New polystyrene-supported stable source of 2-pyridylboron reagent for Suzuki couplings in combinatorial chemistry

Article abstract of DOI:10.1016/j.tetlet.2004.06.098

The first stable polystyrene-supported 2-pyridylboron reagent has been prepared and involved in Suzuki-Miyaura couplings. Very efficient reactions have been obtained with clean release of target coupling products providing a new tool for combinatorial chemistry.

Full text of DOI:10.1016/j.tetlet.2004.06.098

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6239–6241
New polystyrene-supported stable source of 2-pyridylboron
reagent for Suzuki couplings in combinatorial chemistry
Philippe Gros, Abdelatif Doudouh and Yves Fort*
*
Synth e` se Organique et R e´ activit e´ , UMR 7565, Facult e´ des Sciences, Universit e´ Henri Poincar e´ , Nancy,
Boulevard des Aiguillettes, BP 239, 54506 Vandoeuvre-l e` s-Nancy, France
Received 8 June 2004; revised 22 June 2004; accepted 23 June 2004
Abstract—The first stable polystyrene-supported 2-pyridylboron reagent has been prepared and involved in Suzuki–Miyaura cou-
plings. Very efficient reactions have been obtained with clean release of target coupling products providing a new tool for combi-
natorial chemistry.
Ó 2004 Elsevier Ltd. All rights reserved.
The Suzuki–Miyaura reaction is one of the most popu-
lar processes for preparation of unsymmetrical biaryl
compounds. This Pd(0)-catalyzed coupling can be run
sequence leading to N-phenyldiethanolamine-2-pyridy-
boronate apparently stabilized by an excess of i-PrOLi.
We thought that a valuable alternative could be
the immobilization of 2-pyridylboron derivatives on a
solid support. From our knowledge, such an approach
1
under mild conditions with tolerance of a wide range
of functionalities and weak sensitivity to steric effects.
However, the literature essentially reports couplings be-
tween aryl boronic acids or esters and (het)aryl halides
but only scarce examples of use of hetarylboronic deriv-
atives. This is particularly obvious in pyridine series due
to the strong tendency of these sensitive species to
6
successfully used to bind phenylboronic acids, has
never been developed in the far more sensitive pyri-
dine series. Herein, we report the first stable polysty-
rene-supported 2-pyridylboronate and its ability to
effect efficient Suzuki reactions with clean release of
desired bi(het)aryl products thus providing a new tool
for combinatorial synthesis of pyridyl containing
libraries.
2
undergo protodeborylation. The increasing need for
these versatile reagents has drawn the chemists to devel-
op new methodologies to obtain stabilized pyridine bor-
on compounds. The preparation of stable unsubstituted
2
-pyridylboron derivatives remains a synthetic challenge
since Rault and co-workers have shown recently that the
presence of halogens (bromine or chlorine) on the pyri-
dine ring is necessary to ensure the stability of 3-pyridyl
and 2-pyridyl boronic acids. Other works report the
introduction of boron via palladium catalyzed coupling
of 2-halogeno-pyridines with the expensive bis-
OH
Cl
i)
3
N
OH
(
2%DVB)
1
(
pinacolato)diboron reagent but the obtained pyridyl-
boronates were found instable and in situ homocou-
O
B
N
4
5
ii)
Li+
iii)
pled. Hodgson and Salingue recently described a large
scale preparative procedure from 2-bromopyridine using
an in situ lithiation–borylation–transesterification
-
N
N
Br
N
B(OiPr)3
O
2
3
Scheme 1. Reagents and conditions: (i) NH(CH
2
CH
2
OH)
2
(20equiv),
Keywords: Suzuki–Miyaura; Pyridine; Polystyrene.
*
NaI (5equiv), DMF, rt, 48h. (ii) BuLi (1.2equiv), B(Oi-Pr)
3
Corresponding authors. Tel.: +33-3-83-68-43-20; fax: +33-3-83-68-
7-85; e-mail: philippe.gros@sor.uhp-nancy.fr
(1.2equiv), THF, ꢀ78°C then rt, 4h. (iii) 1 (0.3equiv), THF, reflux,
4
12h.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.098

