Solid-phase synthesis of phenols and pyridinones via arylboronation/oxidation protocol using aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2006.05.034

A sequence of two known reactions, palladium catalyzed arylboronation of arybromide and subsequent oxidation of arylboronate with oxone, has been carried out to prepare functionalized phenols and pyridin-2(1H)-one which were later loaded on to resin for solid-phase synthesis. Using these resin-bound templates, a number of solid-phase methods were developed to generate libraries of substituted phenols and pyridin-2(1H)-one.

Full text of DOI:10.1016/j.tetlet.2006.05.034

Tetrahedron Letters 47 (2006) 4897–4901
Solid-phase synthesis of phenols and pyridinones via
arylboronation/oxidation protocol using aryl bromides
Younghee Lee* and Martha J. Kelly
Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA
Received 9 November 2005; revised 4 May 2006; accepted 8 May 2006
Abstract—A sequence of two known reactions, palladium catalyzed arylboronation of arybromide and subsequent oxidation of
arylboronate with oxone, has been carried out to prepare functionalized phenols and pyridin-2(1H)-one which were later loaded
on to resin for solid-phase synthesis. Using these resin-bound templates, a number of solid-phase methods were developed to
generate libraries of substituted phenols and pyridin-2(1H)-one.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Substituted phenols are prevalent in many compounds
aq Oxone
acetone
PdCl2(dppf)
that are of biological interest, and also serve as synthetic
building blocks in organic synthesis.1 Synthetic methods
developed for the formation of phenols include classical
aromatic substitution,2 metal-catalyzed coupling reac-
tions,3 ortho-metalation, and functionalization reac-
tions.4 In recognition of their importance, many
innovative approaches to phenols have been reported.5
Ar-BPin
Ar-Br + B2Pin2
KOAc / DMSO
Mitsunobu reaction
Wang resin
Ar-O
Ar-OH
Scheme 1.
Recently, a variety of phenols were prepared by an
iridium-catalyzed C–H activation/borylation/oxidation
protocol.5a By slight modification of the literature meth-
od,6 phenols were obtained in one-pot by oxidation of
arylboronic esters with oxone. This novel approach
can efficiently provide meta-substituted phenols bearing
ortho-/para-directing group. The regiochemistry of aryl-
boronate and phenols prepared in this manner is deter-
mined by iridium-catalyzed borylation of arenes.
(Scheme 1) would be a very practical synthetic route
to phenols. Although this unified route has a potential
to provide phenols which are not readily accessed by
other synthetic methods, there is no literature precedent
addressing this merit. Here, we report the synthesis of
phenols and pyridine-2-one by an arylboronation/oxida-
tion strategy and discuss solid-phase methodologies
which are designed for further diversification of phenols
and pyridin-2-one.
We were interested in obtaining a diverse set of highly
functionalized phenols which would be used as core tem-
plates to build small molecule libraries for pharmaceuti-
cal evaluation. Since it is known that arylboronate can
be synthesized by palladium-catalyzed arylboronation
of arylhalides (ArBr or ArI),7 we envisioned that a uni-
fied Miyaura arylboronation/oxidation protocol
The reaction conditions for arylboronation of aryl-
bromides (1–4)7 and oxidation of the resulting arylboro-
nates5a were adapted from literature procedures. The
crude arylboronate intermediates, without further puri-
fication except simple extraction during workup, were
subjected to subsequent oxidation with oxone to provide
phenols (5–7) and pyridin-2-one 8. The dibromopyridine
analog 4 gave rise to pyridin-2-one 8 which is believed to
be the more stable tautomeric form of 2-hydroxypyri-
dine. For solid-phase synthesis, loading of the phenols
and pyridin-2-one to Wang resin (9–12) were carried
out under Mitsunobu conditions. As summarized in
Table 1, the desired ArOH (5–8) were obtained in
Keywords: Solid-phase synthesis; Arylboronation; Oxidation; Phenol;
Pyridinone.
*
Corresponding author. Tel.: +1 215 358 2082; fax: +1 215 358
2030; e-mail addresses: ylee@locuspharma.com; yhleechem@yahoo.
com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.034

4898
Y. Lee, M. J. Kelly / Tetrahedron Letters 47 (2006) 4897–4901
Table 1. Phenols and pyridine-2-one via arylboronation/oxidation and loading to Wang resina
Yieldb (%)
c
Ar–Br
Ar–OH
Ar-O
Br
Br
Br
Br
OH
O
1
2
41
NO2
NO2
NO2
1
5
9
Br
Br
Br
OH
Br
O
46
O
O
O
N
N
6
2
3
10
N
Br
Br
Br
OH
Br
O
3
4
47
77
O
OMe
Br
O
O
OMe
O
O
OMe
O
7
11
H
Br
N
Br
N
Br
N
Br
N
O
O
O
O
O
O
4
O
O
8
12
a Typical conditions: Ar–Br, bis(pinacolato)diboron (B2Pin2), PdCl2(dppf), KOAc, DMSO, 80 ꢁC, 6–12 h; then extraction, aqueous oxone, 25 ꢁC,
10 min.
