Chem 634 Fall 2013
Metal Mediated Substitution Chemistry
Prof. Donald Watson
"
Assistant Professor"
"
"
Copper Promoted Substitution Chemistry
SN2 –type Reactions:
Br H
Me
Me
H Ph
Ph2CuLi
Me
Me
SN2 reaction
1°>2°>>3°
TfO~TsO~I>Br>Cl
•  Mechanism not clear
•  Review: Comp. Org Synth, Vol 3, Section 1.5
Copper Promoted Substitution Chemistry
Also sp2 systems:
TfO
H
Bu
Bu
Me2CuLi
Me
H
Bu
Bu
+ 10% E-isomer
•  Also works with ArX
•  But not used very often now...see later
TL, 1980, 21, 4313
Copper Promoted SN2' Chemistry
Me
isotopic
label
D
O
Me
Me
BuMgBr
Cat. CuX
O
+
Bu
D
Me
Bu
D
Me
Me
w/ 10% CuCl:
w/ 10% CuCN:
However, with PhMgBr + CuCN:
61%
100%
39%
0%
Me
Me
D
Ph
+
Ph
General SN2' mechanism:
Nuc
LG
Nuc
Goering, JOC, 1986, 51, 2884
D
Reactions With Acid Chlorides
Recall:
R'Li
or R'MgX
O
R
R
Cl
OH
O
R'
R'
R'
R
cannot stop here,
ketone more reactive
However:
O
R
O
R'2CuLi•LiX
Cl
R
R'
clean
Palladium (and Nickel) Catalyzed Cross Coupling
R
X
+
R'
LnPd(0) cat.
R
M
aryl or vinyl
C-C bond
X: TfO>I>Br>OTs~Cl
M= -SnR3 (Stille reaction)
-B(OR)2 or B(OH)2 w/ base (Suzuki reaction)*
-SiR3 (Hiyama reaction)
-MgX (Kumada-Curriu reaction)
-ZnBr (Negishi reaction)*
* = 2010 Nobel Prize
R'
Basic Mechanism
Ar X
LnPd(0)
Ar Ar'
oxidative addition
reductive elimination
Ln
PdII
Ar
Ar
LnPdII
MX
Ar' M
transmetalllation
Ar
X
Palladium and Nickel Sources
Palladium (0) Sources
Palladium (II) Sources
(Reduced In Situ)
Pd(OAc)2
O
Pd2(dba)3
Pd(Cl)2
dba:
Ph
Ph
(MeCN)2PdCl2
Pd(PPh3)4
Pd
Cl
Note: dba and PPh3 are ligands.
Nickel Sources
Ni(COD)2
NiX2 (X=Cl, Br, I)
1,5-COD:
2
Ligands
Ar X
X = TfO, I, Sometimes Br (easy oxidative addition)
PPh3
Ph2P
PPh2
PPh2
Fe
dppe
PPh2
dppf
X = Br
P(o-tol)3
O
PPh2
PPh2
R'
X = Cl
PR'2
Pt-Bu3, PCy3, NHC's
R
R'=Cy, t-Bu
Ligand is the most important part of the catalyst for controlling reactivity,
Active Catalysts for Oxidative Addition
18 e-
16 e-
14 e-
Pd(PR3)4
Pd(PR3)3
Pd(PR3)2
-PR3
12 e-
-PR3
Pd(PR3)1
-PR3
ArX (with PPh3)
Ar
(PR3)2Pd
X
Larger more electron-rich ligands favor lower coordination numbers
required for ArCl
•  Note: the need for low valent Pd(0) explains why Pd2(dba)3 and Pd(PPh3)4
can be problematic.
•  Also, this trend explains why metal:ligand ratio can be very important to
reactivity.
Sonagashira Reaction
R
Ar X
Pd(0) cat
CuI cat
Et3N
Ar
R
Formation of Copper Acetylide
I
Cu(I)
CuI
R
pka ~ 20
H
R
H
I
Cu(III)
R
H
NEt3
pka' ~ 9
R
Cu
Mechanism
Ar
Ar X
LnPd(0)
R
oxidative addition
reductive elimination
Ln
PdII
Ar
Ar
LnPdII
X
R
transmetalllation
Cu
CuX
R
R
H
NEt3
XHNEt3
Hartwig-Buchwald Enolate Arylation
O
R'
RO
O
Ar X
R'
RO
Pd(0) cat
NaOtBu
Ar
O
R'
RO
Ar X
LnPd(0)
Ar
Ar
Ln
PdII
CO2R
LnPdII
R'
Ar
X
ONa
NaX
R'
OR
O
tBuONa
R'
OR
H
Buchwald-Hartwig Amination
Ar X
HNR2
LnPd(0), base
Ar NR2
X=Br, Cl, OTf
Similar cross couplings with ROH, F-, etc. These are challenging due to RE.
