Boronic acids: New coupling partners in room-temperature Suzuki reactions of alkyl bromides. Crystallographic characterization of an oxidative-addition adduct generated under remarkably mild conditions

Article abstract of DOI:10.1021/ja0283899

The Suzuki reaction is an exceptionally useful cross-coupling process that has been widely applied in synthetic chemistry, and boronic acids are, by far, the most commonly employed coupling partner. To date, however, no versatile method has been developed for cross-coupling boronic acids with unactivated alkyl (as opposed to aryl or vinyl) electrophiles. This report describes a catalyst system that achieves this objective at room temperature. On the mechanistic side, this study demonstrates that Pd(P(t-Bu)₂Me)₂ undergoes oxidative addition under surprisingly mild conditions (0 °C). The resulting adduct is sufficiently stable toward β-hydride elimination that it can be structurally characterized, and it is a chemically competent intermediate in the cross-coupling process. Copyright

Full text of DOI:10.1021/ja0283899

Published on Web 10/23/2002
Boronic Acids: New Coupling Partners in Room-Temperature Suzuki
Reactions of Alkyl Bromides. Crystallographic Characterization of an
Oxidative-Addition Adduct Generated under Remarkably Mild Conditions
Jan H. Kirchhoff, Matthew R. Netherton, Ivory D. Hills,1 and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received September 3, 2002
Table 1. Suzuki Cross-Coupling of n-OctBr with PhB(OH)2 (5%
Pd(OAc)2, 10% ligand, rt): Effect of Additive, Solvent, and Ligand
Although tremendous progress has been made in recent years in
the development of effective methods for palladium-catalyzed cross-
couplings of aryl and vinyl electrophiles,2 comparable success has
not yet been achieved for reactions of alkyl electrophiles, particu-
larly unactivated (e.g., not allylic or benzylic) substrates that possess
â hydrogens.3-6 During the past few years, we have described
catalyst systems that can accomplish Suzuki cross-couplings7 of
alkyl bromides, chlorides, and tosylates with alkyl-(9-BBN)
derivatives.4b-d
While the generally straightforward synthesis of alkyl-(9-BBN)
derivatives via the hydroboration of olefins makes them attractive
coupling partners, they suffer from the drawback of not being
readily handleable in air or commercially available. In contrast, a
wide array of boronic acids, which are air-stable, can be purchased.8
As a consequence of these practical considerations, the ability to
employ boronic acids in Suzuki cross-couplings of alkyl electro-
philes represents a very important objective.9 In this Communication
we describe the progress that we have made toward realizing this
goal; specifically, we report a catalyst system that effects room-
temperature cross-couplings of alkyl bromides with a range of aryl-,
vinyl-, and alkylboronic acids (eq 1). In addition, we present
mechanistic work that establishes that oxidative addition of an alkyl
bromide to a Pd(0) complex can occur under remarkably mild
conditions (0 °C) to generate a stable adduct that can be character-
ized by X-ray crystallography.
entry
additive
solvent
ligand
yield (%)a
1b
2
3
4
5
6
7
8
9
K3PO4‚H2O
KF
THF
THF
THF
THF
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy2Et
P(t-Bu)3
P(t-Bu)2Et
P(t-Bu)2Me
<2
<2
3
11
64
63
39
<2
4
NaOMe
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
dioxane
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
10
85
a Average of two runs. Determined by GC versus a calibrated internal
standard. b Conducted according to the procedure in ref 4b.
