Palladium-catalyzed cross-coupling reactions of pyridylboronic acids with heteroaryl halides bearing a primary amine group: Synthesis of highly substituted bipyridines and pyrazinopyridines

Article abstract of DOI:10.1021/jo0402226

(Chemical Equation Presented). A range of halogenated aromatics and heteroaromatics bearing a primary amine group are shown to be suitable substrates for Suzuki cross-coupling reactions with arylboronic acids and pyridylboronic acids under standard conditions, without the need for protection/deprotection steps. New amino-substituted arylpyridines, bipyridines, and pyrazinopyridines have thereby been obtained. Conditions for the efficient syntheses of 2-methoxy-5-pyridylboronic acid 1 and 2-methoxy-3-pyridylboronic acid 2 in ca. 75 g batches have been defined. A 2-fold reaction of 2-amino-5-bromopyrazine with 2,5-dimethoxy-1,4-benzenediboronic acid affords 1,4-dimethoxy-2,5-bis[2-(5-aminopyrazyl)]benzene 31. The X-ray crystal structures of 1 and 31·DMF are reported.

Full text of DOI:10.1021/jo0402226

attempted Suzuki reactions on 2-chloropyridin-3-car-
boxamide, and 2-chloro-3-hydroxypyridine gave only a
very low yield of cross-coupled product.3 3-Iodoanthranilic
acid failed to react with a range of arylboronic acids.4
More recently, Caron et al. reported that attempted
Suzuki reaction between phenylboronic acid and 2-chloro-
3-aminopyridine was unsuccessful, although the acet-
amide and benzaldehyde imine derivatives reacted in
high yield.5
It is notable, therefore, that Meier et al. have recently
reported Suzuki coupling reactions of unprotected bro-
mopyridylcarboxylic acids with formylphenylboronic acid.2
We now report our studies on halogenated aromatics and
heteroaromatics bearing a primary amine group as
substrates for Suzuki couplings. There are only isolated
examples in the literature of successful reactions in the
presence of NH2 groups, and many of these are low
yielding. Substrates include 2-amino-3-bromoquinoxa-
line,6 2-bromo-5-halopyridazine,7 6-chloro-2,4-diamino-
pyrimidine,8 4-chloroaniline,9 and 2-bromo-5-aminopy-
razine.10 Hitherto there is no report of a systematic study
using the same catalyst and reaction conditions while
varying the amino-containing substrate and the arylbo-
ronic acids.
Palladium-Catalyzed Cross-Coupling
Reactions of Pyridylboronic Acids with
Heteroaryl Halides Bearing a Primary
Amine Group: Synthesis of Highly
Substituted Bipyridines and
Pyrazinopyridines
Amy E. Thompson,† Gregory Hughes,†
Andrei S. Batsanov,† Martin R. Bryce,*,†
Paul R. Parry,†,‡ and Brian Tarbit‡
Department of Chemistry, University of Durham,
Durham DH1 3LE, England and Rutherford
Chemicals LLC, Seal Sands, Middlesbrough,
Cleveland TS2 1UB, England
m.r.bryce@durham.ac.uk
Received June 25, 2004
We chose to develop the chemistry of 2-methoxy-5-
pyridylboronic acid 1 and 2-methoxy-3-pyridylboronic
acid 2 in these reactions as there is widespread interest
in pyridylboronic acid derivatives and their derived
libraries of aryl/heteroarylpyridines (Chart 1).10-12 Ex-
amples of reactions of 2-chloro-5-pyridylboronic acid 3
A range of halogenated aromatics and heteroaromatics
bearing a primary amine group are shown to be suitable
substrates for Suzuki cross-coupling reactions with arylbo-
ronic acids and pyridylboronic acids under standard condi-
tions, without the need for protection/deprotection steps.
New amino-substituted arylpyridines, bipyridines, and pyrazi-
nopyridines have thereby been obtained. Conditions for the
efficient syntheses of 2-methoxy-5-pyridylboronic acid 1 and
2-methoxy-3-pyridylboronic acid 2 in ca. 75 g batches have
been defined. A 2-fold reaction of 2-amino-5-bromopyrazine
with 2,5-dimethoxy-1,4-benzenediboronic acid affords 1,4-
dimethoxy-2,5-bis[2-(5-aminopyrazyl)]benzene 31. The X-ray
crystal structures of 1 and 31‚DMF are reported.
