Chem 634
Reduction of C=C π-Bonds (Continued)
Announcements
•  Midterm 2 is Tues, Nov 17. Everything through alkyne synthesis.
•  Presentations on Sat, Dec 5. Paper choices were due last week!
Richard F. Heck Lectureship
101 Brown Laboratory
November 11, 2015, 4:00pm
Developing Strategies for the C–H Functionalization of
Aliphatic Amines
Aliphatic amines serve as core structures of a wide variety of bioactive molecules.
Despite much recent progress in the area of the area of transition metal-catalyzed
C-H bond functionalization, there are still relatively few methods for the selective C-H
functionalization of aliphatic amines, particularly at sites remote to nitrogen. This
talk will present three complementary strategies developing in our lab to tackle this
challenge, involving Pd, Fe, and Pt catalysis. The optimization and scope of these new
methods will be described as well as their application to the late-stage functionalization of bioactive molecules.
Melanie Sanford Ph.D.
The University of Michigan
Department of Chemistry
http://www.umich.edu/~mssgroup/
**Refreshments at 3:45
Enantioselective Alkene Hydrogenation Using Ruthenium
•  L2Ru(II)(OAc)2 are very effective at hydrogenating functionalized alkene.
Unsaturated Carboxylic Acids:
CO2H
Me
cat. [Ru-(S)-BINAP(OAc)2]
MeOH, 13 atm H2
CO2H
MeO
MeO
97% ee
(S)-Naproxen
Me
Me
CO2H
Me
cat. [Ru-(R)-BIPHEMP(OAc)2]
MeOH, 180 atm H2
F
CO2H
F
Me
Me
CO2H
cat. [Ru-(S)-H8BINAP(OAc)2]
MeOH, 1.5 atm H2
Me
94% ee
Me
Me
CO2H
97% ee
Mechanism for Ruthenium Cat. Hydrogenation of Alkenes
O
Me
R
HO
O
O
H R
R
HO
P
*
R
O
Ru
O
O
P
P
O
Me
P
*
R
O
Ru
*
R
O
Ru
P
O
O
O
R
O
P
Me
R
H2
O
R
H
2 HOR
H
HO2CR
P
*
P
R
R
H
O R
Ru
R
O
O
P
P
*
R
O
H
*
H
HOR
P
H
O R
Ru
O
O
P
HOR
R
O
H H
O
Ru
O
O
Me
R
R
HO2CR
R
Halpern
Allylic Alcohols Also Effective Substrates
Me
Me
Me
cat. [Ru(S-BINAP)(CF3CO2)2]
OH
30 atm H2, rt
Me
Me
Me
OH
96% ee
Me
Me
cat. [Ru(S-TolBINAP)(OAc)2]
Me
30 atm H2, rt
OH
Me
Me
Me
OH
98 % ee
•  Homoallylic alcohols are also reasonable substrates, but not longer homologues.
Me
cat. [Ru(S-BINAP)(OAc)2]
Me
OH
Me
100 atm H2, rt
Me
Me
OH
Me
92 % ee
Me
Me
Me
cat. [Ru(S-BINAP)(OAc)2]
OH
no reaction
100 atm H2, rt
Noyori JACS 1987,109,1596.
Enantioselective Alkene Hydrogenation with Iridium
Me
cat. [Ir]BArf
Me
50 atm H2
97% ee
MeO
Me
Me
cat. [Ir]BArf
MeO
[Ir]BArf =
50 atm H2
Me
Me
Me
CF3
O
Me
otol2P
N
Ir
B
tBu
CF3
81% ee
cat. [Ir]BArf
CO2Et
Me
50 atm H2
CO2Et
Me
84% ee
Pfaltz ACIE 1998, 37, 2897
•  Tri-substituted alkenes work best.
•  First example of asymmetric tetra-substituted alkene hydrogenation.
4
Enantioselective Alkene Hydrogenation with Iridium
Me
Me
Me
cat. [Ir]BArf
Me
50 atm H2
MeO
MeO
AcO
Me
Me
Me
Me
93% ee
Me
[Ir]BArf =
Me
Me
cat. [Ir]BArf
50 atm H2
AcO
Me
Me
Me
Me
O
otol2P
Me
CF3
N
B
Ir
Ph
CF3
4
Me
Me
>98% de
Pfaltz Science 2006, 311, 642.
