N-vinylpyridinium and -ammonium tetrafluoroborate salts: New electrophilic coupling partners for Pd(0)-catalyzed suzuki cross-coupling reactions

Article abstract of DOI:10.1021/ol063027h

N-Vinylpyridinium and -trialkylammonium tetrafluoroborate salts represent a new class of electrophilic coupling partner for Pd(0)-catalyzed Suzuki cross-coupling reactions and give very good to excellent yields of products with a wide range of boronic acids. The salts are easily prepared from activated acetylenes and pyridinium or trialkylammonium tetrafluoroborates to form crystalline, air-stable, and nonhygroscopic crystals.

Full text of DOI:10.1021/ol063027h

ORGANIC
LETTERS
2
007
Vol. 9, No. 4
07-710
N-Vinylpyridinium and -ammonium
Tetrafluoroborate Salts: New
Electrophilic Coupling Partners for
Pd(0)-Catalyzed Suzuki Cross-Coupling
Reactions
7
Keith R. Buszek*,†,‡,§ and Neil Brown‡,§
Department of Chemistry, Kansas State UniVersity, 111 Willard Hall, Manhattan,
Kansas 66506, Center for Chemical Methods and Library Design, UniVersity of
Kansas, 1501 Wakarusa DriVe Lawrence, Kansas 66047, and Department of
Chemistry, UniVersity of Missouri, 205 Spencer Chemical Laboratories,
5100 Rockhill Road, Kansas City, Missouri 64110
buszekk@umkc.edu
Received December 14, 2006
ABSTRACT
N-Vinylpyridinium and -trialkylammonium tetrafluoroborate salts represent a new class of electrophilic coupling partner for Pd(0)-catalyzed
Suzuki cross-coupling reactions and give very good to excellent yields of products with a wide range of boronic acids. The salts are easily
prepared from activated acetylenes and pyridinium or trialkylammonium tetrafluoroborates to form crystalline, air-stable, and nonhygroscopic
crystals.
The Suzuki reaction is a powerful member of the important
organic synthesis. Suzuki coupling additionally plays a major
role in the production of diverse compound libraries in
combinatorial chemistry employing either parallel or solid-
and versatile suite of palladium catalyzed carbon-carbon
1
bond-forming reactions. The versatility is enhanced by the
coupling of aryl, vinyl, and alkyl1
f-h
halides or their
2
phase methods. Notwithstanding these advantages, the
corresponding triflates with literally hundreds of com-
mercially available boronic acids and is thus ubiquitous in
requisite vinyl halides and triflates can be unstable or rely
on expensive or toxic reagents for their preparation. As part
3
of an ongoing program to build novel natural product-like
libraries that rely on Suzuki cross-coupling protocols, we
searched for a robust and reliable vinyl halide or triflate
equivalent. We now report that the readily available N-
vinylpyridinium and ammonium tetrafluoroborate salts such
as 1 and 2 (Figure 1) represent new and excellent electro-
*
To whom correspondence should be addressed. Current address:
University of MissourisKansas City.
†
Kansas State University.
University of Kansas.
University of MissourisKansas City.
‡
§
4
(
1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Stanforth, S. P. Tetrahedron 1998, 54, 263-303. (c) Miyaura, N. In
AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI: London,
1
998; Vol. 6, pp 187-243. (d) Suzuki, A. In Metal-Catalyzed Cross-
philic coupling partners for the Suzuki reaction.
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 1998; Chapter 2. (e) Suzuki, A. J. Organomet. Chem. 1999, 576,
147-168. (f) Gonz a´ lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128,
5360-5361. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-
1341. (h) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
3910-3912.
(2) (a) Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549-1581.
(b) Dolle, R. E. J. Comb. Chem. 2005, 7, 739-798.
(3) (a) Pillot, J.-P.; Dunogues, J.; Calas, R. Synth. Commun. 1979, 9,
395-406. (b) Ritter, K. Synthesis 1993, 735-762.
1
0.1021/ol063027h CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/25/2007

