Chem 634 Alkyne Synthesis
and the Reduction of C=C π-Bonds
Announcements
•  Problem Set 3 due Fri, 11/6, by 5pm to my mailbox.
•  Office hours: Fri, 11/6, 10:30-12, 221 BRL (computer lab)
Alkyne Synthesis
Previously Discussed
1) Sonogashira Rxn
R
Ar X
Pd(0) cat
CuI cat
Et3N
Ar
R
2) SN2
1° R'-I
R
R'
LDA
R
H
BuLi, etc
R
Li
R'CHO
R
OH
R'
Dehydrohalogenation
Br
Br2
R
R
Br
KOH
( E2 )
R
H
Corey–Fuchs Reaction
O
R
PPh3
H
CBr4
Br
R
Br
2 eq BuLi
then H+
R
H
TL, 1972, 13, 3769
Corey–Fuchs Reaction
Mechanism:
First pot:
CBr3
Br-PPh3 +
Br-CBr3
Ph3P
Br
Ph3P C Br Ph3P
Br
O
Ph3P=CBr2
R
H
Br
R
steps
Br
Second pot:
H
Br
R
BuLi
H
R
Li
then H+
H
acidic
(cannot stop deprotonation)
Carbene
BuLi
R
R
R
Br
Br
1,2
R
H
TL, 1972, 13, 3769
Seyferth - Gilbert Reagent
O
MeO P
MeO
O
R
O
MeO P
MeO
N2
N2
R
t-BuOK
H
O
MeO P
MeO
H
O
N2 R
H
O
P
MeO
H
t-BuOO
MeO P O
MeO
N2
O
MeO
R
N2
H
R
R
N2
-N2
R
R
H
JOC, 1979, 44, 4997
Eschermoser-Tanabe Fragmentation
Ts
H N N
Base
O
R DMDO
or m-CPBA
N
O
R
O
R
H2N-NH-Ts
O
Ts
R
N
R
O
H
+
N2 + HO2S-Tol
O
Hel. Chim. Acta 1967, 50, 708
TL, 1967, 40, 344
Reduction of C–C π-Bonds
Alkene Hydrogenation
H
R
H
H2 Cat
R'
H H
H
R
H
R'
Heterogenous catalyst
Cat = Pd/C
Pd(OH)2/C Pearlman's cat
Raney Ni
Pt/C
PtO2 Adam's cat
Rh/Al2O3 etc
weak
aggressive
Heterogeneous Reductions Rates
H
Sterics
>
>
>
>
e- Rich > e- Poor
H2 pressure
1 ATM
100 ATM
>
Stereochemistry
Me
Pt/ H2
Me
Suprafacial Addition
Me
H
H
Me
Stereoselectivity Often Controlled by Steric Accessibility
Me
H2 Cat
Me
Me
Pt/ H2
H
H
Me
Me
Me
H
Me
70:30
Wilkinson’s Catalyst (Homogeneous)
Synthesis:
Ph3P
EtOH
RhCl3·xH2O + PPh3
Cl
+ Ph3P=O + HCl
Rh
Ph3P
PPh3
Most effective for simple Ar3P.
Cl
Rh
2
nL
LnRh
Cl
L = PPh3, PAr3, PR3, etc
Suprafacial Addition of Hydrogen Across Alkene
R'
R'
R
H2 (1 to 100 atm)
cat. (PPh3)3RhCl
rt to >100 °C
R
R' H
R
R
H
R'
Example:
R
Me
AcO
R
D2
cat. (PPh3)3RhCl
Me
AcO
Note: No H/D scrambling.
D D H
Rate Difference With Alkene Substitution
•  Approximately 50-fold rate difference depending on alkene substitution.
•  In general, better ligand = faster rate.
•  Some alkenes (e.g. ethylene, butadiene) bind so tightly they are slow to reduce.
Ph3P
Cl
Rh
Ph3P
~
PPh3
k25°C (x 102 M–1s–1)
32
R
≥
R
30
>
R1
R1
>
R
27
R
R1
10
2
Example in synthesis:
MeMe
Me
Me
Me
O
MeMe
H2
cat. (PPh3)3RhCl
OBz
Me
O
OBz
R
>
0.6
Good Chemoselectivity
vs.
NO2
H2
cat. (PPh3)3RhCl
NH2
NO2
w/ Pd/C or Ri-Ni
H2
cat. (PPh3)3RhCl
+
CO2Me
CO2Me
96%
vs.
