722
www.elsevier.com/locate/fluor
Polyhalogenoheterocyclic compounds
Part 54: [1] Suzuki reactions of 2,4,6-tribromo-3,5-difluoropyridine
a,**
Hadjar Benmansour a, Richard D. Chambers a, , Graham Sandford
*
,
Andrei S. Batsanov b, Judith A.K. Howard b
a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
Received 24 January 2007; received in revised form 20 February 2007; accepted 20 February 2007
Available online 24 February 2007
In commemoration of the centenary of the birth of Professor Ivan Ludvigovich Knunyants.
Abstract
Palladium catalysed Suzuki cross-coupling reactions between 2,4,6-tribromo-3,5-difluoropyridine and a short series of aromatic boronic acid
derivatives gave 4-bromo-3,5-difluoro-2,6-diphenylpyridine derivatives arising from displacement of bromine atoms attached to positions ortho to
ring nitrogen or the corresponding triaryl systems depending on the reaction conditions. Consequently, the use of polybromofluoropyridine
scaffolds for the synthesis of polyfunctional heteroaromatic derivatives is expanded further.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Heterocycle; Heterocyclic scaffold; Pyridine; Fluoropyridine; Suzuki; Palladium catalysis
1. Introduction
The palladium catalysed Suzuki cross-coupling reaction is a
versatile method for the synthesis of biaryl and hetero-aryl
derivatives [10] and the wide range of commercially available
boronic acids, the relatively low toxicity of the by-products
formed and the possibility to work under aqueous conditions
has been widely exploited in all aspects of synthetic organic
chemistry.
Polybromofluoropyridine derivatives are, potentially, very
valuable scaffolds for the synthesis of multifunctional pyridine
derivatives [2,3] because not only are nucleophilic substitution
reactions possible, involving either replacement of fluorine or
bromine depending upon the nature of the nucleophile, but also,
for example, palladium catalysed processes involving activa-
tion of a carbon–bromine bond [1,2]. We have developed
effective methodology for the synthesis of various polybromo-
fluoroheteroaromatic systems [2] and are exploring the use of
these novel scaffolds for a variety of synthetic applications in
both the medicinal chemistry and materials arenas. A
surprisingly high proportion of commercially important
pharmaceutical and plant protection products are based upon
a small heterocyclic ring core scaffold [4–7] and, consequently,
efficient methodology for the synthesis of polyfunctional
heterocyclic systems is an important research goal [8,9].
In this paper, we describe representative Suzuki cross-
coupling reactions between a short series of aromatic boronic
acid derivatives and 2,4,6-tribromo-3,5-difluoropyridine 1 and
demonstrate how this readily accessible system can be used as a
building block for the synthesis of polyfunctional fluoroaryl-
pyridine derivatives.
2. Results and discussion
Electron rich arene boronic acids are prone to deboronation
under the reaction conditions [Pd(PPh3)4, Cs2CO3/H2O,
toluene] first reported by Suzuki for the synthesis of biaryl
derivatives but, subsequently, Gronowitz demonstrated that
such deboronations can be suppressed by using glycol
dimethyl ether (DME) as the solvent. Consequently, we have
used refined Gronowitz conditions [11,12] [Pd(PPh3)4,
* Corresponding author. Tel.: +44 191 334 2020; fax: +44 191 384 4737.
** Corresponding author. Tel.: +44 191 334 2039; fax: +44 191 384 4737.
E-mail addresses: R.D.Chambers@durham.ac.uk (R.D. Chambers),
Graham.Sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.02.012

H. Benmansour et al. / Journal of Fluorine Chemistry 128 (2007) 718–722
719
Ba(OH)2/H2O, DME] for Suzuki coupling reactions between a
short range of boronic acids 2 and 2,4,6-tribromo-3,5-
difluoropyridine 1 and the results are collated in Table 1.
Using one equivalent of boronic acid generally afforded a
mixture of diphenyl 3 and triphenylated 4 pyridine derivatives
with complete conversion of the starting material whereas an
excess of boronic acid led to good yields of the corresponding
triphenyldifluoropyridine systems 4. All products were
isolated and fully characterised and, in addition, the diphenyl
derivative 3b was characterised by X-ray crystallography
(Fig. 1). The phenyl group at C(6) is almost coplanar to the
pyridine ring (dihedral angle 8.88) whilst the phenyl group at
C(2) is disordered equally between two orientations (A and B),
which are inclined to the pyridine ring by similar, opposite
angles (29.48 and 26.88). Molecules related by the b translation
˚
form a p–p stack with an interplanar separation of ca. 3.6 A
and have the same orientation of the disordered ring, whereas
molecules related by the inversion—x1–y–z, must have
different orientations (i.e. A versus B), to avoid impossibly
short intermolecular contacts.
