The Development of Metal Catalyzed, OneStep Approaches to α-Amino Acids,
Pyrroles and α-Substituted Amides
21/09/2011
Yingdong Lu
Who Am I
In Canada
Ph.D supervisor
Dr. B. Arndtsen
McGill University
PDF supervisor
Dr. C. Crudden
Queen’s University
Direct Synthesis
Building Blocks
R2
R1
R1
R1
O
R1
X
R2
R1NH2
R1OH
R1-M
R2
CO
N
R3
Metal
Catalysis
Target Products
CO2
Can complex molecules be constructed directly from simple building blocks,
via the mechanistic design of new metal catalyzed reactions?
Efficient, Green, Diversified
A One Pot Synthesis of Münchnones
N
R1
R2
+
H R3
O
+ CO
Cl
O
5 mol % Pd cat.
NEtiPr2 / Bu4NBr
O
R1 – N +
R2
50-90%
55 oC
CH3CN / THF
O
R2
N
H
H
Pd(0)
O
O
–
R1
O
C
R3
N+
R2
R1
S
R3
O
Pd
O
Base.HCl
N
ClR1
Oxid. add
R1
R2
N
R3
R2
O
+
H R3 Cl
CO
L Sub.
R1 R2
N
H
OCPd
R3
O
Cl
O
Cl
3
R1
Pd
Cl O
N R3
R2
H R1 R2
N
Pd cat. =
Pd
Cl O R
R3
R1
H
N
R2
insertion
R3
Dhawan, R., Dghaym, R. and Arndtsen, B. A. JACS 2003,125,1474
2
Münchnone Chemistry
O
C
R1
R1
O
N
R
R2
O
R
+ R
A B
N
N
R2
O
B
1,3-dipolar
R
2
O
addition O R1 A
R
R1
-CO2
N
A B
Heterocycles
ketene
reactivity
-amino acid
derived products
Typical Münchnone Synthesis:
O
available
starting materials
HO
R2
N
R1 H
R3
O
-H2O
R2
R1
O
Potts, K. In . 1,3-Dipolar Cycloaddition Chemistry, Padwa, A. Ed. ; Wiley: New York, 1984: Vol.2 p.1
O
+ R2
N
R3
Previous Work
N
R2
H
O R2
O
R3
R1
Cl
R3
N
R1 O
O
MeOH
CO
Dhawan, R.; Dghaym, R. D.; Arndtsen, B.
A. J. Am. Chem. Soc. 2003; 125, 1474.
R2
O
H
R1 N
R3
R2
O
R3
R4
Cl
R3
R1 N N
R3
N
N Ts
R4 H
Cl
Siamaki, A. R.; Arndtsen, B. A. J. Am.
Chem. Soc 2006; 128, 6050.
R5
R4
R1
N R2
R2
R4
R5
Dhawan, R.; Arndtsen, B. A. J.
Am. Chem. Soc. 2004; 126, 468.
R1
H
Request from Organic Synthesis
R1
N
R2
O
+
H
+ CO
R3
Cl
Pd catalyst.=
Pd catalyst
NEtiPr2/Bu4NBr
55 oC
CD3CN
O
O
R1
N+
R2
H R2 R1
N
Pd
R3
Cl
O
2
Scale up failed: no more than 1 mmol of
reagents
My answer: Need a new catalytic system
•How?
•Kinetic study to figure out mechanism
R3
R1
N
+
R3
H
R2
+ CO
Cl
55 oC/CD3CN
NEtiPr2/Bu4NBr
rate α [Pd]
rate = 9.67E-05x s -1
R2 = 0.98
rate (s -1)
ln([Yield] ∞/([ Yield] ∞ - [Yield]))
2.5
1.5
1
0.5
0
0
5000
10000
15000
0.00016
0.00014
0.00012
0.0001
0.00008
0.00006
0.00004
0.00002
0
20000
R2 = 0.99
0
0.002
tim e (s)
0.004
0.006
0.008
[Pd] (M)
rate α CO pressure
rate α [base]
0.00012
0.00012
0.00011
0.0001
0.0001
rate (s -1)
rate (s -1)
R3
N+
R2
R1
rate α [iminium salt]
2
O
O
Pd cat.
O
0.00009
0.00008
0.00008
0.00006
0.00007
0.00004
0.00006
0.00002
0.00005
0
0
0.5
1
1.5
[baae] (M)
2
2.5
0
2
4
6
CO pressure (atm )
8
10
Mechanism
O
Rate α [iminium], [Pd], [CO]
R3
R2
N
R2
Pd(0)
O
R2
O
O
C
R3
N+
R1
R2
R1
-
Cl
fast
R1
+
H
R3
H
H R2 R1
L
N
Pd
R3
Cl
O
CO
H R2 R1
N
OC
Pd
R3
O
Cl
O
N R3
R1
O
Cl
R2
H
Pd
O
Base.HCl
N
O
N
R3
R1
An e-rich and bulky
ligand is need to
accelerate
Oxidative addition and
CO coordination
Cl
p-tolyl
N
H
O
+
Ph
Bn
+
Cl
Pd cat. (5 mol%)
15% P(o-tolyl)3
CO
Ph
N+
NEtiPr2
–
CH3CN/THF, 55 oC p-tolyl
Bn
rate α [iminium]
rate α CO pressure
3
0.00035
R2 = 0.99
0.0003
-1
2.5
)
rate = 1.5E-04x s -1
R2 = 0.98
reaction rate (s
ln([Yield] ∞/([ Yield] ∞ - [Yield]))
O
O
2
1.5
1
0.5
0
0.00025
0.0002
0.00015
0.0001
0.00005
0
0
2000
4000
6000
8000
10000
time (s)
12000
14000
16000
18000
0
1
2
3
4
5
6
7
CO pressure (atm)
Though phosphine ligand accelerate the oxidative addtion, it slow the CO
coordination step
8
9
Ligand Effect
Ligand
Rate
Bu4NBr
18h
P(oTol)3
6h
(tBu)2P(oTol)
4h
tBu
(tBu)2P(biphenyl)
3h
P
tBu
p-tolyl
N
H
O
+
Ph
Bn
+
Cl
Pd cat. (5 mol%)
15% tBu2P(biphenyl)
CO
reaction rate (s -1)
ln([Yield]∞/([Yield]∞ - [Yield]))
2
1.5
1
0.5
0
0
2000
4000
6000
tiem (s)
Ph
rate α CO pressure
rate = 2.6E-04x s -1
R2 = 0.99
2.5
O
N+
NEtiPr2
–
CH3CN/THF, 55 oC p-tolyl
Bn
rate α [iminium]
3
O
8000
10000
12000
0.0005
0.00045
0.0004
0.00035
0.0003
0.00025
0.0002
0.00015
0.0001
0.00005
0
0
2
4
6
8
10
CO pressure (atm)
higher reaction rate of both oxidative addition and CO coordination was achieved

