Single-flask preparation of polyazatriaryl ligands by sequential borylation/Suzuki-Miyaura coupling

Article abstract of DOI:10.1016/j.tetlet.2011.01.136

We report a convenient single-flask methodology for the preparation of polyazatriaryl products with relevance to luminescence, catalysis, and pharmacology. The diborylation of 1,3-dibromobenzenes and double Suzuki-Miyaura coupling produces 1,3-diheteroarylbenzenes. Similarly, borylation of heteroaryl halides and double coupling to 2,6-dichloropyridine produces 2,6-diheteroarylpyridines. This methodology appears general in producing challenging polyheteroaryl targets as long as the boronic esters have no ortho heteroatoms and coupling avoids adjacent oxygens.

Full text of DOI:10.1016/j.tetlet.2011.01.136

Tetrahedron Letters 52 (2011) 1631–1634
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Single-flask preparation of polyazatriaryl ligands by sequential
borylation/Suzuki–Miyaura coupling
⇑
Bertoldo Avitia, Eric MacIntosh, Samuel Muhia, Eric Kelson
Department of Chemistry and Biochemistry, California State University, Northridge, 18111 Nordhoff Street, Northridge, CA 91330, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a convenient single-flask methodology for the preparation of polyazatriaryl products with rel-
evance to luminescence, catalysis, and pharmacology. The diborylation of 1,3-dibromobenzenes and dou-
ble Suzuki–Miyaura coupling produces 1,3-diheteroarylbenzenes. Similarly, borylation of heteroaryl
halides and double coupling to 2,6-dichloropyridine produces 2,6-diheteroarylpyridines. This methodol-
ogy appears general in producing challenging polyheteroaryl targets as long as the boronic esters have no
ortho heteroatoms and coupling avoids adjacent oxygens.
Received 14 September 2010
Revised 24 January 2011
Accepted 26 January 2011
Available online 1 February 2011
Keywords:
Single-flask
Ó 2011 Elsevier Ltd. All rights reserved.
Suzuki–Miyaura coupling
Borylation
Terpyridines
Tridentate ligands
1. Introduction
1,3-di(pyridin-2-yl)benzene has been replaced by the more effi-
cient reaction of 1,3-dicyanobenzene with excess acetylene cata-
Bisheteroarylbenzenes and bisheteroarylpyridines have at-
tracted recent interest for their application in electroluminescent
displays, catalysts, and pharmaceuticals. Ruthenium, iridium, and
platinum complexes with 1,3-di(pyridin-2-yl)benzene ligands
have been studied for their luminescent and electroluminescent
properties particularly in conjunction with 2,20:60,200-terpyridines
(terpys).1–5 Palladium, platinum, and mercury complexes with
1,3-di(pyridin-2-yl)benzene itself have been demonstrated as
catalysts for the Heck reaction, and analogy of 1,3-diheteroaryl-
benzenes and 2,6-diheteroarylpyridines to terpy suggests an
application to other catalytic systems.6,7 Further, 1,3-di(benzo[d]-
thiazol-2-yl)benzene and 3,20:60,300-terpyridine themselves have
even been studied as pharmaceuticals for calcium transport
control and antitumor activity, respectively.8,9
Several methodologies have been reported for preparing 1,3-
diheteroarylbenzenes and 2,6-diheteroarylpyridines but each is
somewhat limited in its scope. The older methods entail condensa-
tion of the end rings such as the reaction of 2-aminothiophenol
with phthaldialdehyde to produce 1,3-di(benzo[d]thiazol-2-
yl)benzene.9 Substituted 1,3-di(pyridin-2-yl)benzenes have simi-
larly been prepared by condensing pyridine rings through the reac-
tion of 1,3-diacetylbenzene, the corresponding enones, and
ammonium acetate.6,10 The ring condensation method of preparing
lyzed by organometallic cobalt complexes.7,11,12 Stille coupling of
3-trimethylstannylpyridine or 2-tri-n-butylstannylpyridine to
1,3-dibromobenzenes represents a more modern and modular
methodology for preparing 1,3-di(pyridinyl)benzenes.3,5,13–16 The
analogous Suzuki–Miyaura coupling of pyridin-3-ylboronic pinacol
ester to 2-chloropyridine to form 2,30-bipyridine as well as
pyridin-3-ylboronic acid to 2,6-dichloropyridine to form 3,20:
60,300-terpyridine offers the advantage of lower toxicity than Stille
coupling.16–19
Recently, the inconvenience of isolating boronic esters for Suzu-
ki–Miyaura arene coupling reactions has been side-stepped by sin-
gle-flask methodologies that produce these sensitive intermediates