Table 1
Suzuki reactions of 2,4,6-tribromo-3,5-difluoropyridine
Boronic acid 2
3, Yield %
4, Yield%
–
2b, 3 equiv.
–
4b, 52
2c, 3 equiv.
–
4c, 80
–

720
H. Benmansour et al. / Journal of Fluorine Chemistry 128 (2007) 718–722
Scheme 2.
Fig. 1. X-ray molecular structure of 3b, showing 50% thermal ellipsoids and
the alternative orientations of the disordered phenyl group (A solid; B dashed).
nucleophile occurs at the weaker and softer carbon–bromine
bond rather than at the stronger carbon–fluorine bond.
However, attack occurs unusually at positions that are ortho
to ring nitrogen. Although most other nucleophiles attack
preferentially at the 4- rather than the 2-position in
polyhalogentated pyridines, these insertion reactions present
a further example where transition metal induced reactions give
a different outcome for displacement of either fluorine or
bromine in heteroaromatic systems, suggesting some involve-
ment of charge on nitrogen in the transition state [13,14]. The
transmetalation step has been proposed to proceed by an
enhancement of the nucleophilicity of the organic group on the
boron atom by quaternization of the boron with the base to
afford the ate complex (Scheme 2). Reductive elimination
occurs from the cis RPd(II)R0complex to afford the coupled
product.
Scheme 1. General mechanism of the Suzuki coupling.
When coupling with 4-methoxybenzeneboronic acid 2e was
performed (Scheme 3), the dimerised product 1-methoxy-4-(4-
methoxyphenyl)benzene 5 was obtained indicating a change in
mechanism. In this case, the stronger p-methoxy aryl
nucleophile displaces the electron withdrawing polybromo-
fluoropyridyl group leading to the coupled product as an
effective competing process (Scheme 2).
Coupling with 3-nitrobenzene boronic acid 2d afforded
unexpected results since when both equimolar and excess
amounts of the nucleophile were used we observed the
exclusive formation of 3d. We suggest that 3d is formed
because the introduction of the strongly electron withdrawing
group at the 2 and 6 positions activates the pyridine ring
towards nucleophilic substitution and attack at the carbon–
fluorine bond by free hydroxide ion present in solution occurs.
The generally accepted mechanism for Suzuki cross-
coupling processes [10] involves slow oxidative addition of
the aryl halides to Pd(0) complexes to give a stable trans
s-Pd(II) complex with retention of configuration (Scheme 1).
In the first stage, the palladium species acts as a nucleophile
and reaction with an electron deficient polyhalogenated
heterocycle is, therefore, a favoured process because such
systems are especially prone to nucleophilic aromatic
substitution reactions. Also, insertion of the palladium
In summary, bis-aryl- and tri-aryl-pyridine derivatives may
be synthesised by Suzuki cross-coupling processes using
polybromofluoropyridine as polyfunctional substrates.
3. Experimental
All starting materials were obtained commercially. All
solvents were dried using literature procedures. NMR spectra
were recorded in deuteriochloroform, unless otherwise stated,
on a spectrometer operating at 500 MHz (1H NMR), 376 MHz
(19F NMR) and 100 MHz (13C NMR) with tetramethylsilane
and trichlorofluoromethane as internal standards. Mass spectra
were recorded on either a VG 7070E spectrometer coupled with
Scheme 3.

H. Benmansour et al. / Journal of Fluorine Chemistry 128 (2007) 718–722
721
a Hewlett Packard 5890 series II gas chromatograph. Accurate
mass measurements were performed by the EPSRC Mass
Spectrometry Service, Swansea, UK. Elemental analyses were
obtained on an Exeter Analytical CE-440 elemental analyser.
Melting points and boiling points were recorded at atmospheric
pressure unless otherwise stated and are uncorrected. The
progress of reactions was monitored by 19F NMR Column
chromatography was carried out on silica gel. 2,4,6-Tribromo-
3,5-difluoropyridine was prepared following the literature
procedure [2].
(t, 3JCF 3.4, C4–C), 139.1 (s, N C–C), 141.7 (m, N C), 152.7
1
(d, JCF 264.7, CF); m/z (EI+) 385 ([M]+, 100%), 193 (7).
By a similar procedure, 1 (0.3 g, 0.855 mmol), monoglyme
(5 mL), Pd catalyst (6%, 59.3 mg), 2b (0.34 g, 256 mmol),
Ba(OH)2 (0.36 g, 2.2 mmol) and water (2 mL), after heating at
90 8C for 18 h and column chromatography on silica gel using
dichloromethane–hexane (2:1) as the eluent, gave 4b (52%,
0.17 g), as a white solid; spectral data as above.
