Versatile synthesis of 3,5-disubstituted 2-fluoropyridines and 2-pyridones

Article abstract of DOI:10.1021/jo026864f

5-Bromo-2-fluoro-3-pyridylboronic acid (3) was prepared in high yield by ortho-lithiation of 5-bromo-2-fluoropyridine (1), followed by reaction with trimethylborate. Suzuki reaction of 3 with a range of aryl iodides gave 3-monosubstituted 5-bromo-2-fluoro

Full text of DOI:10.1021/jo026864f

SCHEME 1
Ver sa tile Syn th esis of 3,5-Disu bstitu ted
2-F lu or op yr id in es a n d 2-P yr id on es
Andrew Sutherland and Timothy Gallagher*
School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom
t.gallagher@bristol.ac.uk
Received December 18, 2002
Abstr a ct: 5-Bromo-2-fluoro-3-pyridylboronic acid (3) was
prepared in high yield by ortho-lithiation of 5-bromo-2-
fluoropyridine (1), followed by reaction with trimethylborate.
Suzuki reaction of 3 with a range of aryl iodides gave
3-monosubstituted 5-bromo-2-fluoropyridines 4 in excellent
yields. A second Suzuki reaction utilizing the bromo con-
stituent of 4 with aryl and heteroaryl boronic acids provided
3,5-disubstituted 2-fluoropyridines 5, which in turn could
be converted to the corresponding 2-pyridones 6.
tuted pyridines.4a 2-Bromopyridine provides an entry to
2,3- and 2,4-disubstituted pyridines,4a and 3,4-disubsti-
tuted and 3,4,5-trisubstituted pyridines are available by
application of directed ortho-lithiation procedures to
4-bromopyridine.4b Rault and co-workers have described
a series of other boronated halopyridines, including
2-halo-5-pyridyl, 2-, 4-, or 5-halo-3-pyridyl, and 2- or
3-halo-4-pyridyl boronic acids, which undergo efficient
Suzuki coupling reactions.5 Bryce has also reported the
synthesis and Suzuki reactions of 2-halo(or 2-methoxy)-
5-pyridyl boronic acids, and trisubstituted pyridines have
been generated via 3-chloro-6-methoxy-4-pyridinyl bo-
ronic acid.6
We were interested in developing a flexible route
toward more highly substituted and functionalized vari-
ants such as 3,5-diarylpyridin-2-ones. Previously, 3,5-
diarylated pyridin-2-ones have been prepared using a
nickel-catalyzed coupling of an arylmagnesium bromide
with a 3,5-dihalopyridine, with the resulting symmetrical
3,5-diarylpyridine then converted to the corresponding
2-pyridone using a three-step oxidation/rearrangement/
hydrolysis sequence.7 We now describe an effective
methodology that provides rapid, efficient, and regiocon-
trolled entry to unsymmetrical 3,5-disubstituted 2-pyri-
dones. This is based on the regioselective metalation of
5-bromo-2-fluoropyridine and the subsequent chemose-
lective coupling reactions of 5-bromo-2-fluoropyridine-3-
boronic acid 3, as outlined in Scheme 1.
The efficient synthesis of libraries of multiring aryl and
heteroaryl small molecules is vitally important to both
the pharmaceutical and agrochemical sectors in the
search for biologically active compounds. In particular,
the development of an efficient methodology toward the
regiocontrolled preparation of highly substituted py-
ridines and pyridones represents a major challenge in
heterocyclic chemistry.
A common strategy used to prepare substituted py-
ridines is directed ortho-lithiation (DoM) reactions, where