Large scale Münchnone synthesis (multigram)
p-Tol
N
H
O
+
Bn
Ph
Cl
+
O
0.25% [Pd(allyl)Cl]2
CO (20 atm) 0.75% JohnPhos,
NEtiPr2,
p-Tol
CH3CN, 45 oC, 18h
O
Ph
N+
Bn
–
89%

Pd loading lower to 0.1%

Milder reaction condition (room temperature)
p-Tol
N
H
O
+
Bn
Ph
Cl
+
CO (4 atm)
5% [Pd(allyl)Cl]2
15% JohnPhos,
NEtiPr2,
CH3CN, r.t., 48h
O
O
–
p-Tol
Ph
N+
Bn
68%
Application: Lipitor Synthesis
O
O
N
O
O
O
O
H
O
tBu
+ Ph
tBu
O
COOMe +
Cl
O
F
5% Pd allylchloride
15% JohnPhos
45 0C
1.5 eq of collidine O
N
O
48%
O
O
tBu
O
O
N
F
H
N
O
95%
F
NH2
DMF
Reflux
With Benzyl Protected Product
N
H
+ Ph
COOMe +
Cl
F
O
5% Pd allylchloride
15% JohnPhos
45 0C
1.5 eq of collidine O
N
O
65%
N
F
H
N
O
99%
F
NH2
DMF
Reflux
Limitations of N-acyl Iminium Salt Intermediates