CO2Me
4%
>49%
26%
w/ PtO2 or Pd/BaSO4
Mechanism: Hydrogen First
L
L
Rh
L
Cl
–L/+solv
L
H H
+L/-solv
Rh
Cl
L
Cl
solv
L
H
Rh
solv
solv
L
L H
Cl
L
Cl
H
Rh
H
L
Note: Neutral complexes less
Lewis acidic and electron-rich.
H2
H
Rh
solv
H
L
Oxidative addition to hydrogen
fast.
Cationic Rhodium Complexes
•  Alkene or diene complexes are pre-catalysts:
2 H2
Ph2P
Rh
PPh2
solv.
Ph2
P
solv
+
Rh
P
solv
Ph2
•  Most common type of catalyst for asymmetric alkene
hydrogenation (with chiral ligands).
•  Highly efficient. Often can use <<0.1% catalyst in reaction.
•  Prepared with non-coordinating counter-ion (BF4- , PF6- ,
B[3,5-C6H3(CF3)]4-.
•  Less alkene scrambling than with neutral complexes.
•  Because of Lewis-acidity of the complex, can be substrate
directed… see more later.
Cationic Rhodium Complexes
•  More active complexes from more electron-rich ligands.
complex [substrate] (mM) kint x 104 (s-­‐1) [Rh(NBD)(PPh3)2]+ 5.3 0.1 [Rh(NBD)(PPh2Me)2]+ 3.7 3.0 [Rh(NBD)(PPhMe2)2]+ 3.5 6.0 •  Complexes with bidentate ligand more active than those with monodentate ligands.
•  Sensitive to acidity (basicity) of reaction… deprotonation can lead to
neutral complex.
Mechanism: Olefin First
L
•  Cationic complexes are:
Rh
L
H2
–C8H16/+solv
H
:D H
L
R
Rh
L
•  More electrophlic,
therefore more likely to
bind alkene or directing
group.
•  Less likely to undergo
oxidative addition.
R
solv
solv
:D
solv
L
L
H
R
H
R
L
Rh
solv
D
L
rds
solv
Rh
L
H
Rh
L
D
D
H2
H
R
•  D = Directing Group,
typically imine, alcohol,
ether, carbonyl, etc.
•  Note: L2Rh(solv)2 can react
with H2 but is not kinetically
relevant.
Cationic Iridium Catalysts
•  Prototypical (and first) example is Crabtree’s catalyst:
+
Ir
PF6–
N
PCy3
Crabtree, Acc. Chem. Res. 1979, 12, 331.
•  Precatalyst. Diene reduced to give LnIr(III)H2+.
O
Br Br
H2
cat. [Ir(COD)(Cy3P)(py)]PF6
O
Br Br
Cationic Iridium Catalysts Are Very Reactive
complex T (°C) Solvent Turnover Frequency (h-­‐1) 1-­‐hexene cyclohexene Me2C=CMe2 [Ir(COD)(PCy3)(py)]+ 0 CH2Cl2 6,400 4,500 4,000 [Ir(COD)(PPh2Me)2]+ 0 CH2Cl2 5,100 3,800 50 [Ir(COD)(PPh3)2]+ 0 acetone 10 0 0 [Rh(COD)(PPh3)2+ 25 CH2Cl2 4,000 10 0 [Ru(H)Cl(PPh3)3] 25 C6H6 9,000 7 0 [RhCl(PPh3)3] 25 C6H6/EtOH 650 700 0 [RhCl(PPh3)3] 0 C6H6/EtOH 50 70 0 •  Note: the fact that it reacts at all was surprising (3rd row).
Directed Hydrogenation
Binding Directs
Metal to the
Proximal Face of
the Alkene
Lewis Basic
"Directing Group"
DG:
LnM + H2
Ln H
DG M H
Reduction Occurs on
Proximal Face of the
Alkene
Ln H
DG M H
DG
H H
- LnM
•  Works best with highly Lewis Acidic Catalysts (ie cationic ones).
•  Requires conformationally defined substrate.
Directed Hydrogenation Examples
R
OH
H2 (1 atm)
20% [Ir(COD)(Cy3P)(py)]PF6
R
OH
R = H, >99:1
R = Me, 33:1
rt, CH2Cl2
Me
Me
Me O
H2 (1 atm)
5% [Ir(COD)(Cy3P)(py)]PF6
N
N
H
Me O
N
rt, CH2Cl2
O
N
H
O
>99:1
Me
Me
H2 (800 psi)
10% [Rh(nbd)(diphos)]BF4
OH
Me
Me
Me
H
Me
70:1
OH
Note: reaction
happens
towards large
isopropyl group!
