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7/18/2019 Stille Coupling Reaction
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Stille Coupling ReactionRebecca C. Deocampo
Abstract. The Stille Coupling is a versatile C-C bond forming reaction
between stannanes and halides or pseudohalides, with very few limitationson 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 theMigita-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 via!le methods for the
formation of "#" !onds in organic
chemistry Their use has !een
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 !een proven to !e
a useful synthetic method for
car!on#car!on !ond formation in
organic synthesis "onse$uently,
many e%ective palladium catalytic
systems have !een developed for
Stille cross coupling reaction
&enerally, the com!ination of
palladium catalysts with various
phosphine ligands results in
e'cellent yields and high eciencyowever, phosphine ligands and
their palladium comple'es are
often air-sensitive and are o!*ect to
+#" !ond 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 "oupling is a
versatile "-" !ond forming reaction
!etween stannanes and halides or
pseudohalides, with very few
limitations on the -groups ell-
ela!orated methods allow the
preparation of di%erent products
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from all of the com!inations of
halides and stannanes depicted
!elow The main draw!ack is the
to'icity of the tin compounds used,
and their low polarity, which makes
them poorly solu!le in waterStannanes are sta!le, !ut !oronic
acids and their derivatives undergo
much the same chemistry in what
is known as the Suzuki "oupling
.mprovements in the Suzuki
"oupling may soon lead to the
same versatility without the
draw!acks of using tin compounds
"onvenient electrophiles and
stannanes/
Mechanism
The mechanism of the Stille
reaction is one of the most
e'tensively studied pathways for
coupling reactions The !asic
catalytic cycle, as seen !elow,
involves an o'idative addition of ahalide 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
owever, the detailed mechanism
of the Stille coupling is e'tremely
comple' and can occur vianumerous reaction pathways 0ike
other palladium-catalyzed coupling
reactions, the active palladium
catalyst is !elieved to !e a 12-
electron +d(3) comple', which can
!e generated in a variety of ways
1.xidative !ddition
4or most sp5-hy!ridized
organohalides, a concerted three-
center o'idative addition to this 12-
electron +d(3) comple' is
proposed This process gives the
cis-tetravalent 16-electron +d(..)
species .t has !een suggested the
presence of anionic ligands, such
as 78c, accelerate this step !y the
formation of 9+d(78c)(+:)n;<,
making the palladium species more
nucleophillic
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owever, despite normally forming
a cis-intermediate after a
concerted o'idative addition, this
product is in rapid e$uili!rium withits trans-isomer, which is
thermodynamically more sta!le
This cis#trans isomerism is a
complicated process which involves
at least four concurrent
mechanisms, two of which are
autocatalyzed and two which are
assisted !y solvent association to
the metal
". Transmetalation
The transmetalation of the
trans intermediate from the
o'idative addition step is !elievedto proceed via a variety of
mechanisms depending on the
su!strates 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 !onded to an allyl,
alkenyl, or aryl group, cancoordinate to the palladium via one
of these dou!le !onds This
produces a =eeting pentavalent,
1>-electron species, which can
then undergo ligand detachment to
form a s$uare planar comple'
again ?espite the organostannane
!eing coordinated to the palladium
through the 5 group, 5 must !e
formally transferred to the
palladium (the 5-Sn !ond must !e
!roken), and the @ group must
leave with the tin, completing thetransmetalation This is !elieved to
occur through two mechanisms
4irst, when the organostannane
initially adds to the trans metal
comple', the @ group can
coordinate to the tin, in addition to
the palladium, producing a cyclic
transition state Areakdown of this
adduct results in the loss of :Sn-@
and a trivalent palladium comple'
with 1 and 5 present in a cis
relationship 8nother commonly
seen mechanism involves the same
initial addition of the
organostannane to the trans
palladium comple' as seen a!oveB
however, in this case, the @ group
does not coordinate to the tin,
producing an open transition state
8fter the C-car!on relative to tinattacks the palladium, the tin
comple' will leave with a net
positive charge .n the scheme
!elow, please note that the dou!le
!ond coordinating to tin denotes
5, so any alkenyl, allyl, or aryl
group 4urthermore, the @ group
can dissociate at any time during
the mechanism and !ind to the SnD
comple' at the end ?ensityfunctional theory calculations
predict that an open mechanism
will prevail if the 5 ligands remain
attached to the palladium and the
@ group leaves, while the cyclic
mechanism is more pro!a!le if a
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ligand dissociates prior to the
transmetalation ence, good
leaving groups such as tri=ates in