Buchwald: ACIE, 2008, 47, 6338
Hartwig: Acc. Chem. Res., 2008, 41, 1534
Buchwald-Hartwig Amination
Ar X
HNR2
LnPd(0), base
Ar NR2
X=Br, Cl, OTf
Consider pka’s:
typical bases: K3PO4 or tBuONa
pKa': 8
vs.
HNR2
pka: 35
17
Buchwald-Hartwig Amination
•  Reductive Elimination Difficult
•  Typical Ligands:
Ar NR2
Ar X
LnPd(0)
iPr
PCy2
iPr
PtBu2
iPr
iPr
Ar
Ar
LnPdII
L1PdII
X
NR2
X-Phos
Ar
L1
BHX
OMe
PdII
X
N
R
R
B
H
tBu-X-Phos
R3NH+ like (pka ~ 9)
MeO
iPr
PCy2
iPr
BrettPhos
Heck Reaction
R
Ar X
(or
LnPd(0), base
X
Ar
R
)
•  Alkenes as nucleophiles.
•  Achieves the arylation or vinylation of an alkene.
•  Historically, the Heck Reaction proceeded all other palladium catalyzed
cross-couplings.
•  2010 Nobel Prize
Mechanism
Base·HX
LnPd(0)
Ar X
oxidative addition
Base
Ln
Ar
R
PdII
H
LnPdII
X
β-Hydride
elim.
H
X
R
R
alkene binding
Ar
LnPdII
X
Ar
R
LnPdII Ar
X
migratory insertion
Notes on the Heck Reaction
Intermolecular (alkene and halide on different molecules):
•  Somewhat limited scope.
•  Normally limited to CH2CH2, mono- and di-substituted alkenes.
•  Tri- and tetra-sub. alkenes are too poor of ligands to engage Pd(II)
intermediate.
Electron-rich alkenes generally better than electron-poor.
•  Regioselectivity is often poor.
Intramolecular (alkene and halide tethered together):
•  Much better scope.
•  Can form carbocycles and hetereocycles of all types.
•  Mono-, di-, tri- and tetra-substituted, electron-rich and electronpoor alkenes all work.
Example of Intramolecular Heck Reaction
Pd(OAc)2 cat.
PPh3, Et3N
O
N
Me
I
O
Me
N
Stereospecificity
R'
PdII
Ar
R'
R
H
Ar
NOT
R'
Ar
H
R
H
H
R
cis-migration
cis-β-Hydride
elimination
R'
H
PdII
R'
H
PdII
H
R
Ar
R
Ar
H
Exo Cyclization Preferred
O
Pd(OAc)2 cat.
PPh3, Et3N
O
N
Me
O
Me
N
N
Me
I
exo-cyclization
endo-cyclization
PREFERRED
NOT
•  exo strongly preferred
•  5-exo, 6-exo very easy to accomplish
•  difficult to form small rings (3-exo, 4-exo, etc)
Via:
O
PdII
O
H
Me
N
or
H
PdII
N
Me
Asymmetric Intramolecular Heck Reaction
MeO
I
OSiR3
O
N
Me
OSiR3
Me
Pd(OAc)2
(S)-Binap
MeO
O
N
Me
84% yield
95% ee (97.5:2.5)
Me
PPh2
PPh2
Binap:
Chiral
Can be resolved
Overman, JACS, 1998, 120, 6500
Shibisaki has also contributed to this area
Heck Carbonylation
O
X
CO, Nuc
Nuc
LnPd(0), base
X = I, OTf
X = Br
X = Cl
L= PPh3, etc
L = Xantphos
L=
PCy2 PCy2
Nuc =
Product =
H2O
ROH
O
O
OH
H2NR
O
OR
Bu3SnH
HNR2
O
NHR
O
NR2
H
Mechanism
O
Ar
LnPd(0)
Ar X
Nuc
Ln
PdII
Ar
X
C O
Nuc
Ln
PdII
X
O
O
C
LnPdII Ar
Ar
X
Reductive Elimination Details
Transmetallation:
LnPdII
X
O
Nuc-H
Ar
transmetallation
or salt metathesis
Ln
O
PdII
Nuc
Ar
O
R.E.
Nuc
Ar
Or:
Addition-Elimination:
Ln
PdII
X
O
Ar
O
Nuc-H
base
Ln Pd
X
Nuc
Ar
Both mechanisms are known.