b After silica gel column chromatography.
c Typical conditions for loading to resin: Ar–OH, Wang resin (0.9 mmol/g), PPh3, DIAD, THF, 1–2 days (loading level of resins: 9 0.78 mmol/g; 10
0.55 mmol/g; 11 0.74 mmol/g; 12 0.62 mmol/g).
reasonable yields (41–77%) from the arylboronation/
oxidation protocol. Only mono-arylboronates have been
apparently obtained from the palladium-catalyzed aryl-
boronation of dibromoaryls as other side products, such
as substituted resorcinols, were not detected by LC/MS
analysis of the products.
60 ꢁC, 8 was consumed to give a mixture of O-benzyl
13 and N-benzyl isomer 14 in a ratio of 2.5–1. On the
other hand, only N-benzyl isomer was isolated as a single
product from the alkylation reaction of 8 with benzyl
bromide in the presence of K2CO3. Analysis of the chem-
ical shifts of 13C NMR for the benzylic carbon was used
as a tool to assign 13 (69.1 ppm) as an O-benzyl isomer
and 14 (52.4 ppm) as a N-benzyl isomer, respectively.
On the basis of this solution-phase model reaction, we
expect that both O-benzyl and N-benzyl isomers exist
on the resin-bound template 12 derived from 8.
The pyridine-2-one 8, with an electron withdrawing
group at the a-carbon to the nitrogen, possesses a N–
H which is capable of competition with oxygen under
Mitsunobu conditions. Therefore, it was not clear if
the compound 8 was attached to the polymeric resin
via a covalent bond with the oxygen or nitrogen atom.
Solid-phase synthesis on resin-bound template 9 is illus-
trated in Scheme 3. The nitro group was reduced and the
As a model study to understand how 8 was connected to
the resin under Mitsunobu conditions, Wang linker was
mimicked in solution using benzyl alcohol as shown in
Scheme 2. Under typical Mitsunobu conditions at
Br
O
O
OH
c, d
OCH3
a, b
9
O
NH
Ph
O
NH
Br
N
O
Ph
Br
N
O
a
b
+
8
14
16
O
O
O
O
15
13
14
Scheme 3. Solid-phase synthesis using 9. Reagent and conditions: (a)
SnCl2 2H2O, DMF, 16 h. (b) Benzoyl chloride, DIEA, DCM, 6 h. (c)
3-(Methoxycarbonyl)-phenylboronic acid, KF, Pd(II),8 THF, 65 ꢁC,
16 h. (d) 50% TFA/DCM, 3 min.
Scheme 2. Solution-phase model reactions of 8. Reagent and condi-
tions: (a) Benzyl alcohol, PPh3, DIAD, THF, 60 ꢁC, 3 h. (b) Benzyl
bromide, K2CO3, acetone/THF, rt, 7 h.

Y. Lee, M. J. Kelly / Tetrahedron Letters 47 (2006) 4897–4901
4899
resulting amine was benzoylated in the presence of base
to afford 15. The substitution of bromide 15 by a Pd8-
catalyzed Suzuki coupling with boronic acid and subse-
quent cleavage reaction under acidic conditions (50%
TFA in DCM) gave 16 in 48% yield.
O
O
Br
O
OH
a
b, c
11
N
O
N
H
N
O
N
H
24
23
Copper-catalyzed amidation of arylhalides has been
recently reported by Buchwald’s group.9 A number of
amides including lactams and formamides were success-
fully demonstrated to undergo amidation. As shown in
Scheme 4, translation of this carbon–nitrogen bond
forming process to solid-phase cleanly converted resin-
bound bromide 10 to a (pyridin-3-yl)acetamide deriva-
tive 17 by copper-catalyzed reaction in the presence of
a diamine ligand. Subsequent reduction of ketone to
an alcohol and cleavage from the resin provided 18 in
37% yield.
d
H
H
N
N
O
OH
c
N
N
O
N
H
O
N
H
26
25
Scheme 6. Solid-phase synthesis using 11. Reagent and conditions: (a)
3-Aminopyridine, LiN(TMS)2, 60 ꢁC, 3 h. (b) 1,4-Benzodioxane-6-
boronic acid, KF, Pd(II), THF, 65 ꢁC, 16 h. (c) 50% TFA/DCM,
3 min. (d) Aniline, Pd2(dba)3, xantphos, Cs2CO3, dioxane, 60 ꢁC, 16 h.