Table 2. Pd/P(t-Bu)2Me-Catalyzed Suzuki Cross-Couplings of
Alkyl Bromides with Boronic Acids (eq 1)
Unfortunately, the conditions that we had found to be optimal
for Suzuki couplings of alkyl bromides with 9-BBN-derived
reagents are ineffective for reactions of boronic acids (Table 1, entry
1; <2%). We surveyed a broad spectrum of parameters, and an
illustrative subset of our findings is provided in Table 1. For
example, we explored the use of a variety of Lewis basic additives,
and we determined that KOt-Bu is the best among those that we
have examined (entries 1-4). The choice of solvent has a significant
impact on the efficiency of the cross-coupling; employing either
dioxane or tert-amyl alcohol, rather than THF, leads to a marked
enhancement in yield (entries 5 and 6; ∼63%).10
ineffective (entry 8; <2%), less bulky P(t-Bu)2Et furnishes a
detectible quantity of the target compound (entry 9; 4%). Remark-
ably, a further decrease in the size of the phosphinesto com-
mercially available P(t-Bu)2Me11sprovides a dramatic increase in
reactivity (entry 10; 85%).4d,12
These conditions have proved to be useful for coupling a range
of alkyl bromides with an array of boronic acids (Table 2). Thus,
the catalyst system tolerates a wide variety of functional groups,
including esters (entry 2), ethers and thioethers (entries 2-5),
amides (entry 5), acetals (entry 6), and nitriles (entry 8). An
electronically diverse set of boronic acids can be coupled (entries
2-4),13 as can hindered substrates (entries 5-7). Aryl- as well as
vinyl- (entry 8) and unhindered alkyl- (entry 9) boronic acids are
suitable partners in this process.14
Not surprisingly, the structure of the phosphine plays an
important role in determining the outcome of the reaction. The use
of PCy2Et, which is less sterically demanding than PCy3, leads to
a lower yield of the cross-coupling product (entry 6 vs entry 7;
63% f 39%). Although very hindered P(t-Bu)3 is completely
* Corresponding author. E-mail: gcf@mit.edu.
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J. AM. CHEM. SOC. 2002, 124, 13662-13663
10.1021/ja0283899 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Because, like most trialkylphosphines, P(t-Bu)2Me is susceptible
to oxidation and can therefore be inconvenient to handle, we decided
to determine if the corresponding phosphonium salt, [HP(t-Bu)2Me]-
BF4, which is air- and moisture-stable and will soon be com-
mercially available,15 can be used in place of the phosphine in these
cross-couplings.16 Not surprisingly, on the basis of our prior work,
the two reagents are interchangeable, furnishing nearly identical
yields of the desired product (Table 2).
The reluctance of unactivated alkyl halides to oxidatively add
to Pd(0) is generally believed to be one of the barriers that impedes
the development of efficient methods to cross-couple this class of
substrates.3 In view of the report of Suzuki that Pd(PPh3)4-catalyzed
coupling reactions of alkyl iodides require heating to 60 °C,4a the
ability of Pd(OAc)2/P(t-Bu)2Me to cross-couple more challenging
alkyl bromides at room temperature is noteworthy. Indeed, we have
discovered that alkyl bromides oxidatively add to Pd(P(t-Bu)2Me)2
at 0 °C (eq 2).17,18
acids. Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
the Deutsche Akademie der Naturforscher Leopoldina (Leopoldina
fellowship to J.H.K., BMBF-LPD 9901/8-48), the Natural Sciences
and Engineering Research Council of Canada (postdoctoral fellow-
ship to M.R.N.), and Novartis.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Correspondence concerning the X-ray crystal structure should be directed
to I.D.H.
(2) (a) Topics in Current Chemistry, Vol. 219; Miyaura, N., Ed.; Springer-
Verlag: New York, 2002. (b) Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(3) For overviews, see: (a) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem.
ReV. 2000, 100, 3187-3204. (b) Ca´rdenas, D. J. Angew. Chem., Int. Ed.
1999, 38, 3018-3020.
(4) Palladium-catalyzed Suzuki couplings. (a) Alkyl iodides: Ishiyama, T.;
Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-694. (b) Alkyl
bromides: Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 10099-10100. (c) Alkyl chlorides: Kirchhoff, J.
H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945-1947. (d)
Alkyl tosylates: Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed., in
press.
(5) Nickel-catalyzed Negishi couplings of alkyl bromides and iodides:
Devasagayaraj, A.; Stu¨demann, T.; Knochel, P. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2723-2725. Jensen, A. E.; Knochel, P. J. Org. Chem.
2002, 67, 79-85, and references therein.
(6) Nickel-catalyzed Kumada couplings of alkyl bromides, chlorides, and
tosylates: Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N.
J. Am. Chem. Soc. 2002, 124, 4222-4223.
Moreover, adduct 1 is sufficiently stable to be crystallographically
characterized (eq 2). Thus, because of the high reactivity of Pd/
P(t-Bu)2Me toward oxidative addition, it is possible to generate
complex 1 under conditions that are sufficiently mild that â-hydride
elimination, which is believed to be the other major impediment
to effective cross-coupling of alkyl halides, does not occur.19
Finally, we have established that adduct 1 is chemically
competent; upon treatment with a boronic acid, cross-coupling
occurs to furnish the anticipated product (eq 3).20
(7) For reviews of the Suzuki reaction, see: (a) Miyaura, N. Top. Curr. Chem.