(3) Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.; Wallbank,
P. J. Tetrahedron 1992, 48, 8117.
(4) Lisowski, V.; Robba, M.; Rault, S. J. Org. Chem. 2000, 65, 4193.
(5) Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi. M. J.; Braish,
T. F. Org. Proc. Res. Dev. 2001, 5, 254. In this paper, no information
was given about the reaction conditions or the catalyst used for the
attempted Suzuki coupling between phenylboronic acid and 2-chloro-
3-aminopyridine. The conditions reported for the successful reaction
of the acetamide derivative are as follows: aq Na2CO3, toluene/ethanol/
water, Pd[PPh3]4, reflux, 8 h. In contrast to this paper, using our
standard conditions given in Table 1, we obtained 3-amino-2-phenyl-
pyridine in 86% yield from the reaction of phenylboronic acid and
2-chloro-3-aminopyridine.
(6) Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507.
The Suzuki-Miyaura protocol for palladium-catalyzed
cross-coupling of aryl/heteroaryl boronic acids (or esters)
with aryl/heteroaryl halides is of paramount importance
for the synthesis of biaryl and heterobiaryl systems.1 It
is often stated that compounds bearing labile protons
(especially primary amines, carboxylic acids, and alco-
hols) are not suitable coupling partners in these reac-
tions,2 thereby necessitating additional protection/depro-
tection steps. For instance, no product was obtained from
(7) Maes, B. V. W.; Lemiere, G. L. F.; Dommisse, R.; Augustyns,
K.; Haemers, A. Tetrahedron 2000, 56, 1777.
(8) Cooke, G.; de Cremiers, H. A.; Rotello, V. M.; Tarbit, B.;
Vanderstraeten, P. E. Tetrahedron 2001, 57, 2787.
(9) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(b) Littke, A.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(10) Parry, P.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
J. Org. Chem. 2002, 67, 7541.
(11) (a) Lehmann, U.; Henze, O.; Schlu¨ter, A. D. Chem. Eur. J. 1999,
5, 854. (b) Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy. P. R.; Rault,
S. Tetrahedron 2002, 58, 2885. (c) Bouillon, A.; Lancelot, J.-C.; Collot,
V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 3323. (d) Bouillon, A.;
Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
4368. (e) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.;
Larsen, R. D.; and Reider, P. J. J. Org. Chem. 2002, 67, 5394. (f) Cai,
D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43, 4285. (g)
Mandolesi, S. D.; Vaillard, S. E.; Podesta´, J. C. Organometallics 2002,
21, 4886. (h) Sciotti, R. J.; Pliushchev, M.; Wiedeman, P. E.; Balli, D.;
Flamm, R.; Nilius, A. M.; Marsh, K.; Stolarik, D.; Jolly, R.; Ulrich, R.;
Djuric, S. W. Bioorg. Med. Chem. Lett. 2002, 12, 2121. (i) Parry, P. R.;
Bryce, M. R.; Tarbit, B. Synthesis 2003, 1035. (j) Sutherland, A.;
Gallagher, T. J. Org. Chem. 2003, 68, 3352. (k) Bouillon, A.; Lancelot,
J.-C.; de Oliveira Santos, J. S.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2003, 59, 10043. (l) Saygili, N.; Batsanov, A. S.; Bryce,
M. R. Org. Biomol. Chem. 2004, 2, 852. (m) Cioffi, C. L.; Spencer, W.
T.; Richards, J. J.; Herr, R. J. J. Org. Chem. 2004, 69, 2210.
* Corresponding author.
† University of Durham.
‡ Rutherford Chemicals LLC.
(1) Reviews: (a) Stanforth, S. P. Tetrahedron 1998, 54, 263. (b)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter
2. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (d) Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry; Tetrahedron
Organic Chemistry Series; Pergamon: Amsterdam, 2000; Vol. 20. (e)
Hassan, J.; Se´vignon, M.; Gozzi, C.; Schultz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(2) Meier, P.; Legraverant, S.; Mu¨ller, S.; Schaul, J. Synthesis 2003,
551.
