Stille Coupling Reaction

Rebecca C. Deocampo
Abstract. The Stille Coupling is a versatile C-C bond forming reaction
between stannanes and halides or pseudohalides, with very few limitations
on the R-groups. The mechanism of the Stille reaction is one of the most
extensively studied pathways for coupling reactions. The basic catalytic
cycle, as seen below, involves an oxidative addition of a halide or
pseudohalide to a palladium catalyst, transmetalation of with an organotin
reagent, and reductive elimination of to yield the coupled product and the
regenerated palladium catalyst.

Introduction
The Stille reaction, or the
Migita-Kosugi-Stille coupling, is a
chemical reaction widely used in
organic synthesis which involves
the coupling of an organotin
compound
(also
known
as
organostannanes) with a variety of
organic electrophiles via palladium-

catalyzed coupling reaction.

Stille reactions remain one of the

most viable methods for the
formation of CC bonds in organic
chemistry. Their use has been
highlighted
in
various
areas,
including countless elegant natural
product
syntheses,
material
science,
and
in
synthetic
methodology.

The Stille cross-coupling reaction of

organohalides
with
organotin
compounds has been proven to be
a useful synthetic method for
carboncarbon bond formation in
organic synthesis. Consequently,
many effective palladium catalytic
systems have been developed for
Stille cross coupling reaction.
Generally, the combination of
palladium catalysts with various
phosphine
ligands
results
in
excellent yields and high efficiency.
However, phosphine ligands and
their palladium complexes are
often air-sensitive and are object to
PC bond degradation at elevated
temperature. Thus, the use of other
supporting ligands for the Stille
cross-coupling reaction emerged as
an attractive alternative to the
phosphine ligands.
The Stille Coupling is a
versatile C-C bond forming reaction
between stannanes and halides or
pseudohalides, with very few
limitations on the R-groups. Wellelaborated methods allow the
preparation of different products

from all of the combinations of

halides and stannanes depicted
below. The main drawback is the
toxicity of the tin compounds used,
and their low polarity, which makes
them poorly soluble in water.
Stannanes are stable, but boronic
acids and their derivatives undergo
much the same chemistry in what
is known as the Suzuki Coupling.
Improvements
in
the
Suzuki
Coupling may soon lead to the
same
versatility
without
the
drawbacks of using tin compounds.

Convenient electrophiles and

stannanes:

However, the detailed mechanism

of the Stille coupling is extremely
complex and can occur via
numerous reaction pathways. Like
other palladium-catalyzed coupling
reactions, the active palladium
catalyst is believed to be a 14electron Pd(0) complex, which can
be generated in a variety of ways.

1.Oxidative Addition

Mechanism
The mechanism of the Stille
reaction is one of the most
extensively studied pathways for
coupling reactions. The basic
catalytic cycle, as seen below,
involves an oxidative addition of a
halide or pseudohalide
to a
palladium catalyst, transmetalation
of with an organotin reagent, and
reductive elimination of to yield
the coupled product
and the
regenerated palladium catalyst.

For
most
sp2-hybridized
organohalides, a concerted threecenter oxidative addition to this 14electron
Pd(0)
complex
is
proposed. This process gives the
cis-tetravalent 16-electron Pd(II)
species. It has been suggested the
presence of anionic ligands, such
as OAc, accelerate this step by the
formation
of
[Pd(OAc)(PR3)n],
making the palladium species more
nucleophillic.

However, despite normally forming

a
cis-intermediate
after
a
concerted oxidative addition, this
product is in rapid equilibrium with
its
trans-isomer,
which
is
thermodynamically more stable.
This cistrans isomerism is a
complicated process which involves
at
least
four
concurrent
mechanisms, two of which are
autocatalyzed and two which are
assisted by solvent association to
the metal.

2. Transmetalation
The transmetalation of the
trans
intermediate
from
the
oxidative addition step is believed
to proceed via a variety of
mechanisms depending on the
substrates and conditions. The
most
common
type
of
transmetalation
for
the
Stille
coupling involves an associative
mechanism. This pathway implies
that the organostannane, normally
a tin atom bonded to an allyl,
alkenyl,
or
aryl
group,
can
coordinate to the palladium via one
of these double bonds. This
produces a fleeting pentavalent,
18-electron species, which can
then undergo ligand detachment to
form a square planar complex
again. Despite the organostannane

being coordinated to the palladium

through the R2 group, R2 must be
formally
transferred
to
the
2
palladium (the R -Sn bond must be
broken), and the X group must
leave with the tin, completing the
transmetalation. This is believed to
occur through two mechanisms.
First, when the organostannane
initially adds to the trans metal
complex,
the
X
group
can
coordinate to the tin, in addition to
the palladium, producing a cyclic
transition state. Breakdown of this
adduct results in the loss of R3Sn-X
and a trivalent palladium complex
with R1 and R2 present in a cis
relationship. Another commonly
seen mechanism involves the same
initial
addition
of
the
organostannane
to
the
trans
palladium complex as seen above;
however, in this case, the X group
does not coordinate to the tin,
producing an open transition state.
After the -carbon relative to tin
attacks the palladium, the tin
complex will leave with a net
positive charge. In the scheme
below, please note that the double
bond coordinating to tin denotes
R2, so any alkenyl, allyl, or aryl
group. Furthermore, the X group
can dissociate at any time during
the mechanism and bind to the Sn +
complex at the end. Density
functional
theory
calculations
predict that an open mechanism
will prevail if the 2 ligands remain
attached to the palladium and the
X group leaves, while the cyclic
mechanism is more probable if a

ligand dissociates prior to the

transmetalation.
Hence,
good
leaving groups such as triflates in
polar solvents favor the former,
while bulky phosphine ligands will
favor the latter.

