Suzuki coupling: Intoduction
Suzuki coupling has
become increasingly popular since its discovery in the 1970’s and is well recognized as a
successful approach for the formation of heteronuclear species. A general Pd
catalyzed Suzuki reaction is shown in figure 1, where Ar / Ar’ = aryl group
and X = halide. Steps 1-4 in the catalytic cycle will also be examined
individually in figures 1, 2, 3 & 4.
Figure 1: General catalytic cycle for Suzuki
cross-coupling
The general
catalytic cycle for the Suzuki[i]
cross-coupling reactions of organoboranes with oganohalides involves oxidative addition, transmetallation and reductive
elimination.[ii], [iii]
Although each step involves further intricate processes including ligand
exchanges, there is no doubt about the presence of the intermediates which have
been characterized by isolation and spectroscopic analysis.[iv],
[v]
Oxidative addition is the initial step
of the catalytic cycle as shown in figure 1. This process occurs between an
aryl halide and the palladium(0) complex to afford a stable trans-palladium(II)
complex. [vi] This
process results in bond formation between a coordinately unsaturated species
(Pd catalyst) and the appropriately functionalized aryl halide, to produce a
coordinately saturated species, such as the organopalladium halide as shown in
figure 2.
Figure 2: Oxidative addition of the metal catalyst into the single bond of the
substrate
This is often
the rate determining step within the catalytic cycle, with the relative
reactivity of the functional groups decreasing in the order of I > OTf >
Br >> Cl. Also aryl halides with electron withdrawing groups in close
proximity are, in general, more activated towards coupling then those with
electron donating groups present.
The second step
we observe is transmetallation were
the nucleophile, in this case boronic acid, is transferred from the
organometallic reagent to the organopalladium(II) halide complex to provide the
diorganopalladium complex as shown in figure 3. In Suzuki cross-coupling this
step is previewed by the displacement of the halide ion from the
organopalladium halide complex from the oxidative
addition step to a base. This is the key difference between the Suzuki
cross-coupling and other general cross-coupling reactions.
Figure 3: Transmetallation of an active complex with an organometallic substrate.
This step can
prove problematic due to organoboron compounds being unlikely to participate in
the catalytic cycle since they are inert to organopalladium(II) halides. However it has been reported that the addition
of sodium hydroxide or other bases exerts a remarkable effect on the transmetallation
rate of organoboron reagents with metallic halides. [vii] Thus the transmetallation step with transition metal complexes can proceed
well, but the choice of a suitable base and ligands on transition metal
complexes are essential. The suitable base chosen enhances the reactivity of
the organoboron complex, which has a low nucleophilicity due to the organic
group attached to the boron atom. This is achieved by quaternization of the
boron atom with a negatively charged base giving the corresponding “ate”
complex as shown above in figure 3.[viii],
[ix]
This reaction is particularly important because it allows the coupling of two
different components. It is conceivable that the coordination of the palladium(II)
species to the carbon-carbon multiple bonds constitute the initial step for the
interaction of both species and probably this π-interaction serves to
accelerate the ligand exchange.[x]
The final step
observed in the catalytic cycle is
reductive elimination were the metal atom is removed and a new single bond
is formed. This is the reverse of the initial step, oxidative addition, with the palladium catalyst being recycled from
a higher oxidation state to a lower oxidation state[xi],
[xii]
and beginning the coupling process again, with the desired cross-coupled product
also being formed. The reaction takes place directly from the cis-intermediate to the trans-intermediate after its isomerization
to the corresponding cis-complex,
figure 4.
Figure 4: Schematic representation of the isomerization of the Pd intermediate
from its trans to its cis form (step 3) and the final process of reductive
elimination (step 4).
The removal of
the ligands from the coordination sphere of the metal is an active process and
is driven by the formation of a more stable product, rather than the
organopalladium complex which has higher energy.
Within the 4 steps of this catalytic
cycle other variables must also be considered, such as
1) catalyst,
2) base,
3)
solvent,
4) temperature and
5) reaction time.
Each of these five factors can be
varied to generate the optimum reaction conditions for coupling for Suzuki
coupling.
