The Heck Reaction: Mechanistic Insight into a ... - The Stoltz Group

The Heck Reaction: Mechanistic Insight into
a Synthetically Useful Reaction
Uttam K. Tambar
Stoltz Group Literature Series
Thursday, April 17, 2003 (right after group meeting)
L 2 Pd II X 2 or Pd(0) precatalyst
X - H + NR 3
red. elim.
NR 3
L 2 Pd(0)
preactivation
Br
oxid. addn.
R
H
Pd
X
L
Ph
L
Pd
L
X
Ph
L
Pd
X
L
Ph
R
R H
Pd
X
L
R
Ph
Pd
X
L
Ph
Ph
!-H
elimination
R
Pd
L X
migratory
insertion
General Reaction
R
+ R'X
L 2 Pd II X 2 or Pd(0) cat.
R
+ Base H + X -
H
Base
R'
R' = aryl, heterocyclic, vinyl, benzyl
X = Br, I, OTf, Cl, and some other miscellaneous FG
Base = 2° or 3° amine, NaOAc, K 2 CO 3 , KHCO 3 , KOAc
Catalyst:
Pd(II) sources- Pd(OAc) 2 , PdCl 2 (PR 3 ) 2 , PdCl 2 (CH 3 CN) 2
Pd(0) sources- Pd(PPh 3 ) 4 , Pd(dba) 2 + PR 3
General Reviews:
Chem. Rev. 2000, 100, 3009 (Beletskaya)
Acc. Chem. Res. 1995, 28, 2 (Cabri)
Angew. Che. Int. Ed. Engl. 1994, 33, 2379 (Meijere)
History
Mizoroki and Heck independently discovered the novel Pd-mediated coupling of aryl halides with olefins,
but Heck developed it into a general method for synthetic chemistry
Bull. Chem. Soc. Jpn. 1971, 44, 581 (Mizoroki)
J. Org. Chem. 1972, 37, 2320 (Heck)
Preactivation of Catalyst
Oxidative Addition
Migratory Insertion
Possible Termination Steps
!-Hydride Elimination
Reductive Elimination
Phosphine-Assisted vs. Phosphine Free Catalysis
Outline
1

Preactivation of Catalyst
• if a Pd(II) source is used in a Heck reaction, it must be reduced to Pd(0) before entering the catalytic cycle
Reduction by Phosphines
outer shell mechanism
nucleophillic
attack
H 2 O
L n Pd II PR 3
L n Pd(O) + NuPR 3
Nu
H
+
O PR 3
Nu
phosphonium
inner shell mechanism
Nu
reductive
elimination
H 2 O
L n Pd II PR 3
L n Pd(O) + NuPR 3
Nu
H
+
O PR 3
phosphonium
• electron-withdrawing group on phosphine increases rate of Pd(II) to Pd(0) reduction,
because phosphine is more susceptible to attack by nucleophile
• hard nucleophiles assist Pd(II) to Pd(0) reduction (eg. - OH, - OR, H 2 O, AcO - /H 2 O, F - /H 2 O)
Preactivation of Catalyst - continued
• in the absence of phosphines, Pd(II) can be reduced to Pd(0) by other means
Reduction by Tertiary Aliphatic Amines
L n Pd II
X
X
coordination
R 2 N
R
L
X
R 2
N
Pd
H
R
!-hydride
elimination
R 2 N
R
L n Pd II
X
H
reductive
elimination
HX
L n Pd(0)
Reduction by Olefins (Wacker-Type Process)
L n Pd II
X
X
coordination
R
L n Pd II
R
X
Wacker-type
attack
Nu
H
L n Pd II
X
Nu
R
!-hydride
elimination
R
L n Pd II
X
H
reductive
elimination
HX
L n Pd(0)
Nu
• when a high catalyst loading is used, the yield may be diminished if the substrate olefin
undergoes this Wacker-type reaction
Reduction by Other Functional Groups
• phosphonium and 4° ammonium salts can also reduce Pd(II) to Pd(0) (via oxid. addn. to C-N or C-P)
2

