Suzuki coupling reaction for the solid-phase preparation of 5-substituted nicotinic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.11.153

The application of the Suzuki coupling reaction to the preparation of small combinatorial libraries using 5-bromonicotinic acid as a scaffold onto three different types of solid support (Wang, Rink, and BAL resin) is described. The application of the Suzuki coupling reaction to the preparation of small combinatorial libraries using 5-bromonicotinic acid as a scaffold onto three different types of solid support (Wang, Rink, and BAL resin) is described.

Full text of DOI:10.1016/j.tetlet.2004.11.153

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 581–585
Suzuki coupling reaction for the solid-phase preparation of
5-substituted nicotinic acid derivatives
a,
Joan-Carles Fernandez, Laia Sole-Feu, Dolors Fernandez-Forner,
a
b
*
`
´
´
Natalia de la Figuera,a Pilar Fornsa and Fernando Albericioc
aAlmirall Prodesfarma-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
bResearch Center, Almirall Prodesfarma, Cardener 68-74, 08024 Barcelona, Spain
cBarcelona Biomedical Research Institute, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
Received 22 October 2004; revised 23 November 2004; accepted 29 November 2004
Abstract—The application of the Suzuki coupling reaction to the preparation of small combinatorial libraries using 5-bromonicot-
inic acid as a scaffold onto three different types of solid support (Wang, Rink, and BAL resin) is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The formation of carbon–carbon bonds on solid-phase1
is a particularly useful transformation but has been
slower in coming of age than other solid-phase reac-
tions. Pd-catalyzed coupling reactions2 are the most pre-
valent method for creating carbon–carbon bonds in
both solution and solid-phase. The Pd-catalyzed Suzuki
reaction of aryl halides with boronic acids has emerged
as a powerful tool in SPOS owing to its mild reaction
conditions, compatibility with most functional groups
and the wide availability of boronic acids.
coupling reactions is demonstrated in this work. We
have thus found that Suzuki reactions employing either
Wang or amide-bound resins afford distinct results.
Application of the Suzuki coupling reaction to the pre-
paration of small combinatorial libraries on three differ-
ent types of solid-support using 5-bromonicotinic acid4
as a scaffold is discussed.
In the synthetic approach used, 5-bromonicotinic acid
was first attached to a commercial Wang resin using
1,3-diisopropylcarbodiimide (DIC) and 1-hydroxy-ben-
zotriazole (HOBt) in N,N-dimethylformamide (DMF)
in the presence of a catalytic amount of N,N-dimethyl-
aminopyridine (DMAP). In order to optimize the Suzuki
reaction conditions, several bases and palladium cata-
lysts were first studied using 3 equiv of 4-fluoro-
phenylboronic acid (Table 1). Reactions were carried
out on a 60 lmol scale, using Pd(PPh3)4 or [PdCl2(dppf)]
Our group is developing strategies for generating pri-
mary screening small libraries3 from which pharmaceu-
tically attractive lead compounds may arise.
The success of a solid-phase synthesis is highly depen-
dent on both the starting solid support and linker used.
The relevance of these factors to the outcome of Suzuki
Table 1. Representative conditions found for Suzuki Coupling on Wang Resin
Entry
Solvent
Catalyst
Base
4 eq 2M Na 2CO3
10 eq Et3N
Purity (%)
Yield (isolated) (%)
1
2
3
4
5
6
DMF
0.2eq PdCl 2(dppf)
0.2eq PdCl 2(dppf)
5% Pd(PPh3)4
75
80
50–60
50
50
DMF/H2O (9:1)
DMF/H2O (9:1)
Toluene/EtOH (9:1)
DMF
3 eq K3PO4
4 eq 2 M Na2CO3
3 eq K3PO4
3 eq K3PO4
75
50
5% Pd(PPh3)4
5% Pd(PPh3)4
5% Pd(PPh3)4
60–80
>80
70
>95
80
DME
Keywords: Combinatorial chemistry; Wang resin; Rink resin; Bal resin; 5-Bromonicotinic acid; Suzuki coupling; Solid-phase organic synthesis.
*
Corresponding author. Tel.: +34 934 034 705/06; fax: +34 934 037 109; e-mail: jcfernandez@pcb.ub.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.153