Limitation of Substituents
N
R1
O
R2
O
+
H
R3
R2
Cl
N
H
R1 and R2 can not be e-withdrawing or bulky
R3 can not be enolizable (non-alkyl)

Stability of starting materials
R3
R1
Cl-
Use α-Alkoxy Amides as N-acyl Iminium
Precusor?
O
R1




O
R3
N
R2
OR
R1
R3
N
ClR2
Stability
Easily synthesized
Easily diversified
Challenge: activation of the ether C-O bond
Oxidative Addition Ethers to Pd ???
O
p-Tol
+
p-Tol
N
Bn
OPh
Pd2(dba)3
No reaction
CH3CN
Oxidative Addition Ethers to Pd ???
O
p-Tol
+
p-Tol
N
Bn
OPh
No reaction
Pd2(dba)3
CH3CN
PdLn
O
p-Tol
p-Tol
N
Bn
OPh
L.A
C-O bond is too strong to oxidative addition to Pd0 , adding Lewis acid might weak
the C-O bond and help the oxidative addition
Oxidative Addition to Pd with the Assistance of
Lewis Acids
O
p-Tol
p-Tol
p-Tol
N
Bn
OPh
+ 2 BF3 + Pd2(dba)3
RT 15 min MeCN
CH3CN
-PhOBF2
Pd
MeCN O
N Bn
BF4-
p-Tol
Pd Catalyzed Amidoester Synthesis
O
p-Tol
p-Tol
N
Bn
OPh +
CO
10% Pd catalyst
P(o-Tol)3
65 0C CH3CN
10% BF3
O
p-Tol
p-Tol
N
Bn
20%
O
OPh +
p-Tol
O
N
H
Bn
68%
H R2 R1
N
MeCN
Pd catalyst =
Pd
R3
MeCN
O
BF4-
Pd Catalyzed Amidoester Synthesis
O
p-Tol
p-Tol
OPh +
N
Bn
0
65 C CH3CN
30% BF3 2h
O
Bn
N
p-Tol
H
quantitative
CO
10% Pd catalyst
P(o-Tol)3
65 0C CH3CN
10% BF3
O
p-Tol
p-Tol
N
Bn
20%
O
OPh +
p-Tol
O
N
H
Bn
68%
H R2 R1
N
MeCN
Pd catalyst =
Pd
R3
MeCN
O
BF4-
BF3 is too strong Lewis acid for this reaction we need something milder
Pd Catalyzed Amidoester Synthesis
O
p-Tol
p-Tol
N
Bn
OPh
+
CO
10% Pd catalyst
P(o-tolyl)3
O
p-Tol
0.5 Bu4NBr
OPh
p-Tol
N
65 0C CH3CN
Lewis Acid
Bn O
Lewis Acid
Yields
0.1eq BF3
20%
1eq Y(OTf)3
0
1eq SnCl4
0
2eq AlF3
72%
0.3 eq AlF3
70%
We can carbonylate the C-O bond and generate products that can not be
synthesized through imines and acid chlorides
Diversity
O
R1
10% Pd catalyst
P(o-tolyl)3
0.5 Bu4NBr
65 0C CH3CN
2 eq AlF3
R3
N
R2
+
OPh
CO
O
O
N
O
OPh
51%
Br
OPh
N
Bn O
55%
p-Tol
O
OPh
N
O
94%
O
p-Tol
OPh
N
Bn
O
OPh
O
62%
O
OPh
R3
N
R2
O
74%
O
p-Tol
R1
p-Tol
N
PMB O
O
O
p-Tol
N
Bn
OPh
O
74%
Lu, Y., Arndtsen, B. A. Org. Lett. 2007, 4395