Directed Hydrogenation Acyclic Stereocontrol
OH
Me
R
Ph
OH
H2
Me
(1)
R
H
OH
R
H
Et
favored
P
(1) =
Me
Ph
Rh
P
Ph Ph
H
Et
R
OH
BF4-
Asymmetric Hydrogenation
Chiral Biaryls
OMe
R'
R'
O
PR2
PR2
R'
O
R'
O
R'
R'
O
BINAP
3,3'-(OR)2-BINAP
3,3'-diAlkyl-BINAP
3,3'-diAr-BINAP
X
PR2
PR2
X
X
PR2
PR2
X
SEGPHOS, R' = H
Difluorphos, R' = F
SunPhos, R' = Me
H8-BINAP, X = CH2
SYNPHOS, X = O
O
n(
)
O
PR2
PR2
Me
PR2
PR2
MeO
MeO
N
R'
TUNEPHOS
(n = 1-6)
Me
Me
PR2
PR2
Me
OMe
MeO-BIPHEP, R' = H
Cl-MeO-BIPHEP, R' = Cl
Garphos
Me
N
PR2
PR2
OMe
OMe
R'
MeO
MeO
PR2
PR2
MeO
MeO
P-Phos
Me
HexaPHEMP
•  BINAP first example in class, reported by Noyori.
•  Biaryl axis in tetra-sub. biaryls stable to racemization (to >100 °C).
Lots of Phosphine Substituents!
R'
R'
PR2
PR2
tBu
Me
R=
Me
Me
oTol
Ph
pTol
Xyl
Me
DMTB
tBu
CF3
iPr
O
NMe2
Me
Me
Me
Me
Me
CF3
iPr
DIPDMA
OMe
bisCF3
Furyl
iPr
Cy
tBu
Ferrocene Backbones
NMe2
Me
Fe
PR'2
PR2
Fe
Ph
Ph
Fe
PR2
Ph
Me2N
Josiphos
PR2
Me
PR2
Mandyphos
Me
PR2
Mandyphos
Ph
PR'2
PR2
Fe
Me
Walphos
Chiral Backbones
Me
Me
Me
O
PAr2
PAr2
O
Me
Me
O
PAr2
PAr2
O
Me
DIOP
NorPhos
Phanephos
Me
PAr2
H
H
PPh2
PPh2
MeDIOP
PAr2
PPh2
PPh2
R
PAr2
PAr2
N
O
N
PAr2
PAr2
R
Me
BDPMI
BDPP
SPIROPhos
Aliphatic Bisphosphines
Me
P
Me Me
P
Me
Me-DuPHOS
Ph
Ph
P
P
Ph
P
P
Ph
Ph-BPE
BINAPHANE
P-Chiral Phosphines
P
MeO
P
Me
tBu
OMe
P Me
tBu
P
Me
tBu
P
Tri-chicken-foot Phos
tBu-MiniPhos
DIPAMP
H
P
tBu
H P
tBu
TangPhos
H
P
tBu
P tBu
tBu
H P
tBu
DuanPhos
Chiral P,N Ligands
Me
Me
O
O
Ar2P
Ar2PO
N
O
N
O
N
R
R
PHOX
N
Ar2P
SimplePhox
Fe
R
PryPHOX
N
PR2
R
Phosphites, Phosphates,Phosphoramidites
O
Phosphite
P tBu
O
Ph
O
Phosphate
O
P OiPr
P O
O
Ph
O
Me
P O
O
O
Ph
Me
P N
Me
O
O
Phosphoramidite
Me
O
P N
P N
Me
O
Ph
MonoPhos
Ph
Me
O
Me
Me
O
Me
P N
O
Me
O
Ph
SIPhos
Monsanto L-Dopa Process: Entry Into Asymmetric Reductions
CO2H
MeO
AcO
HN
CO2H
[Rh(I)+]/DIPAMP MeO
Me
HN
AcO
H2
O
CO2H
HO
Me
HN
HO
O
Me
O
95 %ee
L-DOPA
Parkinson's Treatment
Ph
H3C P
Ph
PAMP
ee <100 °C
P
OMe
P
OMe
O
PPh2
PPh2
PPh2
O
PPh2
PPh2
PPh2
Chiraphos
Prophos
DIOP
Ph
DIPAMP
•  Over 57 different ligands have been shown to be effective in this reaction.
William Knowles, Nobel Prize 2001
Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998.
Tang, W.; Zhang, X. Chem Rev 2003, 103, 3029.