in situ. In one such strategy employed specifically toward pyri-
dines, boronic ester intermediates are produced by the directed
ortho metallation–borylation of chloro-, fluoro-, O-carbamoyl pyr-
idines followed by coupling to aryl iodides and bromides. Unfortu-
nately, this method requires the pyridine ring to bear electron
withdrawing directing groups and has only been demonstrated
for monoazabiaryl products.20 A more generalized one-flask aryl–
aryl coupling strategy entails the borylation of an aryl chloride
and subsequent Suzuki–Miyaura coupling to a second aryl chlo-
ride.21–24 This method typically utilizes a modest base such as
KOAc to achieve the borylation of aryl chlorides with a palladium
catalyst and subsequent coupling of the product arylboronic ester
to another aryl halide with the addition of a stronger base such
as K2CO3 or K3PO4. While this methodology is applicable to a wide
range of aryl–aryl couplings, the borylation of pyridyl rings
⇑
Corresponding author. Tel.: +1 818 677 2699; fax: +1 818 677 4068.
E-mail address: eric.kelson@csun.edu (E. Kelson).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.136

1632
B. Avitia et al. / Tetrahedron Letters 52 (2011) 1631–1634
remains challenging and the coupling of arylboronic esters has
been demonstrated to only 2-pyridine, 2 and 3-quinoline, and
3-thiophene heterocycles.23,24 Overall, the scope of this methodol-
ogy has not been widely explored or optimized for aryl–aryl
coupling with heterocycles.
We report here a single-flask method optimized for the boryla-
tion and subsequent double Suzuki–Miyaura aryl–aryl coupling
with heterocycles for the convenient and efficient preparation of a
variety of 1,3-bisheteroarylbenzenes and 2,6-bisheteroarylpyri-
dines with the potential as chelating or bridging ligands in transition
metal complexes. This work explores the scope and limits of the
borylation/coupling strategy to a range of heterocycles and demon-
strates its applicability to challenging polyheteroaryl targets.
balance of reagent and yield calls for 3 equiv of 3-bromopyridine
with respect to the diboronic ester resulting in a near complete
conversion of diboronic ester into product.
The single-flask borylation/double coupling methodology was
easily extended to the preparation of symmetric 1,3-bisheteraryl-
benzenes and 3,5-bisheteroarylpyridines. 2-Bromopyridines
are readily converted into the boronic esters except that a signifi-
cant amount of homocoupling occurs to form 2,20-bipyridines.
Surprisingly, the Pd(dppf)Cl2 catalyst readily converts 2-chloropyr-
idine into the boronic esters without significant homocoupling.
Though this catalytic system does not boronate 3-chloropyridines,
the 3-bromopyridines are readily boronated with little homocou-
pling. Unfortunately, pyridin-2-ylboronic pinacol esters were prac-
tically unreactive in the Suzuki coupling with bromoarenes using
the Pd(dppf)Cl2 catalyst. This is consistent with the literature re-
ports of poor yields for Suzuki–Miyaura coupling of 2-heterocylic
boronic esters attributed to slow transmetalation from boron to
palladium versus competitive protodeboronation.25 Strategies for
facilitating 2-heterocycle transmetalation through organocopper
intermediates or palladium phosphine oxide or chloride catalysts
have resulted in modest coupling yields.26–28 Efforts are underway
to incorporate these strategies into our single-flask protocols. In
spite of difficulties with pyridin-2-ylboronic pinacol esters, 2-chlo-
ropyridines readily couple with 1,3-phenylenediboronic pinacol
esters (Table 1). The borylation/double coupling proceeds to 70–
95% conversion with 50% excess of a range of 2-chloropyridine
starting materials (entries 2–7). The borylation/double coupling
methodology is tolerant of electron withdrawing and releasing
substituents on the center and outer rings even in the potentially
crowding 6 and 600-positions. This method is also applicable to 5-
or 6-member end rings with one or more nitrogens ortho to the
coupling position (entries 8–11). The coupling reaction tolerates
sulfur (entry 11) but not oxygen adjacent to the coupling carbon
(entry 12). Substitution on the central 1,3-dibromopyridine is also
tolerated (entry 13), and 3,5-dibromopyridine can be used in place
of 1,3-dibromopyridines since the nitrogen is not ortho to either
borylation site (entry 14).