6240
P. Gros et al. / Tetrahedron Letters 45 (2004) 6239–6241
a
Table 1. Conditions screening for cross coupling of 3 with PhI
PhI, PdCl (PPh )
3 2
2
O
N
PPh , base
3
N
B
O
+
DMF, reflux, 12h
N
2
3
4a
5
b
b
5%
Run
PhI (equiv)
Base (equiv)
Additive (%)
Co-solvent
4a%
1
2
3
4
5
6
7
8
9
1.2
2
Et
Et
Et
3
3
3
N (2)
N (3)
N (5)
––
––
––
––
––
Tr
Tr
Tr
Tr
3
30
40
35
15
31
70
19
––
––
5
––
2
K
2
CO
3
(3)
––
––
H
H
2
O
O
2
CsF (3)
CsF (3)
CsF (3)
CsF (3)
CsF (3)
2
2
––
––
––
––
––
––
6
23
1.5
1.5
1.5
c
CuI (10%)
CuI (10%)
90 (85)
d
30
a
b
c
Reaction carried out on 500mg (0.62mmol).
GC yields.
Isolated yield after column chromatography.
d
3
Performed in absence of PPh .
Among suitable linkers, we chose the diethanolamino
group known as an efficient boronic acid scavenger
due to an additional boron chelation by the nitrogen
the resin and subsequent elution of the filtrate through a
short pad of silica. Moreover, elemental analysis of the
resin after coupling revealed a quantitative release of
the pyridine moiety.
6
a
lone pair. The supported 2-pyridinedioxazaborocane
7
3
7
was obtained as a pale pink solid (1.25mequiv/g,
8
0% yield from 1) by refluxing 0.3equiv of aminodiol
The scope of the reaction was then examined by reacting
3 with a range of aromatic and heteroaromatic halides
under the above determined best conditions (Scheme 2
8
resin 1 (1.8mequiv/g) in THF with the ate complex 2
prepared by in situ trapping of 2-lithiopyridine with tri-
isopropylborate (Scheme 1).
1
0
and Table 2).
The obtained supported reagent was then involved in
Pd-catalysed Suzuki coupling under various conditions
All reactions led to the expected cross-coupling products
in good yields with electron-rich and electron-deficient
aryl and heteroaryl halides. Iodo aromatic compounds
were reacted efficiently with an expected slight yield
decrease with 2-iodo and 4-iodo anisole due to steric
effects and deactivating electron-donor effect, respec-
tively. 4-Bromo-N,N-dimethylaniline surprisingly gave
4d in 77% yield. This kind of electron-rich bromo deriv-
ative generally led to poor yields in cross-coupling reac-
(
5
Table 1). We chose to catalyze the reaction with
mol% of the commonly used PdCl (PPh ) complex
2
3 2
in DMF, a good solvent for both the Suzuki coupling
and polystyrene swelling. As shown, the base had a large
impact on the reaction selectivity. CsF was the most effi-
cient (runs 8–9), may be due to the formation of a
PyrBF ate complex enhancing efficiently trans-metalla-
ꢀ
3
tion step. A spectacular improvement was further
obtained by addition of CuI, leading to 4a in very good
9
5
tions. Bromoarenes bearing electron-withdrawing
groups also coupled efficiently. Very good yields were
also obtained for preparation of dissymmetrical bis-het-
erocycles from both brominated or chlorinated
substrates. Interestingly, the coupling of 2,6-dichloro-
pyridine proceeded with full retention of the syntheti-
cally useful C–Cl bond in 4h.
85% isolated yield (run 9) with disappearance of homo-
coupling product 5. Under these conditions a very clean
reaction medium was obtained after simple filtration of
In summary, we have prepared the first supported stable
1
1
source of 2-pyridylboronate. This new useful organo-
metallic reagent has been successfully reacted with a
range of (het)aryl halides leading to coupling products
in high yields. This study opens new perspectives for
the Suzuki coupling in combinatorial chemistry espe-
O
B
O
N
i)
N
N
(Het)Ar
3
4b-k
0
cially for preparation of 2-x bisheterocycles. Work is
now in progress to extend the reaction to immobilization
of functional pyridines and other sensitive heterocyclic
derivatives.
Scheme 2. Reagents and conditions: (i) (Het)ArX (1.25equiv),
PdCl (PPh (5%), PPh
(10%), CuI (10%), DMF, 80°C, 30min, then
CsF (3equiv), 3, DMF, reflux, 12h.
2
3
)
2
3