Directly Activate C-O Bond Without Lewis Acid
Problems with the current system:
 The Lewis acid is expensive
 Limited functionality
Solution:
Activate the C-O directly without Lewis Acids.
How:
 Weaken/polarize C-O bond
 Design better a catalyst
O
R1
R3
N
R2
OR
PdLn
Carbonylation Without Lewis Acids
O
P-Tol
p-Tol
N
Bn
+
OR
R
CO
10% Pd catalyst
P(oTol)3
0.5 Bu4NBr
65 0C CH3CN
O
p-Tol
product
N/A
N/A
O2N
N
N/A
54%
N
N/A
F3C
N/A
NO2
p-Tol
N
Bn
OR
O
Ligand Scanning
O
p-Tol
p-Tol
N
Bn
OPy
+
CO
10% Pd catalyst/L
0.5 Bu4NBr
p-Tol
65 0C CH3CN
tBu
PPh3
PtBu3
0%
0%
3
P
50%
P(o-tolyl)3
54%
O
p-Tol
N
Bn
OPy
O
tBu
P
P
tBu
tBu
56%
87%
Making a more electron rich catalyst allows for efficient C-O activation
Direct Lewis Acid-Free Carbonylation
O
R1
10% Pd catalyst
O
R3
15%(tBu)2P(biphenyl)
OPy
0.5 Bu4NBr
R
N
1
65 0C CH3CN
R2 O
R3
N
R2
OPy
+
CO
F
O
O
p-Tol
OPy
N
Bn O
N
Bn O
73%
68%
O
p-Tol
tBu
OPy
N
Bn O
86%
O
O
O
OPy
p-Tol
OPy
N
Bn O
74%
p-Tol
OPy
N
O
85%
O
p-Tol
p-Tol
OPy
N
PMP O
72%
Pyrrole Synthesis
O
R2
N
R3
R3
R1
R5
R4
Pyrrole
R4
?????
O
O
R2 –
Pd(0)
R5
R3
N+
R1
O
C
R3
H R2 R1
N
L
Pd
R3
Cl
O
Cl
ROH
OR
CO
H R2 R1
N
OC
Pd
R3
O
Cl
R2 N R3
R1
R1
N
R2 O
N OR
R2
O
ROH
O
R1
O R
2
Pd
H
O N
R1
R3
Pyrrole Synthesis
O
p-Tol
p-Tol
N
Bn
O
p-Tol
10% Pd catalyst
COOMe 15% P(oTol)3
2 eq AlF3
OPh + CO +
Ph
p-Tol
p-Tol
N
Bn
65 C, CH3CN
0.5 Bu4NBr
OPy + CO +
COOPh
50%
COOMe 10% Pd catalyst
15% tBu2P(Biphenyl) p-Tol
p-Tol
N
Bn
o
O
Bn
N
p-Tol
65 0C CH3CN
Ph
0.5 Bu4NBr
Ph
COOMe
67%
H R2 R1
N
MeCN
Pd catalyst =
Pd
R3
MeCN
O
BF4-
Compared to PhOH, PyOH is a much weaker nucleophile.
Diversity
O
R2
R3
N
R1
F3C
+
OPy CO + R4
Bn
N
Ph
Ph
COOMe
Bn
N
Ph
38%
Tol
Ph
Bn
N
Tol
COMe
54%
Bn
N
Ph
COOMe
R1
N
R3
Me
Tol
Bn
N
NC
R5
Tol
Bn
N
COOMe MeOOC
48%
tBu
Ph
39%
Bn
N
Tol Tol
H
R2
R4
62%
69%
Tol Tol
H
R5
Bn
N
Tol
42%
Tol
10% Pd catalyst
15% PtBu2(Ph2)
0.5 Bu4NBr
65 0C CH3CN
Tol
N
H
O
58%
Tol
PMB
N
Tol
Ph
COOMe
48%
Lu, Y., Arndtsen, B. A. Angew. Chem. Inter. Ed, 2008, 5430
Importance of Asymmetric Synthesis

Biological importance
DNA, protein, amino acids….