2. Results and discussion
Our single-flask borylation/Suzuki coupling methodology was
first optimized for the preparation of 1,3-di(pyridin-3-yl)benzene
and required significant modification of the previously reported sin-
gle-flask method for biarenes.21 The borylation of 3-bromopyridine
using Pd(dppf)Cl2 catalyst and KOAc in dioxane required modest
hydration of the solid KOAc for reactivity, but the absorbed water
also resulted in a significant reduction of the 3-bromopyridine to
pyridine. Even with an acceptable balance of KOAc hydration, the
reaction in dioxane was slow requiring several hours at reflux to
achieve 90% yield of the pyridine-3-ylboronic pinacol ester. How-
ever, the reaction of 3-bromopyridine with bis(pinacolato)diboron,
KOAc, and 4 mol % Pd(dppf)Cl2 catalyst in DMF resulted in greater
than 95% borylation in 1–2 h (Scheme 1) with no sensitivity to KOAc
hydration. The subsequent addition of 1,3-dibromobenzene and
either aqueous K2CO3 or K3PO4 to the hot DMF reaction results in a
slow double coupling to 1,3-di(pyridinyl-3-yl)benzene over 15 h
without the need for an additional catalyst. However, the use of
aqueous NaOH as the base dramatically achieved complete coupling
within only 2–3 h (Scheme 1). Hydrolysis of DMF by the aqueous
NaOH does not interfere in the aryl coupling or product isolation.
In subsequent testing, the general conditions represented by
Scheme1 proved to be rapid and effectivein producing1,3-dihetero-
arylbenzenes as well as 2,6-diheteroarylpyridines.
The analogous single-flask borylation of 2,6-dibromobenzene
and subsequent double Suzuki coupling to 3-bromopyridine is also
very effective in producing 1,3-di(pyridin-3-yl)benzene (Scheme
2). 2,6-Dibromobenzene readily diboronates with bis(pinacola-
to)diboron, sodium acetate, and 4 mol % Pd(dppf)Cl2 in DMF. The
addition of 3-bromopyridine and aqueous sodium hydroxide to
the reaction solution results in the rapid formation of the single
coupling product that more slowly couples to a second equivalent
of 3-bromopyridine. While the addition of excess 3-bromopyridine
drives the reaction quicker and closer to completion, the addition
of the additional catalyst does not improve the final yield. The best
In general, the tandem borylation/coupling strategy appears
widely applicable as long as the boronic ester itself does not have
a nitrogen ortho to the coupling position. As mentioned, 3,5-dib-
romopyridine serves well as the center ring to form 2,30:50,200-ter-
pyridine. 2,6-Heteroarylpyridine products can be analogously
prepared by boronating the outer rings and coupling them to
2,6-dichloropyridines as long as the outer rings do not have ortho
heteroatoms (Scheme 3). These reactions proceed to the disubsti-
tuted products in good yields and do not need an excess of either
the end or center ring reactants.
Overall, this one-flask borylation/double coupling strategy is
effective and should be applicable to many products beyond those
illustrated in this communication. Further, the Supplementary data
% Yield: 99/90
(GC/isolated)
4.0% Pd(dppf)Cl2, KOAc
O
O
bis(pinacolato)diboron
Br
Br
Br
B
(same flask)
NaOH (aq), 130 °C, 3 h
DMF, 130 °C, 2 h
N
N
N
N
Scheme 1. Single-flask borylation of 3-bromopyridine and Suzuki–Miyaura coupling to 1,3-dibromobenzene.