Table 1. Optimization for the Suzuki Reaction
ligand
yield
base solvent (%)
entry
catalyst (mol %)
(mol %)
none
none
PPh3 (20) DIEA THF
1
2
3
4
5
6
Pd(PPh3)4 (30)
Pd(PPh3)4 (30)
Pd2(dba)3 (5)
Py
THF
34
69
18
20
55
20
DIEA THF
Figure 1. Examples of vinylpyridinium and -ammonium salts.
PdCl2[P(o-tolyl)3]2 (10) none
DIEA THF
DIEA THF
PdCl2(PCy3)2 (10)
Pd2(dba)3 (5)
none
P(p-tolyl)3 DIEA THF
20)
The synthesis of these salts was first reported by Jung and
(
4
Buszek, and they were employed as dienophiles by these
7
8
Pd2(dba)3 (5)
Pd2(dba)3 (5)
PBn3 (20) DIEA THF
PCy3 (20) DIEA THF
80
88
workers in Diels-Alder cycloadditions. However, no other
synthetic applications are found in the literature. This paper
describes the first example of oxidative insertion of Pd(0)
into vinylpyridium and -ammonium bonds. Although a recent
report by MacMillan shows that aryltrimethylammonium
(150 °C) under pressure for brief periods of time (10-12
min). Microwave-assisted chemistry is widely employed as
a powerful tool in library development and organic synthesis
in general for its ability to substantially reduce reaction times
and increase throughput. The use of tetrakis(triphenylphos-
phine)palladium(0) gave reasonable yields of the desired
product but only with a high (30%) catalyst loading (entry
5
triflate salts undergo nickel-catalyzed Suzuki coupling, it
was noted that these same reactions fail with palladium
catalysts. The MacMillan case more closely resembles the
nickel-catalyzed Suzuki, Stille, and Kumada coupling of
8
6
aryldiazonium salts, which have been known for some time.
There are no examples in the literature of any metal-mediated
vinylpyridinium or vinyltrialkylammonium salt carbon-
carbon bond formation, and furthermore, the corresponding
2). It was eventually found that Pd
2 3
(dba) (5 mol %) with
20 mol % of PCy gave superior results (entry 8). Although
3
7
the present unoptimized catalyst loads are relatively high,
especially when compared to those recently reported by
Buchwald in the parts per million range with certain hindered
vinyldiazonium salts are unknown. Accordingly, these salts
represent a completely new and useful class of palladium-
catalyzed electrophilic coupling partner. The salts have the
distinct advantage of being easily prepared almost quanti-
tatively in one step from activated acetylenes and either
pyridinium or trialkylammonium tetrafluoroborates. Ad-
ditionally, they possess the highly desirable properties of
being crystalline, nonhygroscopic, and indefinitely air-stable.
We initially examined the coupling of the (E)-1-(3-oxobut-
9
phosphine ligands, they are not atypical for many Suzuki
cross-coupling applications. We assume an oxidative inser-
tion of Pd(0) into the C-N bond consistent with the accepted
mechanism for conventional substrates. The yields drop
markedly with arylphosphine either as an initial or added
ligand (entries 3, 4, and 6). Although a different set of
conditions was needed for use with the corresponding class
of vinyltrimethylammonium salts (Scheme 2), the yields are
1
0
1-enyl)pyridinium tetrafluoroborate 1 with p-methoxyphe-
nylboronic acid 3 (Scheme 1) and surveyed a range of
Scheme 2. Coupling of Ammonium Salt 2 with
4-Methoxyphenylboronic Acid
Scheme 1. Coupling of Pyridinium Salt 1 with
4-Methoxyphenylboronic Acid
modest (35%) with this system and similary remain unop-
timized. The reasons for this difference are not yet clear.
parameters to optimize the reactions conditions for this class
of substrate (Table 1).
Since our initial objective was to employ these salts in
library synthesis, we elected to use microwave heating
(7) Nitrile-functionalized pyridinium ligands for palladium have been
reported to enhance catalytic activity in ionic liquids, but no examples of
oxidative insertion of Pd(0) into vinyl pyridinium salts are known: Zhao,
D.; Fei, Z.; Geldbach, T. J.; Scopelliti, R.; Dyson, P. J. J. Am. Chem. Soc.
2004, 126, 15876-15882.
(
4) (a) Jung, M. E.; Buszek, K. R. J. Org. Chem. 1985, 50, 5440-5441.
(
(
(
b) Jung, M. E.; Buszek, K. R. Tetrahedron Lett. 1986, 27, 6165-6168.
c) Jung, M. E.; Buszek, K. R. J. Am. Chem. Soc. 1988, 110, 3965-3969.
d) Jung, M. E.; Vaccaro, W. D.; Buszek, K. R. Tetrahedron Lett. 1989,
(8) (a) Lidstr o¨ m, P.; Tierney, J.; Watney, B.; Westmein, J. Tetrahedron
2001, 57, 9225-9283. (b) Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6,
314-320.
3
0, 1893-1896.
5) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
046-6047.
6) (a) Darres, S.; Jeffrey, J. P.; Genet, J. P.; Brayer, J. L.; Demoute, J.
(9) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
(10) (a) Tamao, K.; Hiyama, T.; Negishi, E. J. Organomet. Chem. 2002,
653, 1. (b) Miyura, N. Top. Curr. Chem. 2002, 219, 11. (c) Miyaura, N. In
Metal Catalyzed Cross-Coupling Reactions; de Mejiere, A., Diedrich, F.,
Eds.; John Wiley and Sons: New York, 2004; Chapter 2, pp 41-123.
(
6
(
P. Tetrahedron Lett. 1996, 37, 3857. (b) Kikukawa, K.; Kono, K.; Wada,
F.; Matsuda, T. J. Org. Chem. 1983, 48, 1333-1336.
708
Org. Lett., Vol. 9, No. 4, 2007