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J.-C. Fernandez et al. / Tetrahedron Letters 46 (2005) 581–585
582
salt after cleavage with trifluoroacetic acid (TFA)/
dichloromethane (DCM) (1:1) (Scheme 1). All reaction
1
steps were monitored by H NMR and mass spectro-
metry (MS) of cleaved resin aliquots.
In conclusion, Pd(PPh3)4 is a better catalyst than
PdCl2(dppf), which contaminates the final sample.
When K3PO4 was replaced with stronger bases, such
as Na2CO3 or Et3N, the observation of unreacted start-
ing material in the crude product led to the conclusion
that reaction completion requires an appropriate base
strength. The presence of water in the reaction is detri-
mental to the isolated yield, presumably because of
hydrolysis of the ester bond. Hence the use of water in
the reaction system should be avoided. DMF as a sol-
vent gave slightly better results.
Scheme 1. Reagents and conditions: (i) 5-bromonicotinic acid, DIC,
HOBt, DMAP in DMF, (ii) see Table 1 for conditions, (iii) TFA/DCM
(1:1) (2 · 10 min).
as catalyst; Na2CO3, K3PO4, or Et3N as base, and the
following degassed solvents: toluene/ethanol, dimeth-
oxyethane (DME), DMF and DMF/H2O. Reaction
mixtures were heated at 80 ꢁC for 1 day to produce the
5-(4-fluorophenyl)-nicotinic acid 1 as its trifluoroacetate
A variety of 24 boronic acids were tested in Suzuki reac-
tion5 (representative examples are shown in Table 2)
employing the optimized conditions (entry 5: Pd(PPh3)4,
K3PO4, and DMF as solvent). 5-Substituted nicotinic
Table 2. 5-Substituted nicotinic acids prepared from Wang resin
Reagent
Product
Yielda (%)
Purityb (%)
MSc [M+H]+
F
O
F
HO
84
93
220
B
OH
OH
N
N
1
2
HO
S
O
S
HO
75
78
248
B
HO
O
O
O
HO
O
80
94
246
O
B
OH
N
3
HO
O
O
O
HO
79
81
75
90
96
89
260
208
190
O
N
O
B
OH
4
5
6
HO
B
O
HO
HO
HO
N
N
O
HO
HO
HO
B
N
N
a Yields (%) are based on the weight of crude material and are relative to the initial loading of the resin.
b The purity of the crude material was estimated from analytical HPLC at k = 210 nm.
c Confirmed by mass spectra (ESI).

