The first Suzuki cross-couplings of aryltrimethylammonium salts

Article abstract of DOI:10.1021/ja034908b

The first Suzuki cross-coupling reaction of aryltrimethylammonium triflates based on the use of an IMes·Ni(0) catalyst system is described. A wide range of electron-withdrawing and electron-donating substituents are tolerated on both the aryltrimethylammonium triflate and the boronic acid components of this reaction. In addition to arylboronic acids, the scope of the reaction is extended to encompass both boronate esters and alkenylboranes. This methodology constitutes a novel, mild method to activate anilines for metal-catalyzed cross-coupling reactions. Copyright

Full text of DOI:10.1021/ja034908b

Published on Web 04/29/2003
The First Suzuki Cross-Couplings of Aryltrimethylammonium Salts
Simon B. Blakey and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received February 27, 2003; E-mail: dmacmill@caltech.edu
Table 1. Optimization of the Catalyst Systema
The transition-metal-catalyzed cross-coupling reaction has emerged
as one of the most powerful carbon-carbon bond-forming protocols
available to practitioners of chemical synthesis.1 In this context,
aryl bromides, iodides, triflates, and, more recently, chlorides2 have
found broad utility as electrophilic coupling partners in combination
with a host of metallobenzene systems. Surprisingly, simple
arylamines have yet to be employed directly as oxidative insertion
substrates, a notable deficiency in light of their widespread
availability and application as π-nucleophiles (Friedel-Crafts,
electrophilic aromatic substitution, etc.). While aryl diazonium salts
have been utilized in this context,3 the requirement of primary amine
precursors and the attendant derivatization conditions (H2SO4,
entry
Ni complex
ligand
base
% yieldd
NaNO2) have restricted their general use.
In 1988, Wenkert and co-workers documented the nickel-
catalyzed Kumada reaction of aryltrimethylammonium iodides,4 to
date the only report of a trialkylammonium-insertion cross-coupling
reaction. While the inherent scope and reaction efficiencies were
found to be limited, this pioneering study introduced the attractive
prospect that dialkylanilines might be utilized as metal insertion
precursors via a simple nitrogen-quaternization step. In this
Communication, we advance this catalytic concept to describe the
first Suzuki cross-coupling reaction of aryltrimethylammonium
triflates based on the use of a novel IMes‚Ni(0) catalyst complex.5
This new Suzuki variant can be accomplished with excellent yield
for a broad range of dialkylaniline and boronic acid substrates (eq
1).
b
1
2
3
4
5
6
7
8
9
Ni(dppp)Cl2
Ni(dppf)Cl2
Ni(dppp)Cl2
Ni(dppf)Cl2
Ni(dppf)Cl2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Pd2(dba)3
3c
3c
K3PO4
K3PO4
K3PO4
K3PO4
KF
K3PO4
KF
CsF
10
11
20
27
16
5
57
98
37
6
b
b
IMes‚HCl
IMes‚HCl
IMes‚HCl
IMes‚HCl
IMes‚HCl
IMes‚HCl
b
b
CsF
CsF
CsF
10
11
3
IMes‚HCl
0
a Reaction conditions: 1.0 equiv of ArNMe3X, 1.1 equiv of PhB(OH)2,
10 mol % catalyst, 10 mol % ligand, 3.0 equiv of base, 80 °C, 12 h. b 0.4
equiv of nBuLi was used to reduce Ni(II) to Ni(0). c 20 mol % ligand used.
d Yields based on LCMS analysis. e Reactions run using the corresponding
trialkylammonium iodide resulted in reduced yields.
(2,4,6-trimethylphenyl)imidazole carbene ligand 4 with Ni(dppp)-
Cl2 and Ni(dppf)Cl2; however, reaction efficiencies remained
markedly poor (entries 3-5). In an effort to access a phosphine-
free catalyst system, we next examined Ni(COD)2 as a metal source
(entries 6-8). To our delight, the catalyst complex arising from
Ni(COD)2 and IMes‚HCl,8,9 in the presence of CsF as a mild base,
gave the desired cross-coupled adduct in 98% isolated yield (entry
8). It is important to note that attempts to perform the analogous
Ni(COD)2 protocol with ligand 3 or in the absence of IMes‚HCl
resulted in diminished yields (entries 9 and 10). To date, the use
of palladium catalysts in this coupling reaction has proven unsuc-
cessful.
Our investigation into an effective arylammonium Suzuki reac-
tion began with p-butyl-trimethylammonium benzene triflate (1),
phenyl boronic acid (2), and a series of Ni(0) catalyst complexes
(Table 1). Nickel catalysts have been successfully employed in a
wide range of Suzuki coupling reactions, providing ample prece-
dence for transmetalation with arylboronic acids.6 As such, we felt
the challenge lay in identifying a catalyst that would readily insert
into an aryl-ammonium bond. On the basis of the studies of
Wenkert and Miyaura,7 we examined Ni(dppp)Cl2 and Ni(dppf)-
Cl2 as catalyst precursors, with the addition of 2 equiv of the bulky
electron-rich phosphine ligand 3; however, in each case, only a
trace quantity of the cross-coupled product 5 was observed (entries
1 and 2). Catalyst turnover was accomplished using the 1,3-bis-
The superior reaction efficiencies observed with Ni(0)‚IMes in
the presence of CsF prompted us to select these catalytic conditions
for further exploration.
The scope of this ammonium Suzuki coupling with respect to
the aryl boronic acid component has been investigated (Table 2).
Gratifyingly, a wide range of boronic acids that incorporate electron-
donating groups (entries 1-6) and electron-withdrawing groups
(entries 7-10) at the ortho, meta, and para positions are readily
tolerated (79-98% yield). Furthermore, both boronate esters (entry
12) and alkenylboranes (entry 13) could be cross-coupled using
our standard reaction conditions.
We have also investigated functional group tolerance with respect
to the substituents on the aryltrimethylammonium triflate (Table
9
6046
J. AM. CHEM. SOC. 2003, 125, 6046-6047
10.1021/ja034908b CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ammonium Suzuki Couplings of Arylboronic Acids
Table 3. Suzuki Couplings of Aryltrimethylammonium Triflates
a Reaction times were not optimized.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews, see: (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, 1988.
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alkylation with methyl trifluoromethanesulfonate in dichloromethane.
See: Langer, O.; Dolle´, F.; Valette, H.; Halldin, C.; Vaufrey, F.; Fuseau,
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a Reaction times not optimized. b 1.1 equiv of boronic acid was used.
c K3PO4 was used in place of CsF. d Reaction performed with 4-(carboxylic
acid methyl ester)-N,N,N-trimethylanilinium triflate.
3). It is well established that electron-rich aromatic systems are
generally less susceptible to oxidative addition. As such, we were
delighted to find a range of electron-rich ammonium salts efficiently
coupled with phenylboronic acid (entries 1-5). As expected, aryl
systems with electron-withdrawing substituents performed well
under our standard reaction conditions (entries 6-8).
In summary, we have developed a novel catalyst system, capable
of activating aryl-ammonium bonds for Suzuki cross-coupling
reactions. Full details of this new trialkylammonium Suzuki reaction
will be forthcoming.
(6) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359.
(7) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024.
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Chem. Soc. 1992, 114, 5530.
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1988, 577, 93. (b) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J.
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Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186.
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Acknowledgment. Support was provided by a research founda-
tion grant from Bristol-Myers Squibb.
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