O
Nuc
Ar
Cross Coupling With Alkyl Groups
Dec
Br +
9-BBN
hex
Pd(OAc)2 (cat)
PCy3 (cat)
hex
Dec
85%
9-BBN:
+
hex
2%
B
Limited to 1° electrophiles with Pd.
Fu, JACS, 2001, 123, 10099
Fu, ACIE, 2002, 41, 945 (RCl, ROTs)
2° Alkyl Halides
R
Br +
BrZn
NiBr2•diglyme
(S)-pybox
R'
R
R
R'
Fu, JACS, 2003, 125, 14726
R
R'
NiBr2•diglyme
(S)-pybox
Br
+
BrZn
R'
Fu, JACS, 2005, 127, 10482
Cl
Cl
racemic!
82%, 91% ee
O
(S)-pybox:
N
i-Pr
O
N
N
i-Pr
Iron Catalysis
O
O
OMe
+ HexMgBr
Fe(acac)3
OMe
Hex
Cl
Me
ArMgBr +
Br
Me
FeCl3
tmeda, -78°C
Me
Ar + less than 20%
Me
Furstner, ACIE, 2002, 3856 (Fe2-)
Nakamura, JACS, 2004, 126, 3686
Furstner, Acc. Chem. Res., 2008, 41, 1500
Ullman/Goldberg Coupling
H
N
N
X
X=I,Br
N
N
CuI (cat)
Ligand (cat):
Ligands
, etc
N
MeHN
NHMe
N
Good for weakly basic N-nuc (amide, heterocyclic, etc.)
Limited to ArI and some ArBr.
Buchwald Chem. Sci. 2010, 1, 13.
π-Allyl Chemistry
Tsuji-Trost
X
LnPd(0)
PdLnX
η1
X = Cl, Br, OAc, OC(O)R, OP(O)R2, etc
Pd X
η3
π-Allyl Chemistry
Ln
OAc
D
D
Backside attack
LnPdII
PdII
D
π-Allyl Chemistry
π-allyl fragments can racemize:
Cl
LnPd(0)
Me
PdIIXLn
PdIIXLn
Me
Me
LnXPdII
PdIIXLn
PdIIXLn
Me
achiral
Me
Me
If the metal π-allyl can isomerize to the terminal position, this provides a
pathway for racemization.
PdIIXLn
LnXPdII
LnPd(0)
+ Pd(0)
D
slow
D
Substitution Reaction with π-Allyl Electrophiles
Type 1: Non-basic Nucleophiles (pka’ < 25, DMSO)
Me
PdIIXLn
Cl
LnPd(0)
Me
Me
nuc
Me
O
nuc =
Me
Me
nuc
note: less sub.
side of π-allyl
ONa
RO
OMe
amines
PhOR
etc.
NO2
double backside
displacement =
net retention
Substitution Reaction with π-Allyl Electrophiles
Type 2: Transmetallation
Me
Me
Cl
LnPd(0)
Me
Me
PdIIXLn
Bu3SnPh
Me
LnPdII Ph
Me
transmetallation occurs with: R3SnR, RB(OH)2, etc.
Net inversion observed
Me
Me
Ph
Asymmetric Variant
O
O
NH HN
PPh2 Ph2P
Trost modular Ligand: "TML"
BzO
O
Me
OBz +
PhO2S
O
NO2
Bz =
meso
O
L*XPd
(allyl)PdCl2, L*
OBz
Me
O2N
PhO2S
O
OBz
Trost: Chem. Rev., 2003, 103, 2921
Acc. Chem. Res. 2006, 39, 747
>90% ee
Lloyd-Jones, JACS, 2009, 131, 9945
stereoselectivity in AAA reaction
Other Metal π-Allyl Chemistry
Mo π-allyl
O
OAc D
Ph
Mo(CO)4, L*
H
(CO)4L*Mo
Ph
D
MeO
ONa
OMe
O
MeO
H
X-ray and NMR
Ph
O
OMe
D
H
Double Retension
at more hindered side
Trost, JACS, 1987, 109, 1469
Lloyd-Jones, JACS, 2004, 126, 702
Other Metal π-Allyl Chemistry
Mo π-allyl
O
O
OMe
MeO
OAc
MeO
O
ONa
MeO
OMe
OMe
OMe
Mo(CO)3(tol), L*
OMe
MeO
Br
OMe
Br
95%, 94% ee
L*:
O
NH HN
N
N
O
O
MeO
OH
THC
Trost, OL, 2007, 9, 861
Rhodium and Iridium π-Allyl Chemistry
Me
HO
[Ir(cod)Cl]2, L*
O
O
Me
O
Ot-Bu
87%, 95% ee
L*
Ph
O
P N
O
Me
Me
Ph
Hartwig, JACS, 2003, 125, 3426