a functional group attached to the pyridine ring is used
to direct a regioselective deprotonation. This chemistry
has developed significantly since the early pioneering
work of Gribble,1 and Que´guiner2 has been prominent in
the development and subsequent synthetic application
of the ortho-lithiation and trapping of 2-, 3-, and 4-ha-
lopyridines.3
Recently, a number of groups have reported the
directed lithiation and transmetalation of pyridines,
combined with subsequent Pd(0)-mediated cross-coupling
reactions to provide an entry to substituted pyridines.
We utilized the regioselective C-4 deprotonation of 3-bro-
mopyridine, followed by a Li/Zn transmetalation and Pd-
(0)-mediated Negishi coupling, to provide 3,4-disubsti-
Our initial efforts focused on the synthesis of the
3-substituted 5-bromo-2-fluoropyridines 4 via the orga-
nozinc intermediate 2. Commercially available 5-bromo-
2-fluoropyridine (1) was treated with LDA at -78 °C to
give the lithiated species 7. Subsequent attempts to
transmetalate 7 with zinc(II) chloride to provide 2,
followed by coupling to iodobenzene with Pd(PPh3)4 under
standard Negishi conditions,8 failed to provide the desired
cross-coupled product (Scheme 2). ortho-Lithiation of
* Phone: (44-117)9288260. Fax: (44-117)9298611.
(1) (a) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151-
169. (b) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137-4140.
(2) (a) Gu¨ngo¨r, T.; Marsais, F.; Que´guiner, G. J . Organomet. Chem.
1981, 215, 139-150. (b) Marsais, F.; Laperdrix, B.; Gu¨ngo¨r, T.; Mallet,
M.; Que´guiner, G. J . Chem. Res., Synop. 1982, 278-279. (c) Mallet,
M.; Que´guiner, G. Tetrahedron 1985, 41, 3433-3440. (d) Mallet, M.;
Que´guiner, G. Tetrahedron 1982, 38, 3035-3042. (e) Mallet, M.;
Que´guiner, G. Tetrahedron 1986, 42, 2253-2262. (f) Mallet, M.;
Branger, G.; Marsais, F.; Que´guiner, G. J . Organomet. Chem. 1990,
382, 319-332. (g) Marsais, F.; Pineau, P.; Nivolliers, F.; Mallet, M.;
Turck, A.; Godard, A.; Que´guiner, G. J . Org. Chem. 1992, 57, 565-
573. (h) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont,
L.; Mallet, M.; Godard, A.; Que´guiner, G. J . Org. Chem. 1993, 58,
7832-7838.
(4) (a) Karig, G.; Spencer, J . A.; Gallagher, T. Org. Lett. 2001, 3,
835-838. (b) Karig, G.; Thasana, N.; Gallagher, T. Synlett 2002, 808-
810.
(5) (a) Bouillon, A.; Lancelot, J . C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 4369-4373. (b) Bouillon, A.; Lancelot, J . C.;
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 3323-3328. (c)
Bouillon, A.; Lancelot, J . C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 2885-2890.
(6) Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
J . Org. Chem. 2002, 67, 7541-7543.
(7) Tagat, J . R.; McCombie, S. W.; Barton, B. E.; J ackson, J .;
Shortall, J . Bioorg. Med. Chem. Lett. 1995, 5, 2143-2146.
(8) Negishi, E.; Luo, F. T.; Frisbee, R.; Matsushita, H. Heterocycles
1982, 18, 117-122.
(3) For reviews, see: Que´guiner, G.; Marsais, F.; Snieckus, V.;
Epsztajn, J . Adv. Heterocycl. Chem. 1991, 52, 187-304. Mongin, F.;
Que´guiner, G. Tetrahedron 2001, 57, 4059-4090.
10.1021/jo026864f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/20/2003
3352
J . Org. Chem. 2003, 68, 3352-3355