In Schemes 5 and 6, a number of solid-phase synthetic
approaches were described to diversify both the bromide
N
and carboxylic ester function of 11.10 Hydrolysis of the
ester and subsequent reaction with N,O-dimethylhydr-
oxylamine resulted in Weinreb amide on resin 19. Addi-
tion of Grignard reagent (CH3MgBr) to 19 in THF
followed by copper-catalyzed conversion of bromide to
iodide11 gave the desired intermediate 20. Sonogashira
coupling of 3-ethynylpyridine with iodide 20 was medi-
ated by the well defined copper complex, Cu(phen)-
(PPh3)Br,12 in the absence of palladium catalyst.
Heating of the resulting intermediate in N,N0-dimethyl-
formamide diethylacetal to 120 ꢁC afforded an enami-
none 21. Cyclization of 21 with guanidine at elevated
temperature formed an aminopyrimidine system.13
Cleavage from the resin produced 22 in 36% yield with
a purity higher than 90% in 8-step solid-phase synthetic
process from 11. To the best of our knowledge, this rep-
resents the first successful translation of solution phase
procedure for 2-aminopyrimidine to the corresponding
solid-phase reactions.
N
N
OH
N
O
b, c
O
a
O
10
OH
O
N
N
18
17
Scheme 4. Solid-phase synthesis using 10. Reagent and conditions:
(a) N-(Pyridin-3-yl)acetamide, CuI, N,N0-dimethylethylenediamine,
Cs2CO3, dioxane, 110 ꢁC, 16 h. (b) NaBH4, THF/EtOH (1:1), rt,
16 h. (c) 50% TFA/DCM, 3 min.
Br
O
I
O
c, d
a, b
11
OMe
Alternatively, ester 11 was directly converted to an
amide 23 by amidation with 3-aminopyridine in the
presence of LiN(TMS)2 at 60 ꢁC (Scheme 6). Under
the same reaction conditions as described in Scheme 3,
Suzuki coupling of the bromide 23 with boronic acid fol-
lowed by cleavage gave rise to 24. Arylamine intermedi-
ate 25 was obtained by Buchwald–Hartwig cross
coupling14 of 23 with aniline under mild conditions to
ultimately provide 26 in 24% yield after cleavage reac-
tion from the resin.
O
N
O
20
19
N
N
OH
O
N
e, f
g, h
N
O
H2N
N
The mixture of isomers 12 was used in the solid-phase
reaction sequence as depicted in Scheme 7. Suzuki cou-
pling with m-tolylboronic acid was performed to form a
C–C bond, and the tert-butyl ester group was hydro-
lyzed to yield an acid 27. Amide formation with 3-
aminopyridine in the presence of HBTU and cleavage
from resin afforded 28 in 46% yield. Synthesis of various
pyridine-2-ones is known.15 However, facile introduc-
tion of various substituents to functionalized pyridine-
2-ones such as 8 is scarce in the literature.16
21
22
Scheme 5. Solid-phase synthesis using 11. Reagent and conditions: (a)
LiOH, dioxane/H2O (4:1), 16 h. (b) N,O-Dimethylhydroxylamine
hydrochloride, HOBt, EDCI, DIEA, DCM/DMF, 16 h. (c)
CH3MgBr, THF, 2 h. (d) NaI, CuI, N,N0-dimethylethylenediamine,
Na2CO3, dioxane, 110 ꢁC, 5 h. (e) 3-Ethynylpyridine, Cu(phen)-
(PPh3)Br, K2CO3, toluene, 110 ꢁC, 16 h. (f) N,N0-Dimethylformamide
diethylacetal, 120 ꢁC, 3 h. (g) Guanidine hydrochloride, MeONa,
EtOH, 90 ꢁC, 16 h. (h) 50% TFA/DCM, 3 min.

4900
Y. Lee, M. J. Kelly / Tetrahedron Letters 47 (2006) 4897–4901
4. (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306;
(b) Chauder, B.; Green, L.; Snieckus, V. Pure Appl. Chem.
1999, 71, 1521.
N
O
5. (a) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M.
R., III. J. Am. Chem. Soc. 2003, 125, 7792–7793; (b)
Hoarau, C.; Pettus, T. R. R. Synlett 2003, 127–137; (c)
Guo, Z.; Schultz, A. G.; Antoulinakis, E. G. Org. Lett.
2001, 3, 1177–1180; (d) Marchueta, I.; Olivella, S.; Sola,
L.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2001,
3, 3197–3200; (e) Serra, S.; Fuganti, C.; Moro, A. J. Org.
Chem. 2001, 66, 7883–7888; (f) Hashmi, A. S. K.; Frost, T.
M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553–11554;
(g) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem.
1999, 576, 232–247.
H
N
O
c, d
a, b
O
OH
12
N
N
O
O
N
H
28
O
OH
27
6. Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117–
5118.