Preactivation of Catalyst - continued
• to enter the catalytic cycle, Pd(0) must have a proper coordination shell (eg. L 2 Pd(0) )
there can be no more than 2 strongly bound ligands on palladium
there is a a restriction on the choice of ligands and their concentration in solution
The Proper Coordination Shell for Pd(0) in Monodentate Phosphine Assited Catalysis
• too much phosphine inhibits catalysis by generating a coordinatively saturated complex:
PR 3
R 3 P Pd 0 PR 3
PR 3
R 3 P Pd 0 PR 3
Ar Br
PR 3 ligand
ox. addn.
assoc.
Ar
R 3 P Pd II Br
PR 3
Heck
• but with too little phosphine, the active dicoordinated Pd 0 (PR 3 ) 2 disproportionates
to a stable tricoordinate Pd 0 (PR 3 ) 3 and unstable low-ligated complexes, which leads
to Pd aggregation and cluster formation:
2Pd(PR 3 ) 2 Pd(PR 3 ) 3 + Pd(PR 3 ) Pd n L m Pd-black
(stable)
Preactivation of Catalyst - continued
The Proper Coordination Shell for Pd(0) Complexes Generated from Pd(dba) 2
• once again, with too little phosphine (or other L-type ligand) the active dicoordinated Pd 0 L 2
disproportionates to a stable tricoordinate Pd 0 L 3 and unstable low-ligated complexes, which
leads to Pd aggregation and cluster formation:
Pd(dba) 2
+ 2L 2dba + PdL 2 PdL 3 + PdL Pd n L m Pd-black
• with too little phosphine there may also be incomplete deligation of dba,
which requires at least 4 equivalents of phosphine
• Pd(dba) 2 + excess PR 3 may lead to a coordinatively saturated complex,
which may not react with less reactive substrates
preformed Pd(PPR 3 ) 4 may be more reactive thanPd(dba) 2 + excess PR 3
Electronic Influences on the Proper Coordination Shell for Pd(0)-Triaryl Phosphine Complexes
• there's a fine balance in choosing a triaryl phosphine ligand with the proper electronices
electron withdrawing
group on arylphosphine
higher concentration of reactive Pd 0 (PAr 3 ) 2 via deligation of PAr 3
electron donating
group on arylphospine
higher rate of oxidative addition
3

Oxidative Addition
L 2 Pd(0)
oxid. addn.
Ph
L
Pd
L
X
Ph
L
Pd
X
L
Br
cis
trans
• oxidative addition is a relatively concerted process (C-X breaks synchronously with the formation
of M-C and M-X)
• unlike the stepwise addition-elimination mechanism of nucleophillic aromatic substitution (in which
charge builds up), the concerted mechanism of oxidative addition is less sensitive to the electronics
of the unsaturated R'-X substrate and is more sensitive to the nature of X and the relative bond
strengths of C-X and M-X
order of reactivity in oxidative addition (I >> OTf > Br >> Cl) is roughly
opposite for nucleophillic aromatic substitution
• in most monodentate phosphine examples, the isolable product of oxidative addition is the trans isomer,
but the complex that continues in the catalytic cycle is the cis isomer
Heck Ph X Ph L
Pd
Pd
isolable
L L L X
cis
trans
R X
L
Pd
L
Migratory Insertion
migratory
insertion
R'
R
R'
L
Pd
X
L
• this step is usually responsible for the regioselectivity, stereoselectivity and substrate selectivity
or a Heck reaction
3 Possible Mechanisms
(1) RPdX behaves as a carbanion (like other non-transition or early-transition metals)
R
L
Pd
L
X
Pd
L
X
L
R
O
OMe
migratory
insertion
R
Pd
L
O
X
L
OMe
most data refutes this mechanism
(2) RPdX or RPd + are metal-centered electrophiles being attacked by an olefin
(electrophillic addition mechanism)
X
L
R
Pd
X
L
Pd
R
X
L
Pd
R
there is some data that supports this mechanism, and
sometimes it is the most relevant mechanism
4

Migratory Insertion - continued
(3) RPdX or RPd + add to the olefin in a concerted process
X
L
Pd
R
X
L
Pd
R
X
L
Pd
R
this mechanism is the most realistic (compromise between the 2
other possible mechisms)
the variable TS is adaptable/flexible to electronic demands, so
steric factors are often the main source of selectivitiy
eg. substitution on olefin reduces rate of reaction
> >
Migratory Insertion - continued
Mechanism of Olefin Ligation to Pd(II)
• in order for the olefin to ligate to Pd(II), another ligand must deligate first to open a coordination site
if a neutral L ligand deligates (eg. PR 3 )
non-polar / neutral mechanism
if an anionic X ligand deligates (eg. halide)
polar / cationic mechanism
• neutral mechanism:
L 2 Pd(0)
X
Ar
Ar
L
Pd
L
X
R
R
Ar
Pd
L
X
L
this mechanism is thought to operate when X is a strong !-donor (ie. Cl, Br, I)
• cationic mechanism:
+
X Ar
Ar L
L
Ar L
2 Pd(0)
R
Pd
Pd
X L
R
L
Cl -
X -
this mechanism is thought to operate when X is a weakly associated anionic ligand
(eg. OTf, OAc), or when Ag or Tl salts (eg. AgY or TlY, Y =CO 3 , OTf, OAc)
are used to abstract the halide
5