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J.-C. Fernandez et al. / Tetrahedron Letters 46 (2005) 581–585
583
acids were isolated in good yield (75–89%) and purity
(78–96%). All products were identified by LC-MS
equipped with a diode array detector (Table 2). The re-
sults illustrate the tolerance of the reaction for a broad
array of boronic acids. The final conditions allowed
for a wide variation in arylboronic acids; good results
were obtained for neutral, electron-withdrawing, and
electron-donating functionalities alike.
inferior results (44% of conversion) on Rink-amide re-
sin. These results are in agreement with earlier findings
by Lago et al., who reported that heating Suzuki cou-
pling reactions on Rink resin at 90–95 ꢁC in toluene/eth-
anol (9:1) for 24 h is required in order to achieve total
conversion (see Scheme 3). Taking these findings into
consideration, a small library of 24 nicotinamides was
prepared in high purity (>80%).
In order to introduce an additional point of diversity
into the library and to check the scope and limitations
of the previously optimized Suzuki reaction conditions,
additional syntheses were performed. Fmoc-amino acids
were loaded onto Wang resin and, after Fmoc removal,
were subsequently acylated at their free amines with
5-bromonicotinic acid under standard coupling
conditions.3b
In the BAL approach, primary amines (the second point
of diversity for the case at hand) are attached to a 4-form-
yl-3-dimethoxyphenyloxymethyl-functionalized
poly-
styrene resin (BAL) via reductive amination, and used
to make alkylamino resins, which were subsequently
acylated with 5-bromonicotinic (see Scheme 4).
Although total conversion was achieved when 5-bromo-
nicotinamide-BAL resins were reacted under the opti-
mal Suzuki reaction conditions found for Wang resin
(entry 5 in Table 1), compounds were obtained in
slightly higher purity when the BAL resins were reacted
under the optimized Rink conditions.6 Using the latter
reaction conditions a small library of 180 secondary nico-
tinamides was thus obtained7 in good yield (75–85%)
and high purity (71–96%) (representative examples are
shown in Table 3).
When aminoacyl-bromonicotinic ester-bound resins
were treated with 4-fluorophenylboronic acid under
the aforementioned reaction conditions (Table 1, entry
5), the resulting products were obtained with high purity
and in good yield (see Scheme 2). These results show
that the optimized Suzuki reaction conditions also work
well when an aliphatic ester is bound to the polymer
support.
In summary, libraries of 5-substituted nicotinic acid
derivatives were prepared in extremely good yield and
high purity on three different solid supports (Wang,
Rink, and BAL resin) via the Suzuki cross-coupling
reaction. Fine tuning of the experimental conditions
for each resin was required. For amide resins, the best
reaction conditions employed aqueous Na2CO3 in tolu-
ene/EtOH (9:1) as solvent. In the case of ester-bound
Another point of diversity has been introduced into our
libraries by using Rink and BAL resins3 as a solid sup-
port in order to prepare primary and secondary amides,
respectively. Thus 5-bromonicotinic acid was incorpo-
rated onto commercial Rink and alkylamino-BAL resins
via standard conditions. Application of the best Suzuki
reaction conditions found for Wang-ester resin gave
Scheme 2. Reagents and conditions: (i) Fmoc-L-AA-OH, HOBt, DIC, DMAP in DCM/DMF (1:1), (ii) piperidine/DMF (4:1), (iii) 5-bromonicotinic
acid, DIC, HOBt, DMAP in DMF, (iv) see Table 1, entry 5, for conditions, (v) TFA/DCM (1:1) (2 · 10 min).
Scheme 3.

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J.-C. Fernandez et al. / Tetrahedron Letters 46 (2005) 581–585
584
Scheme 4.
Table 3. 5-Substituted nicotinamides prepared from BAL resin
a
R1
R2Product
Yield
(%)
Purityb (%)
MSc [M+H]+
F
O
O
O
F
NH2
N
H
80
94
275
B
OH
N
10
HO
HO
O
S
O
O
79
71
378
S
N
H
NH2
B
OH
OH
11
N
O
O
H
N
O
O
N
O
O
85
75
90
96
328
299
H
HN
O
NH2
NH2
O
B
N
12
HO
O
O
HO
OH
N
H
B
OH
HO
N
13
a Yields (%) are based on the weight of crude material and are relative to the initial loading of the resin.
b The purity of the crude material was estimated from analytical HPLC at k = 210 nm.
c Confirmed by mass spectra (ESI).
resins, however, anhydrous conditions using K3PO4 in
DMF were required for optimum results.
References and notes
1. For an overview see: Sammelson, R. E.; Kurth, M. J. Chem.
Rev. 2001, 101, 137–202, and references cited therein.
2. Bra¨se, S.; Kirchhoff, J. K.; Ko¨bberling, J. Tetrahedron
2003, 59, 885–939, and references cited therein.
Acknowledgements
´
3. (a) Forns, P.; Sevilla, S.; Erra, M.; Ortega, A.; Fernandez,
J.-C.; de la Figuera, N.; Fernandez-Forner, D.; Albericio,
Authors thank Drs Graham Warelow and Hammish
Ryder for their encouragement to perform the work.
´
F. Tetrahedron Lett. 2003, 44, 6907–6910; (b) Yraola, F.;