Alkene Geometry Often Does Not Matter With Some Catalysts
CO2Me
Me
HN
Me
[Rh(I)+]/(R,R)-Pr-DuPhos
CO2Me
Me
H2
O
HN
Me
O
99.6% ee
Me
CO2Me
HN
Me
O
CO2Me
[Rh(I)+]/(R,R)-Pr-DuPhos Me
H2
HN
Me
O
Other Examples
CO2Me
NHCbz
CO2Me
NHCbz
[Rh(I)+]/DIPAMP
H2
PrO2C
N
OMe
N
PrO2C
OMe
95% ee
Boc
N
N
Boc
R-Phanephos-Rh
OMe
O
Boc
N
N
CBz
H2, 1.5 atm
–40 °C
R-BINAP-Rh
OMe
O
H2, 70 atm
Boc
N
OMe
N
Boc
O
86% ee
Boc
N
N
CBz
OMe
O
99% ee
Process Has Been Very Carefully Studied
CO2Me
Ph
Ph2
P
S
Rh
P
S
Ph2
k1
k–1
k1 = 1.4 x 104 M–1·s–1
k–1 = 5.2 x 10–1 s–1
ΔH‡ = 18.3 kcal/mol
ΔS‡ = +2 eu
S = MeOH
s–1
k4 = 23
= 17 kcal/mol
ΔS‡ = +6 eu
slow step at –40 °C
ΔH‡
k4
Ph2 H
P
Rh
P
Ph2 S
S, –
Ph
CH2Ph
CO2Me
NH
O
observable at low temp
NHAc
CO2Me
Ph2 Ph
P
Rh
P
O
Ph2
k3
S
NH
X-ray
k2
NHAc
H
CO2Me
H2
k2 = 1.0 x 102 M–1·s–1
ΔH‡ = 6.3 kcal/mol
ΔS‡ = –28 eu
slow step at 25 °C
Ph H
Ph2 H
P
Rh
CO Me
P
H NH 2
Ph2 O
k3 > 1 s–1
only invisible species
Halpern and Landis
Enantioselectivity with DIPAMP: A Surprise
CO2Et
HN
Ph
O
Rh
P
P
*
H2
CO2Et
H
H
Ph
H
S
expected
AcHN
NHAc
H
H
Ph
H
R
observed
EtO2C
Halpern, J. Science 1982, 217, 401
minor
major
Rate-determining
step
k"2
≈ 600
k'2
Not
observed!
Observed!
Actual Mechanism
•  Dependence on T and P
Landis and Halpern JACS 1987 109 1746
ee
p H2 (atm)
84% R
1
21% S
20
8% S
100
Curtin-Hammett Kinetics
ΔΔG
MeO2C
P
*
P
Rh
O
NH
Ph
CO2Me
CO2Me
H
HN
P
Ph H Rh
*
P
O
HN
Ph
O
Rh
P
P
*
reactive
observed
MeO2C
H
NH
P
Rh
Ph
*
H
P
O
Other Enamines
NHAc
NHAc
[Rh(I)+]/(R,S,R,S)-Me-PennPhos
R
H
98% ee
P
H
NHAc
tBu
H2
R
Me
[Rh(I)+]/(R,R)-Me-DuPhos
tBu
R
H
H2
P
H
R
PennPhos
NHAc
99% ee
•  Other enamines can also be reduced with these catalyst systems.
•  In general, substrates need to have a stabilized N-carbonyl enamine tautomer.
Me
[Rh(I)+]/DuanPhos
NHAc
H2
Et
NHAc
97% ee
•  In some cases, both alkene isomers can be reduced to the same enantiomer.
Examples of Other Substrate Classes
CO2Et
iPr
[Rh(I)+]/(R,R)-Et-DuPhos
OAc
CO2Et
iPr
H2
OAc
96.1 %ee
[Rh(I)+]/(S,S,R,R)-TangPhos
H2
Me
OAc
OAc
97 %ee
Me
[Rh(I)+]/R,S-Josphos
MeO2C
CO2Me
H2
MeO2C
CO2Me
99 %ee
•  Note: In all cases, alkene is substituted with a donor group
to coordinate and orient catalyst.
Industrially Important Example
CF3
N
F
N
NH2 O
F
F
N
N
CF3
N
F
Rh/Josiphos
N
7 atm H2
F
F
N
N
NH2 O
94% ee
Januvia
•  Januvia is a Merck drug for the treatment of diabetes.
•  First process-scale synthesis: Hansen, K. B.,et al. Org. Proc. Res. Dev. 2005, 9 (5),
634 (won 2006 Presidential Green Chemistry Award)
•  Second process-scale synthesis: Directed evolution to develop a transaminase
enzyme capable of setting the stereocenter. Science 2010, 329, 305 (won 2010
Presidential Green Chemistry Award)
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.