A less common pathway for

transmetalation
is
through
a
dissociative or solvent assisted
mechanism. Here, a ligand from
the tetravalent palladium species
dissociates, and a coordinating
solvent
can
add
onto
the
palladium.
When
the
solvent
detaches, to form a 14-electron
trivalent
intermediate,
the
organostannane can add to the
palladium, undergoing an open or
cyclic type process as above.

3. Reduction Elimination
In
order
for
R1-R2
to
reductively eliminate, these groups
must
occupy
mutually
cis
coordination sites. Any transadducts must therefore isomerize
to the cis intermediate or the

coupling will be frustrated. A

variety of mechanisms exist for
reductive elimination and these are
usually considered to be concerted.
First, the 16-electron tetravalent
intermediate
from
the
transmetalation step can undergo
unassisted reductive elimination
from a square planar complex. This
reaction occurs in two steps: first,
the
reductive
elimination
is
followed by coordination of the
newly formed sigma bond between
R1 and R2 to the metal, with
ultimate dissociation yielding the
coupled product.

The previous process, however, is

sometimes slow and can be greatly
accelerated by dissociation of a
ligand to yield a 14-electron T
shaped
intermediate.
This
intermediate can then rearrange to
form a Y-shaped adduct, which can
undergo
faster
reductive
elimination.

Finally, an extra ligand can

associate to the palladium to form
an 18-electron trigonal bipyramidal
structure, with R1 and R2 cis to each
other in equatorial positions. The
geometry of this intermediate
makes it similar to the Y-shaped
above

The presence of bulky ligands can

also
increase
the
rate
of
elimination.
Ligands
such
as
phophines with large bite angles
cause steric repulsion between L
and R1 and R2, resulting in the
angle between L and the R groups
to increase and the angle between
R1 and R2 to hence decrease,
allowing for quicker reductive
elimination.

Applications
The Stille reaction has been
used in the synthesis of a variety of
polymers. However, the most
widespread use of the Stille
reaction is its use in organic
syntheses, and specifically, in the
synthesis of natural products.
Natural Product Total Synthesis
Overmans
19-step
enantioselective total synthesis of
quadrigemine C involves a double
Stille cross metathesis reaction.
The complex organostannane is
coupled onto two aryl iodide
groups. After a double Heck
cyclization,
the
product
is
achieved.

Paneks 32 step enantioselective

total
synthesis
of
ansamycin
antibiotic (+)-mycotrienol makes
use of a late stage tandem Stille
type macrocycle coupling. Here,

the
organostannane
has
two
terminal
tributyl
tin
groups
attacked to an alkene. This
organostannane stiches the two
ends of the linear starting material
into a macrocycle, adding the
missing two methylene units in the
process. After oxidation of the
aromatic
core
with
ceric
ammonium nitrate (CAN) and
deprotection with hydrofluoric acid
yields the natural product in 54%
yield for the 3 steps.
Stephen F. Martin and coworkers
21 step enantioselective total
synthesis
of
the
manzamine
antitumor alkaloid Ircinal A makes
use
of
a
tandem
one-pot
Stille/Diels-Alder
reaction.
An
alkene group is added to vinyl
bromide, followed by an in situ
Diels-Alder cycloaddition between
the added alkene and the alkene in
the pyrrolidine ring.

Numerous other total syntheses

utilize the Stille reaction, including
those of oxazolomycin, lankacidin
C, onamide A, calyculin A, lepicidin
A, ripostatin A, and lucilactaene.
The image below displays the final
natural product, the organohalide
(blue), the organostannane (red),
and the bond being formed (green
and circled). From these examples,
it is clear that the Stille reaction
can be used both at the early
stages
of
the
synthesis
(oxazolomycin and calyculin A), at
the end of a convergent route
(onamide A, lankacidin C, ripostatin
A), or in the middle (lepicidin A and
lucilactaene). The synthesis of
ripostatin
A
features
two
concurrent Stille couplings followed
by a ring-closing metathesis. The
synthesis of lucilactaene features a
middle subunit, having a borane on
one side and a stannane on the
other,
allowing
for
Stille
reactionfollowed by a subsequent
Suzuki coupling.

References

Mascitti,
Vincent.
Stille
coupling. Name Reactions for
Homologations (2009), (Pt.
1), 133162.
Ragan, J. A.; Raggon, J. W.;
Hill, P. D.; Jones, B. P.;

McDermott, R. E.; Munchhof,

M. J.; Marx, M. A.; Casavant, J.
M.; Cooper, B. A.; Doty, J. L.;
Lu, Y. Org. Proc. Res. Dev.
2003, 7, 676.
S. P. H. Mee, V. Lee, J. E.
Baldwin, Angew. Chem. Int.
Ed., 2004, 43, 1132-1136.
R. Lerebours, A. CamachoSoto, C. Wolf, J. Org. Chem.,
2005, 70, 8601-8604.
L. Del Valle, J. K. Stille, L. S.
Hegedus, J. Org. Chem,
1990, 55, 3019-3023.
C.-W.
Huang,
M.
Shanmugasundaram,
H.-M.
Chang,
C.-H.
Cheng,
Tetrahedron, 2003, 59, 36353641.
H. Huang, H. Jiang, K. Chen,
H. Liu, J. Org. Chem., 2009,
74, 5599-5602.
J.-H. Li, Y. Liang, D.-P. Wang,
W.-J. Liu, Y.-X. Xie, D.-L. Yin, J.
Org. Chem., 2005, 70, 28322834.