Pharmaceutical importance
O
Ph
N
H
N
F
OH
HO2C
Ph
OH
Atorvastatin
Asymmetric Synthesis

Start with chiral starting materials

Chiral auxiliaries

Chiral resolution

Asymmetric catalysis
Asymmetric Alkynylation
10% CuCl
iPr2NEt
O
+ Ph
+
N
EtO
H
N
-78 oC, 6 h
12% L
Cl
Ph
O
OEt
CH3
HN
N
O
O
N
But
Ph
PPh2
H3CO
PPh2
(R)-QUINAP
43% ee
53% ee
O
PPh2
PPh2
O
N
N
PPh2
81% ee
MOP, 0% ee
O
P NR2
O
N
Pri
(R)-BINAP, 2%ee
Ph
N
N
N
tBu
(R)-tBu-BOX, 1% ee
HN
N
PPh2
N
CH3
(R)-iPr-PyBOX, 0% ee
iPr
MONOPHOS, 0% ee
Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008 73, 1906
A Less “Synthetic” Source of Chirality?
L
L
L M L
L
L
Chiral
Fragment
-Amino Acids
Peptides
R
OH
H2N
O
R1
O
H
N
...
R2
N
H
OH
O
Idea: Tunable, Hydrogen Bonding Metal Catalysis
O
Chiral pool
R
OH
+
Substrate
NH
P
LnM R'
Tunable
catalyst
Alkynylation of Imines
N
R2
R1
O
+
R3
H
O
10% CuI
base
+
Cl
R4
H
N
R3
r.t. 15 min
R2
R1
H
R4
Black, D.A.; Arndtsen, B.A Org.Lett. 2004, 6, 1107.
N
R2
R1
R3
+
water
RT 4d
H
O
L=
Ph
CuI/L
R1
R2 *
R3
O
N
N
HN
N
Ph
Li, C.-J. JACS, 2002, 124, 5638.
Chiral Bronsted Acids in Asymmetric Catalysis
N
R
2% catalyst
1.1 equ. acac
Boc
H
R
O
catalyst
HN
*
R
CH2Cl2
r.t, 1h
Boc
Ac
Ac
O
P
O
OH
R
R= 4-(b-Naph)-C6H4
HO
OTMS
+
N
R
H
10 % catalyst
OR2
toluene
-78 oC, 17h
R1
H
Tereda et.al. JACS 2004, 5356
ArNH
O
R
OR2
R1
C6H4-p-NO2
catalyst
O
O
O
P
OH
Akiyama et.al. ACIE 2004, 1566
C6H4-p-NO2
Chiral Bronsted Acid Catalyzed
Alkynylation of Imines
N
MeOOC
R1
+
H
R2
5% AgOAc
10% catalyst
Toluene
H
N
R1
MeOOC
up to 92% ee
Ar
catalyst =
O
O
P
O
OH
Ar
Ar=9-phenanthryl
Rueping et. al ACIE 2007,6903
R2
Proposed Mechanism
O
PHN
OH
R
+
R2
N
R1
H
O
O
R
NH
R2
P
1
H
+ R
1
N
H
H
Cu(R3P)
R3
(PR3)CuX +
R2
N
R1
R3
R3
Initial Attempt
N
H
Ph
+ Ph
p-Tol
H
10% CuPF6(MeCN)2
CH2Cl2, r.t.
36h
Ph
N
*
p-Tol
Ph
a) no acid: 16%
b) PhCO2H: 97%
c)
Fmoc
N
H
95%, 49%
ee H
CO
2
As
pa
Al
rt i
a
c
ac nin
G
e
id
l
(O
C uta
bz
lu
ta min
l)
m
ic e (X
ac
an
id
)
(O
H
ist
bz
id
l)
in
e
(
Is
ol T s)
eu
ci
n
M
et e*
Ph hio
en nin
Th yla e
re lan
on
in
e
in
e
Se (Bu
rin
t)
e
(B
Ty zl)
ro
si
ne
Va
lin
Pr e
ol
in
Pr e
ol
in
e*
Scanning of Amino Acids
N
p-Tol
Ph
+ Ph
H
H
Ph
10% CuPF6(MeCN)2
N
10% Amino acid
p-Tol
CH2Cl2, r.t.
16h
*