In terms of the
catalyst palladium(0) is the most commonly used catalyst in Suzuki coupling.
Palladium chemistry is dominated by two oxidation states both of which may be
used within catalytic cycles. The lower oxidation state (0) is nominally
electron rich and will undergo oxidative addition with suitable substrates such
as halides resulting in a palladium(II) complex. In reactions requiring
palladium(0), formation of the active may be achieved more conveniently by
reduction of the palladium(II) complex in situ. This may be achieved with
amines, phosphines or alkenes without the need to synthesize and isolate the
palladium(0) complex.
Palladium
complexes that contain fewer then four phosphine ligands[xiii]
or bulky phosphines such as tris(2,4,6-tri-methoxyphenyl)phosphine are, in
general, highly reactive for the oxidative
addition because of the ready formation of coordinately unsaturated
palladium species. [xiv]
The most commonly used catalysts generally include tertiary phosphines which
although are useful in controlling reactivity and selectivity in homogeneous
catalysis [xv] they
usually require air-free handling to prevent oxidation. More importantly they
are subject to P-C bond degradation at elevated temperatures. Therefore care
must be taken as in certain catalytic processes as this may result in
deactivation of the catalyst and as a consequence, higher phosphine
concentrations are required.[xvi]
The most commonly used catalyst in Suzuki coupling reactions is Pd(PPh)3,
with PdCl2(PPh)3 and Pd(OAc)2 also being
efficient due to their stability to air and their ability to be readily reduced
to the active Pd(0) complex. [xvii]
A variety of
solvents and bases have been used for Suzuki coupling reactions. Toluene and
THF 47, 49 have proved very popular for the coupling of
organic species with acetonitrile and DMF being used for the coupling of
inorganic species. With respect to the base effect the most widespread include NaOH,
NaCO3 and KCO3.
REFERENCES
[i] Zhuravel, M. A: Nguyen , S. T., Tet. Lett., 2001, 42, 7925
[ii] Miyaura, N: Suzuki, A., Chem. Rev., 1995, 95,
2457
[iii] Suzuki, A:
Diederich, F: Stang, P. J., (Eds.), Metal-Catalysed
Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1998, 49
[iv] (a) Heck, R. F., Palladium Reagents in Organic Syntheses: Academic, New York New York
[v] Aliprantis, A. O: Canary, J. W., J. Am. Chem. Soc., 1994,
116, 6985.
[vi] (a) Tsuji, T., “Palladium
Reagents and Catalysts, Innovation in Organic Synthesis”, 1995, Wiley, Chichester , England
[vii] Brown, H, C: Hebert, N. C: Snyder, C, H., J. Am. Chem. Soc., 1961, 83, 1001
[viii] (a) Onak, T., Organoborane Chemistry, Academic, New York Amsterdam New
York
[ix] Negishi, E., Aspects of Mechanism and Organometallic Chemistry, Brewster, J. H,
Ed: Plenum Press: New York
[x] Farina, V: Krishnan, X., J. Am. Chem. Soc., 1991,
113, 9585
[xi] Gillie, A:
Stille, J. K., J. Am. Chem. Soc., 1980, 102, 4933
[xii] Ozawa, F:
Kurihara, K: Fujimori, M: Hidaka, T: Toyoshima, T: Yamamoto, A., Organometallics, 1989, 8, 180
[xiii] (a) Parshall,
G. W: Ittel, S: Homogeneous Catalysis,
John Wiley and Sons, New York New York
[xiv] Waas, J. R: Sidduri, A. R: Knochel,
P., Tet. Lett., 1992, 33, 3717
[xv] Parshall, G.
W: Ittel, S., Homogeneous Catalysis,
John Wiley and Sons, New York
[xvi] Colman, J. P: Hegedus, L. S: Norton,
J. R: Finke, R. G., Principles and
Applications of Organotransition Metal Chemistry, University Science Books,
Mill Valley , CA
[xvii] Hillier, A.
C: Grasa, G. A: Viciu, M. S: Lee, H. M: Yang, C: Nolan, S., J. Organometallic Chem., 2002,
653, 69
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