Other Reducing Agents
Transfer Hydrogenation
Organic source of "H2”
O
O
H
Me
H
O
H
O
HNEt3
H
Pd/C
Me
Me
Me
Also,
" -2H2"
" -H2"
Me
Me
Diimide
N N
H
H
H
H
Reagent Prepared In Situ From
1) KO2C-N=N-CO2K/ AcOH
2) H2N-NH2/ NaIO4/ EtOH
3) etc
Mech:
N N
H
H
N
H
N
H
Pros)
Cis > trans
Strained > non-Strained
tolerates NO2, C=O, cyclopropyl, Bn, Cbz, etc
Cons)
Can explode - use w/ caution
Alkyne Reductions
Pd/C/Pt/C etc
R
R'
H
H
R'
R
H
R' = H or alkyl, aryl
H
Lindlar Catalyst (Semi-hydrogenation)
Pd/CaSO4
R
R'
N
H
H
R
R'
Cis
•  Works best with non-sterically demanding systems.
•  Quinoline is a poison.
•  Also lead can be used.
Dissolving Metal Reduction of Alkynes
Li/NH3
R
R'
must not have aryl's
R
R'
trans is major
Red-Al Reduction of Propargyl Alcohols
H
H2O
Red-Al
R'
OH
Must be propargylic alcohol
R'
Al O
R2
H
R
OH
H
Thermodynamic Product
Radical Mechanism
Denmark JOC, 1982, 47, 4595
A Twist
Red-Al
R'
OH
OH
I
NIS
H
R
O
N I
H
O
R'
Al O
Diimide With Alkynes
R
H
+
R
H
N
N
fast
R
H
N2H2
R
R
H
slow
R
Birch Reduction
H
H
R
Na/NH3
R
H
or Li/NH3
H
1,4 diene
Mechanism:
Na/NH3
R
or Li/NH3
R
H
H
H
R
H-NH2
M+
M
H
R
R
H
H
-MNH2
R
H
H
R
RO-H
or
R-X
H
H
R
H
H
1,4 diene
Regiochemistry - Stability of First Radical
H
OMe
H
H
H
OMe
OMe
Li
then H-NH2
H H
or other EDG
Extended Radical
O
O
OMe
or other EWG
OMe
Li
then H-NH2
O
H
H
H
captodatively stabilized
(push-Pull)
H
H
OMe
Arene Hydrogenation
Pt/C, Rh/C, Ru/C
R
High Pressure
H2
forcing conditions
H
H
H
H
H
H
R
H
H H
H
Hydroboration
R
NaOH
R
R'
retension
Br2
R
NaOH
R
R
R'2BH
R'
R
R
R
H
BR2
R'
OH
H2O2
O
H2N S OH
O
Br
R'
R
NH2
R
R'
retension
TPAP/NMO
R
O
R
R'
Hydroboration
Regiochemistry:
Hydridic
δ−
H B R
δ+
R
R
Me
H
R
1) B2H6
2) H2O2
BR2
Me H
OH
Other Hydroboration Reagents
HBCl2
BH
9-BBN =
O
catechol borane (BCat) =
B H
O
pinicol borane (BPin) =
Me
Me
O
B H
Me
Me
O
Stereoselectivity
Small Hydroborating Agent:
Me
RL
RL
2) H2O2 /NaOH
RM
X
Me
1) B2H6
OH
RM
H
Me
Vs
RL
Me
H
H
RM
BH2
Favored
RL
Me
H
BH2
H
RM
RL
OH
RM
RL
RM
Me
Stereoselectivity
Large Hydroborating Agent:
Me
RL
RL
2) H2O2 /NaOH
RM
H
RM
RL
Vs
Favored
H
H
B
Me
RL
Me
RM
H
RL
RM
OH
RM
B
H
Me
X
Me
1) 9BBN
H
B
Me
RL
OH
RM
Asymmetric Hydroboration
H
(-) IPC2B-H
Me
B H
1.
2
Me
Me
2) H2O2 /NaOH
HO
Me
Me
98% ee
Asymmetric Hydroboration
O
OH
B H
O
Me
Rh(I)/L*
Major
Me
N
BINAP 98% ee
PPh2
92% ee
Fe
PCy2
PPh2
92% ee
Hydroboration of Alkynes
Terminal:
O
B H
H
O
Me
O
B
Me
O
H
Pd(0) PhI
H
Ph
Me
H
Hydroboration of Alkynes
Internal - Steric Control:
Me
Me
(Sia)2BH
Me
Me
BR2
Me
Me
Me
BH
Me
2
disamylborane
Me
Hydroboration of Alkynes
Note:
R1
R2
H
Cy2BH
BCy2
BCy2
R1
+
H
R1
R2
R2
AcOH 1 equiv required
H
H
R1
R2
Good way to get selective reduction