P. Gros et al. / Tetrahedron Letters 45 (2004) 6239–6241
6241
a
Table 2. Coupling of 3 with aromatic and heteroaromatic halides
References and notes
c
(
Het)ArX
Product
MeO
Yield%
1
. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Suzuki, A. In Metal-Catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Chapter 2; (c) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147; (d) Franzen, R. Can. J. Chem. 2000,
78, 957; (e) Kotha, S.; Lahiri, K.; Kashinath, D. Tetra-
hedron 2002, 58, 9633.
2. Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001,
7, 9813.
3. Bouillon, A.; Lancelot, J.-C.; de Oliveira Santos, J. S.;
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59,
10043.
4. Fuller, A. A.; Hester, H. R.; Salo, E. V.; Stevens, E. P.
Tetrahedron Lett. 2003, 44, 9813.
. Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004,
45, 685.
I
OMe
4
4
b
c
60
N
OMe
MeO
MeO
I
82
N
N
N
N
N
N
5
OMe
4d
67
50
77
I
Br
4
e
5
6
N
4d
4e
4f
N
Br
. (a) Hall, D. G.; Taylor, J.; Gravel, M. Angew. Chem., Int.
Ed. 1999, 38, 3064; (b) Carboni, B.; Pourbaix, C.;
Carreaux, F.; Deleuze, H.; Maillard, B. Tetrahedron Lett.
b
O N
Br
NO2
F
56
2
1
999, 40, 7979; (c) Pourbaix, C.; Carreaux, F.; Carboni, B.
Org. Lett. 2001, 3, 803; (d) Gravel, M.; Thomson, K.; Zak,
M.; B e´ rub e´ , C.; Hall, D. G. J. Org. Chem. 2002, 67, 3.
. From Ref. 5, the immobilized azaborocane 3 was assumed
to have the structure depicted in Scheme 1. Investigations
are in progress to obtain a more accurate structure using
gel phase HRMAS NMR.
. The loadings were obtained by elemental analysis.
9. Wright, S. W.; Hageman, D. L.; Mc Clure, L. D. J. Org.
Chem. 1994, 59, 6095.
F
Br
70
87
67
7
N
N
Br
Br
4
4
g
h
N
N
Cl
8
Cl
N
N
Cl
Br
N
N
1
0. Typical procedure for Suzuki coupling with 3. A mixture
of the (het)aryl halide (1.56mmol), PdCl
%), PPh (32mg, 10%) and CuI (24mg, 10%) in DMF
5mL) was heated at 80°C under inert atmosphere for
0min. CsF (0.57g, 3.75mmol) was then added followed
2 3 2
(PPh ) (44mg,
d
4
4
i
j
85
5
(
3
3
N
N
by resin 3 (1g, 1.25mmol). The suspension was then
maintained under reflux for 12h. After cooling the mixture
was filtered and the filtrate passed through a short pad of
silica. Evaporation and column chromatography afforded
pure homocoupling products, which spectroscopic data
were in full agreement with those of known compounds.
1. After preparation, the resin 3 was simply stored at room
temperature into an argon flushed flask. The nitrogen
content was found constant after 5 months and couplings
proceeded with the same efficiency after such period.
78
79
N
N
N
S
Br
4k
S
a
b
c
All reactions performed on 1g (1.25mmol) of resin 3.
0% GC yield, material was lost by degradation during separation.
Isolated yields after column chromatography.
1
9
d
Bipyridine 4g was obtained in trace amount.