TABLE 1
SCHEME 2
2-fluoropyridine with LDA is well-known,2a,5b and since
the initial lithiation step to give 7 is successful (see
below), it would appear that either Li/Zn transmetalation
fails or the resulting aryl zinc reagent 2 is unreactive
under the palladium cross-coupling conditions used.9
Proof of formation of 7 was obtained by generation of
the 2,5-dihalopyridylboronic acid 3 (Scheme 2). Lithiation
(LDA, -78 °C) of 5-bromo-2-fluoropyridine (1) followed
by trapping with trimethylborate and hydrolytic workup
gave boronic acid 3 in 80% yield. Boronic acid 3 is
thermally stable, nonhygroscopic, and easily purified by
recrystallization from ethyl acetate/hexane and repre-
sents a highly versatile heterocyclic building block.10
Suzuki coupling reactions of boronic acid 3 with a
range of aryl iodides and bromides were explored under
standard conditions (Na2CO3, Pd(PPh3)4, PhMe/EtOH,
reflux) (Table 1). Several points arise from this study.
An extended reaction time (6 h) led to coupling but also
subsequent debromination to give 8 in 30% yield (Table
1, entry 1). This was overcome using shorter reaction
times (2 h), which gave the desired coupled bromopy-
ridines 4a -e in high yields. It is also pertinent to note
that no homocoupled products, resulting from 3 acting
as both a boronic acid and an aryl bromide, were isolated
from these reactions. Although reaction of the boronic
acid with aryl iodides was expected to be faster than that
with aryl bromides, a 1.1 equiv excess of boronic acid is
used during these reactions. An attempt to couple boronic
acid 3 with an aryl bromide (Table 1, entry 7) was not
successful. A significant amount of bromobenzene re-
mained after 2 h, and after 6 h, the debrominated product
8 was only isolated in 38% yield.11 In summary, success-
ful and high-yielding Suzuki cross-coupling of boronic
acid 3 are best achieved using short reaction times with
reactive aryl iodides as substrates.
To explore the ability of 3-aryl-5-bromo-2-fluoropy-
ridines 4 to undergo a second Suzuki coupling step to
give 3,5-diaryl-2-fluoropyridines, two representative de-
rivatives 4b and 4d were studied. Suzuki reaction of 4b
and 4d with a series of aryl and heteroaryl boronic acids
gave the corresponding 3,5-disubstiuted-2-fluoropyridines
5 in excellent yields (Table 2). All reactions were complete
after only 2 h. This observation suggests that the pres-
ence of the boronic acid moiety of 3 exerts an influence
on the reactivity of the 5-bromo component, which may
explain why self-coupling of 3 to itself is also not detected.
Reduction of the C-Br moiety (compare entries 1 and 2,
Table 1) under these conditions occurs only after the
initial Suzuki reaction is complete and the boronic acid
component has been replaced. Once the first cross-
coupling is completed, then the bromo residue (of 4) is
(9) Unsuccessful Li-Zn exchange of the 3-lithiated species of
5-bromo-2-fluoropyridine 7 was expected, as similar results with the
corresponding lithiated species of 2-fluoropyridine during the synthesis
of fluoro analogues of UB-165 were observed. For a discussion of these
results, see: Sutherland, A.; Gallagher, T.; Sharples, C. G. V.;
Wonnacott, S. J . Org. Chem. 2003, 68, 2475-2478.
(10) For the synthesis of other dihalopyridyl boronic acids, see:
Achad, S.; Guyot, M. Potier, P. Tetrahedron Lett. 1993, 34, 2127-2130.
Mongin, F.; Tre´court, F.; Gervais, B.; Mongin, O.; Que´guiner G. J . Org.
Chem. 2002, 67, 3272-3276. 2,6-Difluoropyridyl 3- and 4-boronic acids
have been reported in the patent literature: Reiffenrath, V. Ger. Offen.
4218978, 1993. Boyd, F. L.; Gudmundsson, K.; J ohns, B. A. WO
0278701, 2002. Alberti, M. J .; Baldwin, I. R.; Cheung, M.; Cockerill,
S.; Flack, S.; Harris, P. A.; J ung, D. K.; Peckham, G.; Peel, M. R.;
Stanford, J . B.; Stevens, K.; Veal, J . M. WO 0216359, 2002.
(11) Bryce and co-workers6 examined the Suzuki reaction of a
bromopyridyl boronic acid, and under extended reaction times (22-
43 h) in DMF, only low yields (10-32%) of the coupled products were
isolated.
J . Org. Chem, Vol. 68, No. 8, 2003 3353