2002, 219, 11-59. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
Chapter 2.
(8) For example, Frontier Scientific and Aldrich each sell more than 100
boronic acids.
(9) We are aware of only one report of a Suzuki cross-coupling of a boronic
acid with an alkyl electrophile that bears â hydrogens: Yang, G.-S.; Xie,
X.-j.; Zhao, G.; Ding, Y. J. Fluorine Chem. 1999, 98, 159-161 (reactions
of fluorinated alkyl iodides).
(10) We decided to focus on tert-amyl alcohol, because the reaction components
are more soluble in this solvent.
(11) Strem Chemicals: catalog #15-1020.
(12) Notes. (a) Other ligands that are ineffective: P(o-tol)3, AsPh3, P(t-Bu)2-
OH, and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene). (b) Pd2(dba)3,
[(π-allyl)PdCl]2, and PdCl2(cod) are as effective as Pd(OAc)2.
(13) In preliminary studies, heteroarylboronic acids, as well as certain electron-
deficient arylboronic acids, have not proved to be suitable coupling
partners.
(14) Notes. (a) In the presence of 1 equiv of H2O, the cross-coupling proceeds
in comparable yield. (b) We have not attempted to individually maximize
the turnover number (TON) for these cross-coupling reactions. However,
for the coupling of 1-bromooctane with phenylboronic acid, we have
determined that use of 0.5% Pd(OAc)2 and 1.0% of P(t-Bu)2Me or [HP-
(t-Bu)2Me]BF4 furnishes an 81-84% yield of the desired product,
corresponding to a TON of ∼160. (c) We generally observe lower yields
for reactions of more hindered substrates. To date, we have not achieved
couplings of secondary alkyl bromides or secondary alkylboronic acids.
(15) Strem Chemicals: catalog #15-1023.
In summary, we have described the first palladium- or nickel-
catalyzed method for coupling a diverse set of boronic acids and
unactivated alkyl electrophiles (bromides) that possess â hydrogens.
In view of the well-established utility of the Suzuki reaction and
the important advantages of boronic acids over other coupling
partners, we anticipate that this work may lead to new strategies
for applying Suzuki cross-couplings in organic synthesis. On the
mechanistic side, we have determined that Pd(P(t-Bu)2Me)2 under-
goes oxidative addition under surprisingly mild conditions; the
resulting adduct is sufficiently stable toward â-hydride elimination
that it can be structurally characterized, and it is a chemically
competent intermediate in the cross-coupling process, reacting with
a boronic acid to generate the expected product. Ongoing studies
are directed toward enhancing our understanding of the origin of
the unusual reactivity of this catalyst, as well as expanding the scope
of these coupling reactions.21
(16) For examples of the interchangeability of trialkylphosphines and their
corresponding phosphonium salts in an array of processes, see: Netherton,
M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
(17) Notes: (a) Pd(P(t-Bu)2Me)2 catalyzes the room-temperature coupling of
alkyl bromides with boronic acids. (b) Consistent with the results in Table
1 (entries 9 vs 10), whereas Pd(P(t-Bu)2Me)2 reacts quickly (100%
conversion within 30 min at room temperature) with Br(CH2)3Ph to
predominantly form the oxidative-addition adduct, Pd(P(t-Bu)2Et)2 reacts
much more slowly (20% conversion after 20 h at room temperature) to
exclusively generate the product of â-hydride elimination.
(18) For a recent study of the oxidative addition of an aryl bromide to a Pd(0)
complex at 25-70 °C, see: Stambuli, J. P.; Bu¨hl, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 9346-9347.
(19) Upon warming to 50 °C, complex 1 undergoes â-hydride elimination.
(20) Adduct 1 also serves as a catalyst for the coupling of alkyl bromides
with boronic acids at room temperature.
(21) The conditions described in eq 1 are not suitable for Suzuki cross-couplings
of boronic acids with alkyl chlorides.
Acknowledgment. We thank Johnson Matthey for supplying
palladium compounds and Frontier Scientific for supplying boronic
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