3.1.4. Reactions with 4-trifluoromethoxybenzeneboronic
acid 2c
3.1. Suzuki reactions of 2,4,6-tribromo-3, 5-
difluoropyridine 1
1 (1 g, 2.84 mmol), monoglyme (5 mL), Pd catalyst (6%,
155 mg), 4-trifluoromethoxybenzeneboronic acid 2c (0.47 g,
2.27 mmol), Ba(OH)2 (1.19 g, 4.54 mmol) and water (2 mL),
after heating at 90 8C for 48 h and column chromatography on
silica gel with hexanes as the eluent, gave 2-bromo-3,5-
difluoro-4,6-bis(4-trifluoromethoxyphenyl)-pyridine 3c (22%,
0.32 g) as a white solid; b.p. > 300 8C (found: [MH]+,
513.9689. C19H8BrF8NO2 requires: [MH]+, 513.9693); dH
7.33 and 8.03 (AA‘XX’, JAX 8.0, ArH); dF ꢁ58.1 (3F, s, CF3),
ꢁ115.5 (1F, s, ArF); dC 110.0 (m, C–Br), 120.3 (q, 1JCF 257.8,
CF3), 120.8 (s, ArH), 130.3 (m, ArH), 132.6 (s, N C–C), 140.5
3.1.1. General procedure
2,4,6-Tribromo-3,5-difluoropyridine 1, monoglyme, tetra-
kistriphenylphosphine palladium (6%), boronic acid 2 and
barium hydroxide and water were heated together with stirring.
After completion of the reaction, the crude mixture was filtered
through celite. Water was added and the aqueous solution was
extracted into dichloromethane (3 ꢀ 30 mL), dried (MgSO4)
and evaporated. Purification was achieved by column
chromatography on silica gel, sublimation or recrystallisation.
1
(m, N C), 150.1 (C–O), 153.5 (d, JCF 267.5, CF); m/z (EI+)
515 ([M]+, 16%), 513 ([M]+, 26%), 418 (12), 247 (29), 150
(75), 69 (100); and 3,5-difluoro-2,4,6-tris(4-trifluoromethox-
yphenyl)pyridine 4c (0.13 g, 8%) as a thick orange oil; b.p.
209–211 8C (found: C, 52.2; H, 2.2; N, 2.1. C26H12F11NO3
requires: C, 52.4; H, 2.0; N, 2.3%); dH 7.52 and 8.51 (8H,
AA‘XX’, JAX 8.0, ArH), 7.60 and 7.83 (4H, AA‘XX’, JAX 8.1,
ArH); dF ꢁ58.8 (3F, s, CF3), ꢁ126.1 (1F, s, CF); m/z (EI+) 595
([M]+, 27%), 321 (100), 253 (29), 225 (38).
3.1.2. Reaction with benzeneboronic acid 2a
1 (1 g, 2.84 mmol), monoglyme (5 mL), Pd catalyst (6%,
119.7 mg), benzeneboronic acid 2a (1.04 g, 8.52 mmol),
Ba(OH)2 (2.82 g, 17.1 mmol) and water (2 mL), after heating
at 90 8C for 48 h and column chromatography on silica gel
using dichloromethane-hexane (1:1) as the eluent, gave 3,5-
difluoro-2,4,6-triphenylpyridine 4a (0.42 g, 43%) as a white
solid; m.p. 135–137 8C (found: 343.117393. C23H15F2N
requires 343.117256); dH 7.48–7.95 (m, ArH); dF ꢁ126.4
(s); m/z (EI+) 343 ([M]+, 100%), 267 (17).
By a similar procedure, 1 (0.15 g, 0.43 mmol), monoglyme
(5 mL), Pd catalyst (6%, 30.14 mg), 2c (0.27 g, 1.31 mmol),
Ba(OH)2 (0.144 g, 0.86 mmol) and water (2 mL), after heating
at 90 8C for 48 h and column chromatography on silica gel with
ethyl acetate-petroleum ether 40–60 8C (1:10) as the eluent,
gave 4c (80%, 0.21 g) as a thick orange oil; spectral data as
above.