% Yield: 99/89
(GC/isolated)
4.0% Pd(dppf)Cl2, KOAc
bis(pinacolato)diboron
Br
O
O
N
B
B
DMF, 100 °C, 1 h
(same flask)
NaOH (aq), 130 °C, 3 h
O
O
Br
Br
N
N
Scheme 2. Alternative single-flask diborylation of 1,3-dibromobenzene and Suzuki–Miyaura coupling to 3-bromopyridine.

B. Avitia et al. / Tetrahedron Letters 52 (2011) 1631–1634
1633
Table 1
bis(pinacolato)diboron
Pd(dppf)Cl2, KOAc,
DMF, 130 °C, 2 h
1)
2)
Products of single-flask diborylation of 1,3-dibromobenzenes and subsequent Suzuki–
Miyaura coupling to halogenated heterocyles
Br
X
X
N
X
N
bis(pinacolato)diboron
Pd(dppf)Cl2, KOAc,
DMF, 130 °C, 2 h
1)
(same flask)
2,6-dichloropyridine
NaOH (aq), 130 °C, 3 h
X
X
N
N
3a: X=C–H
3b: X=N
4a: X=C–H (99/60)a
4b: X=N (99/59)a
Br
1a: X=C–H
1b: X=C–Cl
Br
hetAr
hetAr
(same flask)
hetAr–Y (Y=Cl, Br)
NaOH (aq), 130 °C, 3 h
2)
2a: X=C–H
2b: X=C–Cl
2c: X=N
Scheme 3. Products of single-flask borylation of bromoheterocycles and subse-
quent Suzuki–Miyaura coupling to 2,6-dichloropyridine. Percent yields measured
by GC/isolation. Slow, irreversible binding of products to preparative TLC gels
responsible for large yield differences.
1c: X=N
Entry
1
hetAr-Y
2
Yielda
99/89
Br
1
1a
2a
3. General procedure for one-flask borylation/Suzuki–Miyaura
coupling illustrated with borylation of 1,3-dibromobenzene
and coupling to 3-bromopyridine to prepare 2a (hetAr =
3-pyridine) (Table 1, entry 1)
N
Cl
2
3
1a
1a
2a
2a
73/64
67/59
N
Cl
To degassed DMF (8.0 mL) was added Pd(dppf)Cl2 (73 mg,
0.10 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), potassium
acetate (589 mg, 6.0 mmol), and 2,6-dibromobenzene (0.121 mL,
236 mg, 1.0 mmol) in order at room temperature. The mixture
was heated to 130 °C for 1 h to complete formation of the boronic
ester. Then 3-bromopyridine (0.289 mL, 474 mg, 3.0 mmol) and
degassed aqueous sodium hydroxide (2.00 mL, 3.0 M, 6.0 mmol)
were sequentially added to the hot reaction, and heating at
130 °C was continued for another 3 h when the reaction was com-
plete (by GC–MS). The reaction was cooled and evaporated to a res-
idue in vacuo. The residue was extracted with chloroform, and the
combined extracts were concentrated and applied to preparative
silica TLC plates. After development by 1:1 THF/EtOAc the product
bands were removed and extracted with DME. Evaporation of ex-
tract solutions resulted in the yield. The product could be further
purified by sublimation at 180 °C and 10 mm Hg if needed.
N
Cl
4
5
1a
1a
2a
2a
91/28
86/82
N
NC
Cl
N
F3C
Cl
N
6
7
1a
1a
2a
2a
94/37
93/80
Cl
N
O
N
Cl
8
9
1a
1a
2a
2a
62/56
96/75
Acknowledgments
N
Cl
This work was supported by the National Institute of Health
(NIH SCORE S06 GM48680).
N
N
Br
N
Supplementary data
10
11
12
1a
1a
1a
2a
2a
2a
36/32
36/33
None
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.136.
Cl
Cl
S
N
N
References and notes
O
1. For a recent review, see: Williams, J. A. G. Chem. Soc. Rev. 2009, 38, 1781–1801.
2. Wadman, S. H.; Lutz, M.; Tooke, D. M.; Spek, A. L.; Hartl, F.; Havenith, R. W. A.;
van Klink, G. P. M.; van Koten, G. Inorg. Chem. 2009, 48, 1887–1900.