polar solvents favor the former,
while !ulky phosphine ligands will
favor the latter
8 less common pathway for
transmetalation is through a
dissociative or solvent assisted
mechanism ere, a ligand from
the tetravalent palladium species
dissociates, and a coordinatingsolvent can add onto the
palladium hen the solvent
detaches, to form a 12-electron
trivalent intermediate, the
organostannane can add to the
palladium, undergoing an open or
cyclic type process as a!ove
#. Reduction $limination
.n order for 1-5 to
reductively eliminate, these groups
must occupy mutually cis
coordination sites 8ny trans-
adducts must therefore isomerize
to the cis intermediate or the
coupling will !e frustrated 8
variety of mechanisms e'ist for
reductive elimination and these are
usually considered to !e concerted
4irst, the 16-electron tetravalent
intermediate from thetransmetalation step can undergo
unassisted reductive elimination
from a s$uare planar comple' This
reaction occurs in two steps/ Erst,
the reductive elimination is
followed !y coordination of the
newly formed sigma !ond !etween
1 and 5 to the metal, with
ultimate dissociation yielding the
coupled product
The previous process, however, is
sometimes slow and can !e greatly
accelerated !y dissociation of a
ligand to yield a 12-electron T
shaped intermediate This
intermediate can then rearrange to
form a F-shaped adduct, which can
undergo faster reductive
elimination
4inally, an e'tra ligand can
associate to the palladium to form
an 1>-electron trigonal !ipyramidal
structure, with 1 and 5 cis to each
other in e$uatorial positions Thegeometry of this intermediate
makes it similar to the F-shaped
a!ove
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The presence of !ulky ligands can
also increase the rate of
elimination 0igands such as
phophines with large !ite angles
cause steric repulsion !etween 0
and 1 and 5, resulting in theangle !etween 0 and the groups
to increase and the angle !etween
1 and 5 to hence decrease,
allowing for $uicker reductive
elimination
Applications
The Stille reaction has !een
used in the synthesis of a variety of
polymers owever, the most
widespread use of the Stille
reaction is its use in organic
syntheses, and speciEcally, in the
synthesis of natural products
%atural &roduct Total Synthesis
7vermanGs 1H-step
enantioselective total synthesis of
$uadrigemine " involves a dou!le
Stille cross metathesis reaction
The comple' organostannane is
coupled onto two aryl iodide
groups 8fter a dou!le eck
cyclization, the product is
achieved
+anekGs :5 step enantioselective
total synthesis of ansamycinanti!iotic (D)-mycotrienol makes
use of a late stage tandem Stille
type macrocycle coupling ere,
the organostannane has two
terminal tri!utyl tin groups
attacked to an alkene This
organostannane IstichesJ the two
ends of the linear starting material
into a macrocycle, adding the
missing two methylene units in the
process 8fter o'idation of the
aromatic core with ceric
ammonium nitrate ("8) and
deprotection with hydro=uoric acid
yields the natural product in L2
yield for the : steps
Stephen 4 Martin and coworkersG
51 step enantioselective total
synthesis of the manzamine
antitumor alkaloid .rcinal 8 makes
use of a tandem one-pot
StilleN?iels-8lder reaction 8n
alkene group is added to vinyl
!romide, followed !y an in situ
?iels-8lder cycloaddition !etween
the added alkene and the alkene in
the pyrrolidine ring
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umerous other total syntheses
utilize the Stille reaction, including
those of o'azolomycin, lankacidin
", onamide 8, calyculin 8, lepicidin8, ripostatin 8, and lucilactaene
The image !elow displays the Enal
natural product, the organohalide
(!lue), the organostannane (red),
and the !ond !eing formed (green
and circled) 4rom these e'amples,
it is clear that the Stille reaction
can !e used !oth at the early
stages of the synthesis
(o'azolomycin and calyculin 8), at
the end of a convergent route
(onamide 8, lankacidin ", ripostatin
8), or in the middle (lepicidin 8 and
lucilactaene) The synthesis of
ripostatin 8 features two
concurrent Stille couplings followed
!y a ring-closing metathesis The
synthesis of lucilactaene features a
middle su!unit, having a !orane on
one side and a stannane on the
other, allowing for Stillereactionfollowed !y a su!se$uent
Suzuki coupling
References
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Mascitti, Oincent Stillecoupling ame eactions for
omologations (533H), (+t
1), 1::#165
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ill, + ?B Pones, A +B
Mc?ermott, QB Munchhof,
M PB Mar', M 8B "asavant, P
MB "ooper, A 8B ?oty, P 0B0u, F 7rg +roc es ?ev
533:, R, 6R6
• S + Mee, O 0ee, P Q
Aaldwin, !ngew. Chem. 'nt.
$d., 2004, (#, 11:5-11:6
• 0ere!ours, 8 "amacho-
Soto, " olf, ). rg. Chem.,
2005, *+, >631->632
• 0 ?el Oalle, P K Stille, 0 S
egedus, ). rg. Chem,!!0, , :31H-:35:
• "- uang, M
Shanmugasundaram, -M
"hang, "- "heng,
Tetrahedron, 200", , :6:L-
:621
• uang, Piang, K "hen,
0iu, ). rg. Chem., 200!,
*(, LLHH-L635
• P- 0i, F 0iang, ?-+ ang,-P 0iu, F-@ @ie, ?-0 Fin, ).
rg. Chem., 2005, *+, 5>:5-
5>:2
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