3.1.3. Reactions with p-tolylboronic acid 2b
1 (1 g, 2.84 mmol), monoglyme (5 mL), Pd catalyst (6%,
197 mg), p-tolylboronic acid, 2b (0.48 g, 3.55 mmol), Ba(OH)2
(1.17 g, 7.10 mmol) and water (2 mL), after heating at 90 8C for
24 h and column chromatography on silica gel using
dichloromethane-hexane (3:1) as the eluent, gave 4-bromo-
3.1.5. Reaction with 3-nitrobenzeneboronic acid 2d
1 (0.8 g, 2.28 mmol), monoglyme (5 mL), Pd catalyst (6%,
158.5 mg), 3-nitrobenzeneboronic acid 2d (0.48 g, 2.85 mmol),
Ba(OH)2 (0.76 g, 4.56 mmol) and water (2 mL), after heating at
90 8C for 48 h and column chromatography on silica gel with
petroleum ether-ethyl acetate (1:1) as the eluent, gave 4-bromo-
5-fluoro-2,6-bis(3-nitrophenyl)pyridine-3-ol 3d (0.53 g, 54%)
as a white solid; m.p. 145.1–145.8 8C (found: [M + H]+,
432.9708. C17H9BrFN3O5 requires: [M + H]+, 432.9709); dH
7.72 (1 H, t, 3JHH 8.0, H-d50), 7.73 (1H, t, 3JHH 8.0, H-5), 8.33 (2
H, m, H-4,40), 8.40 (1 H, d, 3JHH 7.5, H-6), 8.48 (1 H, d, 3JHH
7.0, H-60), 8.90 (1 H, s, H-2), 9.02 (1 H, s, H-20); dF ꢁ114.3 (s);
m/z (EI+) 435 ([M]+, 95%), 433 ([M]+, 100%), 389 (12), 341
(21), 233 (17).
3,5-difluoro-2,6-bis(4-methylphenyl)-pyridine
3b
(32%,
0.35 g) as a white solid; m.p. 150–151.2 8C (from chloroform)
(found C, 60.8; H, 3.8; N, 3.7. C19H14BrF2N requires C, 60.9;
H, 3.7; N, 3.7%); dH 2.56 (3H, s, CH3), 7.22 and 7.81 (4H,
AA‘XX’, JAX 8.0, ArH); dF ꢁ117.5 (s); dC 21.2 (s, CH3), 109.7
(t, 2JCF 23.2, C–Br), 128.8 (m, ArH), 129.5 (s, ArH), 131.9 (d,
3JCF 7.0, C–C N), 139.8 (s, C–CH3), 141.9 (m, C N), 153.1
1
(d, JCF 271.5, CF); m/z (EI+) 375 ([M]+, 100%), 373 ([M]+,
98%); and, 3,5-difluoro-2,4,6-tris-(4-methylphenyl)pyridine 4b
(0.23 g, 21%), as a white solid; m.p. 152–154 8C (found C,
80.7; H, 5.5; N, 3.6. C26H21F2N requires C, 81.0; H, 5.5; N,
3.6%); dH 2.43 (6H, s, CH3), 2.45 (3H, s, CH3), 7.25 and 7.50
(4H, AA‘XX’, JAX 8.0, ArH), 7.30 and 7.95 (8H, AA‘XX’, JAX
8.0, ArH); dF ꢁ127.0 (s); dC 21.3 (s, CH3), 21.4 (s, CH3), 125.0
3.1.6. Reaction with 4-methoxybenzeneboronic acid
1 (0.18 g, 0.52 mmol), monoglyme (5 mL), Pd catalyst (6%,
35.5 mg), 4-methoxybenzeneboronic acid (1.56 mmol, 0.24 g),
3
(s, ArH), 127.4 (t, JCF 23.2, C-4), 128.9 (s, ArH), 129.0 (s,
ArH), 129.4 (C–CH3), 129.5 (s, C–CH3), 130.2 (m, ArH), 132.9

722
H. Benmansour et al. / Journal of Fluorine Chemistry 128 (2007) 718–722
Ba(OH)2 (0.17 g, 104 mmol) and water (2 mL), after heating at
90 8C for 48 h, recrystallisation from dichloromethane
followed by chromatography on silica gel with dichloro-
methane-hexane (2:1) as the eluent, gave 1-methoxy-4-(4-
methoxyphenyl)benzene (0.12 g, 35%); (H 3.80 (3 H, s, OCH3),
6.90 (2H, m, ArH), 7.80 (2H, m, ArH); dC 55.4 (s, OCH3), 113.8
(s, C-3), 135.5 (s, C-2), 137.7 (C-4), 163.4 (C–O); as compared
to an authentic sample (Aldrich).
Acknowledgement
We thank the European Union for a TMR grant.
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3
˚
b = 95.78(3)8, V = 3085.3(7) A , Z = 8, Dc = 1.611 g cm
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m = 2.68 mmꢁ1
,
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1
CCDC 634126 contains the supplementary crystallographic data for this
paper. These data can be viewed free of charge via http://www.ccdc.cam.ac.uk/
cont/retrieving.html or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK. Fax: +44 1223 336033. E-mail: deposit@ccdc.cam.ac.uk.