10.1021/jo0402226 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/13/2004
388
J. Org. Chem. 2005, 70, 388-390

CHART 1. Structures of Boronic Acids Used in
This Study
pyridines can also be obtained in synthetically viable
yields. The methoxy group ortho to the boronic acid
(compound 2) does not sterically hinder the reaction. The
acetamide derivative 13 reacted in similar high yield to
give 27 (entry 11).
The reactions have been extended to 2-amino-5-bro-
mopyrazine 14 which reacts in moderate yields with the
pyridylboronic acids 1-3 (entries 12-14) to provide the
novel pyrazinylpyridine derivatives 28-30. Entry 14
establishes that 2-chloro-5-pyridylboronic acid 3 shows
comparable reactivity to the methoxy analogues 1 and
2. It is known that Suzuki cross-couplings of arylboronic
acids and less-reactive (electron-rich) chloroaromatics
proceed in the presence of PtBu3/[Pd2(dba)3] (dba )
dibenzylideneacetone) under conditions where [Pd2(dba)3]
alone is ineffective,9 and we have shown that product
yields using 2,3-dichloro-4-pyridylboronic acid and 2,6-
dichloro-3-pyridylboronic acid with 3-bromoquinoline are
significantly increased using PtBu3/Pd[PPh3)2Cl2 com-
pared to Pd[PPh3]2Cl2 alone.15 However, addition of Pt-
Bu3 (10 mol %) to the reaction mixture had no effect on
selected lower yielding reactions in Table 1.
Entries 15-18 extend the reaction to 2-fold couplings
by using the diboronic acid derivatives 4 and 5 (entries
15 and 16) or dihalo reagents 15 and 16 (entries 17 and
18) to yield products 31-34 in good or moderate yields,
demonstrating that this protocol is applicable to the
synthesis of extended amino-substituted tri- and tet-
raarylene structures.
In summary, this work establishes that a wide range
of halogenated aromatics and heteroaromatics bearing
a primary amine group are suitable substrates for Suzuki
cross-coupling reactions under standard conditions, with-
out the need for protection/deprotection steps which are
traditionally considered to be necessary for these reac-
tions to proceed cleanly. This is the first systematic study
of such reactions in the presence of a primary NH2 group.
With the exception of reagent 8 (as discussed above), it
appears that brominated heterocycles are preferable to
the chloro derivatives as coupling partners in these
reactions. Highly substituted pyridines, including het-
eroarylpyridines, continue to attract much attention16 due
to their roles as bioactive compounds, ligands for self-
assembly, and building blocks for materials chemistry
applications.17 The presence of the primary amine group
offers attractive prospects for further synthetic transfor-
mations, as well as applications in supramolecular and
coordination chemistry. The oligo(arylene) systems 31-
34 incorporating electron-deficient pyridine, pyrimidine,
and pyrazine units are candidates as electron-transport-
ing molecules in optoelectronic devices.17
and the aryldiboronic acids 4 and 5 are included for
comparison. We have previously published small-scale
syntheses of 110 and 211i (250-350 mg batches) in 65%
and 13% yields, respectively, using lithium-halogen
exchange (for 1) and directed ortho-metalation reactions13
(for 2). After much experimentation, we have now opti-
mized procedures which afford ca. 75 g batches of
analytically pure 1 and 2 in 65% and 58% yields,
respectively. The X-ray crystal structure of 1 is reported
in the Supporting Information.
The standard conditions for the Suzuki coupling reac-
tions were sodium carbonate (aqueous 1 M) as base and
bis(triphenylphosphino)palladium dichloride as catalyst
(5 mol %) in 1,4-dioxane at reflux for 8 h. The conditions
of the reaction shown in entry 7 were varied to establish
the optimum mol % of catalyst and reaction time. Using
1, 5, and 10 mol % catalyst gave product 23 in 37, 69,
and 67% yields, respectively. With varying reaction times
using 5 mol % catalyst the following product yields were
obtained: 2 h gave 32% yield; 8-48 h gave 67-69%
yields. Yields were independent of the base used (Na2-
CO3, K2CO3, Cs2CO3, or Ba2CO3). The results presented
in Table 1 show that many reactions proceed in high
yields in the presence of primary amine groups, thereby
directly affording new amino-substituted biaryl/hetero-
aryl systems without the need for any protection/depro-
tection steps.