TABLE 2
SCHEME 3
5, which can then be readily converted to the correspond-
ing 2-pyridones 6. Appropriate reaction conditions for
each step have been defined, and the efficiency of these
processes makes this chemistry an attractive and, more
importantly, a highly flexible entry to substituted py-
ridines and pyridones.
Exp er im en ta l Section
5-Br om o-2-flu or o-3-p yr id ylbor on ic Acid (3). Butyllithium
(13.7 mmol, 2.5 M in hexanes) was added dropwise to a solution
of diisopropylamine (1.92 mL, 13.7 mmol) in THF (10 mL) at 0
°C under a nitrogen atmosphere. After 20 min, this solution was
added to 5-bromo-2-fluoropyridine (3) (2.0 g, 11.4 mmol) in THF
(10 mL) at -78 °C under a nitrogen atmosphere. After 30 min,
a solution of trimethylborate (2.31 mL, 13.7 mmol) in THF (5
mL) was added, and the reaction mixture was allowed to warm
to room temperature over l h. After this time, saturated aqueous
sodium hydrogen carbonate (10 mL) was added, the aqueous
layer was separated, carefully acidified to pH 6-7 with 2 M
hydrochloric acid (5 mL), and then extracted with ethyl acetate
(3 × 10 mL). The extracts were dried (Na2SO4) and concentrated
in vacuo, and the residue was recrystallized from ethyl acetate
and hexane to give 5-bromo-2-fluoro-3-pyridylboronic acid (3)
(1.86 g, 80%) as a colorless solid. Mp: 144-146 °C (ethyl acetate/
hexane). IR (neat) ν (cm-1): 3339, 1590, 1562. 1H NMR (270
MHz, CD3OD): δ 8.29 (1 H, dd, J ) 2.7, 1.0 Hz, 6-H), 8.13 (1 H,
dd, J ) 7.3, 2.7 Hz, 4-H). 13C NMR (100.5 MHz, CD3OD): δ 164.4
(d, J ) 238.2 Hz, C), 149.3 (d, J ) 15.1 Hz, CH), 148.9 (d, J )
9.0 Hz, CH), 116.4 (d, J ) 4.0 Hz, C). HRMS: calcd for C5H511B79
-
BrFNO2 (MH+), 219.9581; found, 219.9587.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Su bstitu ted
5-Br om o-2-flu or op yr id in es 4 (Ta ble 1). To a solution of aryl
iodide (0.35 mmol) in toluene (8 mL) and ethanol (2 mL)
containing Pd(PPh3)4 (20 mg, 0.017 mmol, 5 mol %) and 5-bromo-
2-fluoro-3-pyridylboronic acid (3) (0.39 mmol) was added Na2-
CO3 (0.1 g, 0.96 mmol) in water (4 mL). The mixture was heated
under reflux for 2 h, cooled to room temperature, diluted with
water (20 mL), and extracted with ethyl acetate (2 × 20 mL).
The combined extracts were dried (Na2SO4), concentrated, and
purified by flash column chromatography (EtOAc/light petro-
leum) to give adducts 4 as either viscous oils or colorless solids.
For recrystallization solvents and spectroscopic data for adducts
4, see Supporting Information.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e 3,5-
Disu bstitu ted -2-flu or op yr id in es 5 (Ta ble 2). To a solution
of pyridyl bromide 4 (0.14 mmol) in toluene (8 mL) and ethanol
(2 mL), containing Pd(PPh3)4 (16 mg, 0.014 mmol, 10 mol %),
and the requisite boronic acid (0.21 mmol) was added sodium
carbonate (0.1 g, 0.96 mmol) in water (4 mL). The reaction
mixture was heated under reflux for 2 h, cooled to room
temperature, diluted with water (20 mL), and extracted with
ethyl acetate (2 × 20 mL). The combined extracts were dried
(Na2SO4) and concentrated, and purification by flash column
chromatography (EtOAc/light petroleum) gave adducts 5 as
either viscous oils or colorless solids. For recrystallization
solvents and spectroscopic data for adducts 5, see Supporting
Information.
activated. Attempts to couple a vinyl boronic acid (entry
7, Table 2) to 4d failed, with only the debrominated
derivative 9 being isolated.
The final step for the synthesis of 2-pyridiones 6
required hydrolysis of the 2-fluoropyridine of adducts 5.
Several multistep procedures have been reported for this
conversion;7,12 however, direct hydrolysis of 2-fluoropy-
ridines 5a and 5b under acidic conditions (aqueous HCl,
dioxane, reflux, 24 h)13 provided the corresponding 2-py-
ridones 6a and 6b, respectively, in very high yields
(Scheme 3).
In conclusion, we have described the synthesis of the
synthetically versatile dihalopyridylboronic acid 3, which
has been applied to the chemoselective and stepwise
synthesis of a range of 3,5-substituted 2-fluoropyridines
Gen er a l P r oced u r e for th e P r ep a r a tion of th e 3,5-
Disu b st it u t ed 2-P yr id on es 6. To a solution of the 3,5-
disubstituted 2-fluoropyridine 5a or 5b in 1,4-dioxane (6 mL)
and water (2 mL) was added concentrated hydrochloric acid (0.5
mL), and the reaction mixture was heated under reflux for 24
(12) Solomon, M. S.; Hopkins, P. B. Tetrahedron Lett. 1991, 32,
3297-3300.
(13) Bradlow, L.; Vanderwerf, C. A. J . Org. Chem. 1949, 14, 509-
515.
3354 J . Org. Chem., Vol. 68, No. 8, 2003

h. The reaction mixture was cooled and concentrated, and the
resulting residue was dissolved in water (10 mL) and extracted
with ethyl acetate (2 × 10 mL). The combined extracts were
dried (Na2SO4) and concentrated in vacuo, and pyridones 6a and
6b were recrystallized from chloroform and hexane. Spectro-
scopic and characterization data for 6a and 6b are available in
Supporting Information.
is thanked for their gift of 5-bromo-2-fluoropyridine and
for carrying out the large-scale preparation and supply
of boronic acid 3.
Su p p or tin g In for m a tion Ava ila ble: Experimental, spec-
troscopic, and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. The authors thank the EPSRC
and BBSRC (Biomolecular Sciences Project Grant 86/
B11785) for financial support. Lancaster Synthesis, Ltd.,
J O026864F
J . Org. Chem, Vol. 68, No. 8, 2003 3355