Table 2. Suzuki Coupling of Various Boronic Acids with
Pyridinium Salt 1
Table 3. Suzuki Coupling of N-VinylPyridinium Vinyl Aryl
Ketones with 4-Methoxyphenylboronic Acid
a
a
a
Conditions: Pd2(dba)3 (5 mol %), PCy3 (20 mol %), DIEA (2 equiv),
THF, MW (150 °C), 12 min.
In an effort to improve solubility of the salts in various
solvents at ambient temperatures, we substituted the tet-
rafluoroborate anion with tetraphenylborate (Scheme 3) and
found it gave with either vinylpyridinium or vinyltrimethy-
lammonium substrates mainly the product 6 from the
competitive transfer of the counterion ligand. No cross-
coupling products were detected. Although the use of
tetraphenyl borate as a reagent for the Suzuki reaction is
precedented, the mechanism for this process is not fully
1
1
understood.
Finally, we discovered that vinylpyridinium salts can be
made to undergo dimerization, presumably via reductive
1
2
coupling, by substituting 20 mol % triphenylphosphine as
the added ligand for tricyclohexylphosphine, resulting in the
formation of the 1,6-dioxo-2,4-diene 7 in 60% unoptimized
yield (Scheme 4). We are continuing to explore the mech-
a
Conditions: Pd2(dba)3 (5 mol %), PCy3 (20 mol %), DIEA (2 equiv),
THF, MW (150 °C), 12 min.
With the preferred conditions for the pyridinium salts in
hand, we next examined the coupling of 1 with several
represenative aryl- and vinylboronic acids (Table 2). The
yields (67-92%) are uniformly very good to excellent across
the range of acids and are generally consistent and compa-
rable to those found with conventional electrophiles. No clear
trend emerged with respect to the effect of electron-donating
and electron-withdrawing groups, except that yields were
noticeably higher with strong electron donors (entry 3). The
reaction of pyridinum salts of aryl ketones were likewise
examined (Table 3) and, gratifyingly, showed similar be-
havior.
Scheme 4. Homocoupling To Give Dienedione 7
anism and generality of this process, as there are only a few
methods for the preparation of this useful class of com-
13
pound.
In conclusion, we have discovered a new class of pal-
ladium-catalyzed cross-coupling partners involving N-vi-
nylpyridinium and related salts. The ease of preparation of
Scheme 3. Transfer of Tetraphenylborate Anion Ligand
(11) Suzuki reactions with tetraarylborates have been observed: Lu, G.;
Franzen, R.; Zhang, Q.; Xu, Y. Tetrahedron Lett. 2005, 46, 4255-4259
and references cited therein.
(
12) Kuroboshi, M.; Waki, Y.; Tanaka, H. J. Org. Chem. 2003, 68,
938-3942.
13) Ong, C. W.; Chen, C. M.; Wang, L. H.; Jan, J. J.; Shieh, P. C. J.
Org. Chem. 1998, 63, 9131-9134 and references cited therein.
3
(
Org. Lett., Vol. 9, No. 4, 2007
709

these salts in one step, the ready availability of the catalyst
and ligands, and the simple and rapid reaction conditions
make this method especially attractive. This system offers
the added flexibility of introducing further functionality into
the molecule, in this case, with ketones. Further investigations
into the utility of these salts in other metal-mediated
processes are underway and will be reported in due course.
Mr. Benjamin Neuenswander from the KU-CMLD Library
Design and Analysis Core for performing the LC-MS work.
We thank Professor Zhonghua Peng (UMKC) for helpful
discussions during the preparation of this manuscript. This
paper is warmly dedicated to Professor Yoshito Kishi on the
occasion of his 70th birthday.
Supporting Information Available: 1H NMR data for
all compounds reported in Tables 2 and 3 and experimental
details for the cross-coupling reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge support of this work
by the National Institutes of Health (The University of
Kansas Chemical Methodology and Library Development
Center of Excellence), P50 GM069663. We wish to thank
OL063027H
710
Org. Lett., Vol. 9, No. 4, 2007