The following points are noteworthy. Entries 1 and 2
establish that the reactions are efficient with bromoben-
zene derivatives bearing an amine substituent. It is
known that some π-deficient heteroaryl chlorides are
reactive partners in Suzuki reactions,3,8,11l although
generally the bromide analogues are preferred if they are
readily available. A comparison of entries 3-6 shows that
3-amino-2-chloropyridine 8 (entries 3 and 4) is especially
efficient and is a better substrate than the isomers 9 and
10, respectively. It can be envisaged that the amino group
will coordinate to an incoming palladium atom of the
catalyst and the high yield with 8 can be ascribed to steric
factors in the complexed intermediate facilitating dis-
placement of the ortho halogen.14 Indeed, 8 also reacted
with phenyl- and 4-methoxyphenylboronic acids to give
the expected cross-coupled products in >80% yields.15
Entries 7-10 using substrates 11 and 12 demonstrate
that more highly-functionalized amino-substituted bi-
(14) Conceptually similar coordination of a nitro group to Pd has
been proposed in Suzuki reactions of 2-nitrofluorobenzene with aryl-
boronic acids: Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003,
578. Coordination of Pd to the pyridyl nitrogen atom of 2-pyridyl esters
has been postulated: Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org.
Lett. 2004, 6, 3597.
(15) Thompson, A. E.; Bryce, M. R. Unpublished results.
(16) (a) Raw, S. A.; Taylor, R. J. K. Chem. Commun. 2004, 508 and
references therein. (b) Constable, E. C.; Housecroft, C. E.; Neuburger,
M.; Reymann, S.; Schaffner, S. Chem. Commun. 2004, 1056 and
references therein.
(12) For a review of heterocyclic boronic acids, see: Tyrrell, E.;
Brookes, P. Synthesis 2003, 469.
(13) Reviews: (a) Mongin, M.; Que´guiner, G. Tetrahedron 2001, 57,
4059. (b) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653,
150. (c) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206.
(17) (a) Review: Mitsche, U.; Bauerle, P. J. Mater. Chem. 2000, 10,
1471. (b) Tu¨rksoy, F.; Hughes, G.; Batsanov, A. S.; Bryce, M. R. J.
Mater. Chem. 2003, 13, 1554.
J. Org. Chem, Vol. 70, No. 1, 2005 389

TABLE 1a
a Reagents: entries 1-14, 17, 18, (i) Pd[PPh3]2Cl2, 1,4-dioxane, Na2CO3 (1 M), reflux, 8 h; entries 15, 16, (i) Pd[PPh3]4, THF, Na2CO3
(1 M), reflux, 24 h.
dimethoxy-[3,3′]bipyridine (from reactions of 1) which was
usually the first compound to elute, and unreacted arylhalide.
Experimental Section
Typical Procedure for the Cross-Coupling Reactions.
The boronic acid (1.0 equiv), the aryl halide (0.9 equiv), and Pd-
[PPh3]2Cl2 (ca. 5 mol %) were sequentially added to degassed
1,4-dioxane, and the mixture was stirred at 20 °C for 30 min.
Degassed aqueous Na2CO3 solution (1 M, 3.0 equiv) was added,
and the reaction mixture was heated under argon at reflux for
8 h. Solvent was removed in vacuo, ethyl acetate was added,
and the organic layer was washed with brine, separated, and
dried over MgSO4. The mixture was purified by chromatography
on a silica gel column. On some occasions additional recrystal-
lization was necessary to remove traces of Ph3PO which coeluted
with the desired product. Other compounds isolated were
variable amounts of the “self-coupled” boronic acid, e.g., 6,6-
Acknowledgment. We thank Rutherford Chemicals
LLC and EPSRC for funding.
Supporting Information Available: Full details of syn-
thetic procedures and characterization data for compounds 1,
2, and 16-34; X-ray crystallographic data and ORTEP plots
for compounds 1 and 31‚DMF and a description of their
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0402226
390 J. Org. Chem., Vol. 70, No. 1, 2005