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J.-C. Fernandez et al. / Tetrahedron Letters 46 (2005) 581–585
585
´
Ventura, R.; Vendrell, M.; Colombo, A.; Fernandez, J.-C.;
de la Figuera, N.; Fernandez-Forner, D.; Royo, M.; Forns,
P.; Albericio, F. QSAR Comb. Sci. 2004, 23, 145–
152.
MeOH (·3). Cleavage was performed using TFA/DCM
(1:1) (2 · 10 min). The solvent was evaporated and the
resulting residue was analyzed by HPLC/LC-MS and 1H
NMR. Compound 1: 1H NMR (400 MHz, DMSO-d6) d
9.10 (d, J = 2.0 Hz, 1H); d 9.06 (d, J = 2.0 Hz, 1H); d 8.47
(t, J = 2.0 Hz, 1H); d 7.85 (dd, J = 9.0, 5.2Hz, 2H); d 7.35
(t, J = 9.0, 2H).
´
4. For examples of Pd(0) catalyzed cross-coupling of such
substrate in solid-phase see: (a) Chamoin, S.; Houldsworth,
S.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4175–4178;
Marquais, S.; Arlt, M. Tetrahedron Lett. 1996, 37, 5491–
5494; For exemples of Pd(0) catalyzed cross-coupling of
such substrate in solution-phase see: (b) OÕNeill, B. T.;
Yohannes, D.; Bundesmann, M. W.; Arnold, P. E. Org.
Lett. 2000, 2, 4201–4204; Doll, M. K.-H. J. Org. Chem.
1999, 64, 1372–1374; Banwell, M. G.; Cameron, J. M.;
Corbett, M.; Dupuche, J. R.; Hamel, E.; Lambert, J. N.;
Lin, C. M.; Mackay, M. F. Aust. J. Chem. 1992, 45, 1967–
1982; Thompson, W. J.; Jones, J. H.; Lyle, P. A.; Thies, J.
E. J. Org. Chem. 1988, 53, 2052–2055; Thompson, W. J.;
Gaudino, J. J. Org. Chem. 1984, 49, 5237–5243.
5. General procedure for Suzuki reactions on Wang solid
support (compounds 1–6): 5-Bromonicotinic ester-bound
resin (1.2mmol/g, 60 mg) was suspended in degassed DMF
(1 mL). Pd(PPh3)4 (5 mol %, 4 mg) was then added to the
resin and the mixture was agitated for 10 min. K3PO4 (3 eq,
0.21 mmol, 42 mg) and boronic acid (3 eq, 0.21 mmol) were
added to the resin, the mixture was degassed under Ar for
1 min and was subsequently shaken for 24 h at 80 ꢁC. The
resin was then filtered and washed with DMF, DCM, and
6. Lago, M. A.; Nguyen, T. T.; Bhatnagar, P. Tetrahedron
Lett. 1998, 39, 3885–3888.
7. General procedure for Suzuki reactions on BAL solid
support (compounds 10–13): 5-Bromonicotinic amide-
bound resin (0.9 mmol/g, 60 mg) was suspended in degassed
toluene/EtOH (9:1) (1 mL:0.2mL). Pd(PPh 3)4 (5 mol %,
4 mg) was then added to the resin and the mixture was
agitated for 10 min. 2M Na 2CO3 (6 equiv, 0.32mmol,
162 lL) and boronic acid (3 equiv, 0.162mmol) were added
to the resin, the mixture was degassed under Ar for 1 min
and was subsequently shaken for 24 h at 90 ꢁC. The resin
was then filtered and washed with DMF, DCM, and
MeOH (·3). Cleavage was performed using TFA/DCM
(1:1) (2 · 15 min). The solvent was evaporated and the
resulting residue was analyzed by HPLC/LC-MS and 1H
1
NMR. Compound 10: H NMR (400 MHz, DMSO-d6) d
9.00 (d, J = 2.0 Hz, 1H); d 8.96 (d, J = 2.0 Hz, 1H); d 8.43
(t, J = 2.0 Hz, 1H); d 7.85 (dd, J = 9.0, 5.2Hz, 2H); d 7.36
(t, J = 9.0 Hz, 2H); d 3.47 (m, 2H); d 3.33 (m, 2H); d 3.27 (s,
3H).