Chem 634
Metal Mediated Substitution Chemistry
Reading: Heg Ch 1–2 (handout),
CS-B 7.1, 8.2–8.3, 11.3,
Grossman Ch 6
Announcements
Problem Set 1 due NOW.
Mary Beth Kramer Lectureship
101 Brown Laboratory
September 25, 2015, 4pm
Weaving Faculty Professional Development with Learning Space Affordances
Gabriela Weaver Ph.D.
University of Massachusetts Amherst
Department of Chemistry
http://www.chem.umass.edu/faculty/
weaver.html
Many institutions are making significant investments in learning spaces that will allow for innovative, student-centered and collaborative forms of teaching and learning.
These approaches to teaching are supported by a broad body of literature. However,
few current faculty were taught in environments like this themselves or have experience teaching in them. Faculty professional development through institutional units/
centers exists in some form at most institutions. Traditional faculty development has
been optimized for improving lecture-based teaching practices. As calls for reform
in STEM education begin to coalesce around active-learning approaches, then, it is
necessary for faculty development to also shift its focus. UMass has been in the process of providing faculty with professional development opportunities tailored to our
team-based learning classrooms for the last 3 years. As faculty access to those spaces
has expanded, our curriculum has responded to the needs of an audience interested
in a broader view of active-learning. In this presentation, I will describe our evolving
professional development approach tailored to active learning, faculty use of our active learning facilities, and current thinking on course and space design that undergirds our work. This is part of a larger multi-institution project through the Bay View
Alliance in which we are exploring the overarching question of how PD-influenced
instructional practices combine with learning space affordances to affect the learning
experience of students.
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:
39%
0%
61%
100%
D
Ph
51–53%
+
Ph
General SN2' mechanism:
Nuc
LG
Nuc
Goering, JOC, 1986, 51, 2884
D
47–49%
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.
Sonogashira 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 preceded all other palladium-catalyzed
cross-couplings.
•  2010 Nobel Prize
•  Also called the Mizoroki–Heck reaction. Mizoroki published similar
findings just prior to Heck’s work.
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 heterocycles 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
PdII
Ar
R'
H
H
R
cis-migratory
insertion
R'
R
H
Ar
NOT
R'
Ar
H
R
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 Retention
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