Migratory Insertion - continued
• for monodentate phosphine ligands, both the neutral and cationic mechanisms are accessible:
neutral
Ar
L Pd L
X
cationic
-L
L
Ar
Pd S L
Ar
Pd
X
X
L
Ar
Pd X
-X - L
Ar
Pd S
L
Ar
Pd
L
L
L
• for bidentate phosphine ligands, the neutral mechanism a lot less likely
when aryl or vinyl halides are used, bidentate ligands often lead to a complete
or partial suppression of the reaction
the neutral mechanism is still possible in special cases
eg. large bite-angle diphosphine in which the spacer between phosphines
is large/flexible and the P-Pd-P angle is greater than 90 °
neutral (less likely)
L
Ar
Pd X
L
cationic
-L
S
Ar
Pd X
L L
Ar
-X - L Pd S
L
L
L
Ar
Pd
L
Ar
Pd
L
X
Migratory Insertion - continued
• for phosphine-free systems, the neutral mechanism is bascially inconceivable
most phosphine-free Heck reactions are performed in polar solvents or with
additives which assist in the exchange of anionic ligands
• the electrophillicity of the arylpalladium complex has little to do with the positive charge of Pd
ArPdX / ArPd + is electrophillic with electron rich olefins
ArPdX / ArPd + is nucleophillic with electron poor olefins
ArPd + is not more electrophillic than ArPdX
• there are several degrees of freedom in the TS
the !-complexed alkene rotates to an in-plane position and therefore adapts
itself to 2 possible TS (representing the 2 possible regioisomeric products of
olefin insertion)
the TS which represents the lower energy barrier is followed
6

Regioselectivity in Migratory Insertion
• "the temptation to find simple rules of regioselectivity should be discarded"
Intermolecular Heck Reaction
• regioselectivity of migratory insertion with neutral Pd complexes
20%
80%
CO 2 Me CN Ph C 4 H 9
1%
40%
99%
60%
CO 2 Me Ph N
O
OMe
neutral Pd complex + electron poor alkene
neutral Pd complex + electron rich alkene
steric control
electronic control
Regioselectivity in Migratory Insertion - continued
• regioselectivity of migratory insertion with cationic Pd complexes
40%
80%
60%
20%
CO 2 Me CN Ph C 4 H 9
95%
O
N
OH
5%
OAc
OAc
cationic Pd complex + electron poor alkene
cationic Pd complex + electron rich alkene
electronic control
electronic control
coordination of the olefin to
a cationic Pd complex results
in a polarization of the C=C bond
7

Regioselectivity in Migratory Insertion
Intramolecular Heck Reaction
• regioselectivity of intramolecular Heck reactions is almost always determined by sterics
exo-trig
endo-trig
Pd
L X
PdL n X
Pd
L X PdL n X
for small rings (5, 6, or 7 carbons)
exo-trig dominates
for large rings / macrocycles (more than 9 carbons)
endo-trig is generally preferred
• disfavored regioselectivity in intermolecular Heck reactions can be
realized by using a cleavable tether to furnish a desirable exo-trig product (TL 1999, 40, 4901)
X
I
+
OMe
X
I
OMe
X
MeO
X
MeO
Y
OBn
RO 2 C
Y
O
O
Y
Heck
O
O
Y
OBn
CO 2 R
Termination Step
• after migratory insertion and before reductive elimination there are several options for transforming the
organopalladium complex
(1) Pd-H elimination / !-hydride elimination (this is the most common)
(2) Pd-M elimination (eg. Pd-SiX 3 )
(3) palladotropic shift: Ar Pd X
O
OMe
XPd
O
OMe
XPd
O
OMe
Ar
if Pd-H elimination is not possible because of stereochemical reasons or is very slow,
Ar
(4) nucleophillic attack at Pd (nucleophillic substitution or reductive elimination),
which results in a net syn Ar-Nu addition across an olefin
(5) cascade reactions: allylic substitution
cross coupling
carbonylation
another Heck
8

!-Hydride Elimination
Ph
Pd
L X
R H
Pd
L
X
R
Ph
• after !-H elimination the olefin is coordinated to Pd-H, so if Pd-H is not
induced to reductively eliminate readdition to the olefin may occur
olefin isomerization in the product
olefin isomerization in the starting material
Heck product with the
wrong stereochemistry
• bases help to minimize olefin isomerization by promoting reductive elimination of PdH
R
H L
Pd
X
Ph
Ph
R
H
Pd
X
L
NR 3
X - H + NR 3
L 2 Pd(0)
• halide scavengers help to minimize olefin isomerization by aiding in the reductive elimination of PdH
Ph
R
Pd
L X
reinsert
R
H L
Pd
X
Ph
Ph
R
H
Pd
X
L
AgOAc
Ag-X
L 2 Pd(0)
!-Hydride Elimination - continued
• syn !-H elimination defines the E-selectivity of Heck products
R
Ph
Pd
L
X
migratory
insertion
H
H
Ph
Pd
H
R
L X
internal
rotation
Ph
H
H
Pd
R
H
L X
(sterically congested
conformer)
Ph
H
H
Pd
L X
R
H
Pd
L
X
R
H
Ph
• a Z-selective Heck reaction can be explained by several factors:
PdH induced isomerization of starting material
PdH induced isomerization of product
different mechanism for !-H elimination (eg. anti !-H elimination)
9