3. Wilkinson, A. J.; Puschmann, H.; Howard, J. A. K.; Foster, C. E.; Williams, J. A. G.
Inorg. Chem. 2006, 45, 8685–8699.
4. Farley, S. J.; Rochester, D. L.; Thompson, A. L.; Howard, J. A. K.; Williams, J. A. G.
Inorg. Chem. 2005, 44, 9690–9703.
5. Williams, J. A. G.; Beeby, A.; Davies, E. S.; Weinstein, J. A.; Wilson, C. Inorg.
Chem. 2003, 42, 8609–8611.
Cl
13
14
1b
1c
2b
2c
89/78
43/12
N
Cl
N
6. Soro, B.; Stoccoro, S.; Minghetti, G.; Zucca, A.; Cinellu, M. A.; Manassero, M.;
Gladiali, S. Inorg. Chim. Acta 2006, 359, 1879–1888.
a
Yields (percent measured by GC/isolation). Slow, irreversible binding of prod-
7. Soro, B.; Stoccoro, S.; Minghetti, G.; Zucca, A.; Cinellu, M. A.; Gladiali, S.;
Manassero, M.; Sansoni, M. Organometallics 2005, 24, 53–61.
8. Zhao, L.-X.; Sherchan, J.; Park, J. K.; Jahng, Y.; Jeong, B.-S.; Jeong, T. C.; Lee, C.-S.;
Lee, E.-S. Arch. Pharmacol. Res. 2006, 29, 1091–1095.
9. Meriç, A.; Incesu, Z.; Isßikdag˘, I. Farmaco 2002, 57, 543–548.
10. Abe, T.; Shinozaki, K.; Ikeda, N.; Suzuki, T. Acta. Crystallogr., Sect. C 2007, 63,
ucts to preparative TLC gels are responsible for large yield differences.
_
of this report detail the preparation and characterization of the new
compounds from entries 4–9 and 13 in Table 1. All of the products
described herein are of particular interest for their potential as tran-
sition metal ligands and as analogs of 2,20:60,200-terpyridine. Efforts
are underway to prepare and study complexes incorporating these
new ligands. Attempts are also underway to develop an analogous
one-flask protocol to couple multiple heterocyclic rings with ortho
nitrogens on both sides of the C–C couplings.
m456–m458.
11. Beley, M.; Collin, J.-P.; Louis, R.; Metz, B.; Sauvage, J.-P. J. Am. Chem. Soc. 1991,
113, 8521–8523.
12. Bönnemann, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505–515.
13. Janka, M.; Anderson, G. K.; Rath, N. P. Inorg. Chim. Acta 2004, 357, 2339–
2344.
14. Cárdenas, D. J.; Echavarren, A. M.; de Arellano, M. C. R. Organometallics 1999,
18, 3337–3341.

1634
B. Avitia et al. / Tetrahedron Letters 52 (2011) 1631–1634
15. Patoux, C.; Launay, J.-P.; Beley, M.; Chodorowski-Kimmes, S.; Collin, J.-P.;
James, S.; Sauvage, J.-P. J. Am. Chem. Soc. 1998, 120, 3717–3725.
16. Beley, M.; Chodorowski, S.; Collin, J.-P.; Sauvage, J.-P. Tetrahedron Lett. 1993, 34,
2933.
17. Wadman, S. H.; Havenith, R. W. A.; Hartl, F.; Lutz, M.; Spek, A. L.; van Klink, G. P.
M.; van Koten, G. Inorg. Chem. 2009, 48, 5685–5696.
18. Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282–
1284.
19. Zhang, J.; Zhao, L.; Song, M.; Mak, T. C. W.; Wu, Y. J. Organomet. Chem. 2006,
691, 1301–1306.
20. Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V.
J. Org. Chem. 2007, 72, 1588–1594.
21. Ishiyama, T.; Itah, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–
3450.
22. Baudoin, O.; Guénard, D.; Guéritte, F. J. Org. Chem. 2000, 65, 9268–9271.
23. Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841–3844.
24. Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46,
5359–5363.
25. Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314.
26. Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.; Dreher, S. D.; Weissman, S.
A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11, 345–347.
27. Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698.
28. Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009,
11, 381–384.