Scheme 7. Solid-phase synthesis using 12. Reagent and conditions: (a)
m-Tolylboronic acid, KF, Pd(II), THF, 65 ꢁC, 16 h. (b) LiOH,
dioxane/H2O (4:1), 110 ꢁC, 3 h. (c) 3-Aminopyridine, HBTU, DIEA,
DCM, rt, 16 h. (d) 50% TFA/DCM, 3 min.
7. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508–7510.
8. Chloro(di-2-norbornylphosphino)(20-dimethylamino-1,10-
biphenyl-2-yl)palladium(II). See also: Liu, B.; Moffett, K.
K.; Joseph, R. W.; Dorsey, B. D. Tetrahedron Lett. 2005,
46, 1779–1782.
In summary, we have demonstrated the synthesis of
phenols or pyridine-2-ones by oxidation of arylboro-
nates which were prepared from arylbromides.17 Since
a variety of arylbromides is readily available, this unified
arylboronation/oxidation protocol provides an access to
substituted phenols or pyridine-2-ones which may not
be easily prepared by other methods. We also have
developed a number of solid-phase methodologies suit-
able for rapid parallel synthesis of substituted phenols
and pyridine-2-one. The bromides of the resin-bound
templates (9–12) have been efficiently replaced with var-
ious building blocks, such as boronic acids, amides,
amines, and acetylenes by well known palladium- or
copper-catalyzed coupling. When combined with other
on-resin functional group manipulations demonstrated
in this report, a very unique set of small molecule
libraries can be generated. Focused libraries prepared
using solid-phase methods described here will be
reported in due course.
9. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421–7428.
10. Other solid-phase synthesis approaches using 11. Reagent
and conditions: (a) LiOH, dioxane/H2O (4:1), 16 h. (b)
N,O-Dimethylhydroxylamine
hydrochloride,
HOBt,
EDCI, DIEA, DCM/DMF, 16 h. (c) CH3MgBr, THF,
2 h. (d) N,N0-Dimethylformamide diethylacetal, 120 ꢁC,
3 h. (e) Guanidine hydrochloride, MeONa, EtOH, 90 ꢁC,
16 h. (f) 50% TFA/DCM, 3 min. (g) NaI, CuI, N,N0-
dimethylethylenediamine, Na2CO3, dioxane, 110 ꢁC, 5 h.
(h) 3-Ethynylpyridine, Cu(phen)(PPh3)Br, K2CO3, tolu-
ene, 110 ꢁC, 16 h. (i) m-Tolylboronic acid, KF, Pd (II),
THF, 65 ꢁC, 16 h.
Br
OH
Br
O
d, e, f
h
a, b, c
11
N
O
g
,
,
f
H2N
N
i, f
Acknowledgments
N
OH
OH
The authors wish to thank Mr. Brandon Campbell and
Dr. Robert Schiksnis for their analytical support.
O
O
Supplementary data
11. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844–14845.
12. Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315–4317.
13. Paul, R.; Hallett, W. A.; Hanifin, J. W.; Reich, M. F.;
Johnson, B. D.; Lenhard, R. H.; Dusza, J. P.; Kerwar, S.
S.; Lin, Y.; Pickett, W. C.; Seifert, C. M.; Torley, L. W.;
Tarrant, M. E.; Wrenn, S. J. Med. Chem. 1993, 36, 2716–
2725.
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2006.05.034.
References and notes
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mixture was diluted with ethyl acetate (100 mL) and
extracted with brine (2 · 50 mL), followed by saturated
sodium bicarbonate (50 mL), and the organic layer was
dried and concentrated. To the crude mixture in acetone
(20 mL) was added an aqueous solution of oxone (12.3 g
in 50 mL of water), and the reaction mixture was stirred
vigorously for 10 min at rt. The reaction was quenched
with aqueous sodium hydrogensulfite. The brown solution
was extracted with ethyl acetate, and the organic layer was
extracted with brine followed by water. After drying of the
organic layer, the resulting crude residue was purified by
silica gel column chromatography using a gradient of
methanol in DCM (0–40%) to obtain 5 (890 mg, 41%). 1H
NMR (400 MHz, acetone-d6) d 9.68 (s, 1H, OH), 7.81 (s,
1H), 7.64 (s, 1H), 7.42 (s, 1H). 13C NMR (100 MHz,
acetone-d6) d 159.1, 149.9, 124.8, 122.6, 117.5, 109.8.
16. Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863–
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17. Synthetic procedure and characterization data of selected
compound 5: To a solution of 1,3-dibromo-5-nitrobenzene
(1, 2.8 g, 10 mmol) in DMSO (30 mL) were added
bis(pinacolato)diboron (2.5 g, 10 mmol), potassium ace-
tate (2.9 g, 30 mmol) and PdCl2(dppf) complex (300 mg),
and the solution was flushed with nitrogen, then the
reactor was sealed. After heating for 6 h at 80 ꢁC, the