70
60
50
40
% ee
30
20
10
0
Ph
Proposed Mechanism
O
PHN
OH
R
+
R2
N
R1
H
O
O
R
NH
R2
P
H
+ R
1
N
H
H
(PR3)Cu
R3
(PR3)CuX
+
N
R1
R2
R3
R3
Tune the phosphine ligands could affect the enantioselectivity
Scanning of Ligands
N
Ph
+ Ph
p-Tol
H
10% CuPF6(MeCN)2
H
Ph
10% Amino acid
N
ligand
*
p-Tol
CH2Cl2, r.t.
16h
Ph
L
mol% L
Yield (%)
ee (%)
PPh3
10%
95
71
PBu3
10%
78
80
P(OPh)3
10%
89
81
P(cyclohexyl)3
10%
92
81
P(1-Nap)3
10%
96
85
JohnPhos
10%
48
80
P(oTol)3
10%
96
88
P(oTol)3
20%
89
96
Diversity
N
R2
R1
+
H
HN
85% yield
95% ee
Ligand=P(o-tolyl)3
R
3
2.5% CuPF6(MeCN)2
5% L
10% Boc-proline
CH2Cl2
0 oC, 72h
Cl
*
R2
R3
HN
87% yield
95% ee
Ligand=P(o-tolyl)3
79% yield
99% ee
Ligand=P(o-tolyl)3
HN Bn
O
nBu
78% yield
89% ee
Ligand=P(c-hexyl)3
N
R1
HN
HN
HN
H
81% yield
92% ee
Ligand=P(1-Nap)3
Ph
92% yield
93% ee
Ligand=P(1-Nap)3
Lu, Y., Johnstone, T. C. Arndtsen, B. A. JACS, 2009, 11284
Pyrrole Synthesis
R2
N R
1
R3
R5
R4
•
Found in a wide range of natural products and
pharmaceuticals
• Antibacterial, antiviral (HIV-1), antiinflammatants,
ntioxidants, cytokine inhibitors, etc.
O
Ph
Ph
N
H
N
CH3
OCH3
F
N
N
H
OH
HO2C
SO2Et
O
CN
N
H
F3C
N
Cl
OEt
OH
Atorvastatin
Br
Antipsychotic
Insecticide
O
O
O
N
H
Cl
N
Cl
DNA cross-linking agent
Existing Pyrrole Syntheses
R1
R2
O
+ H2NR3
R2
R1
N
R3
O
Paal-Knorr Condensation
N
R3
CuI
R1
R2
R2
N
R3
R1
Gevorgyan JACS 2001, 123, 2074
S
R1
R32CuLi
S
+
R2 R4
NR5
R2
R1
N
R5
R4
Luh JACS, 2000, 122, 4992
R2
R2
R1
R3
O
O
NC
+
EtO 2C
R3
Ru4C O12
R1
N
H
CO2Et
Murahashi Org Lett 2001, 3, 421
An Indole Synthesis
Br
+ PPh3
N
R
O
NaOMe
Toluene
relflux
N
R
PPh3
+
PPh3
PPh3
Base
N
R
O
N
R
O
Le Corre,M; Hercouet, A; Le Baron, H. Journal of the Chemical Society,
Chemical Communications 1981,1, 14-15.
Idea
Br
PPh3
N
O
N
R
R
R4
R3
R2
PPh3
R
R2
N
R1
O
R1
R
R1
+
Cl
N
R
N
O
R3
R2
R4
R3
R4
Syntheses of α,β Unsaturated Imines
O
R2
+
R3
R4
O
Base
O
R4
H
Aldol
R2
R3
R1NH2
α,β unsaturated imines can be prepared from
simple starting materials
N
R4
R1
R2
R3
O
R1NH2 +
R2
R3 +
O
R4
H
PPh3
O
+
R5
Cl
R5
R4
R1
N R
2
R3
Proposal
N
R1
+ R
R2
R4
O
O
O
N
R
Cl
PPh3
R2
R4
R3
R1
R3
R
R3
Ph3P
N
R1
R2
R4
Base
O
R1
N
R2
R3
R
R4
O=PPh3
R
R3
Ph3P
N
R1
R2
R4
First Attempt
N
Me
Ph
Bn
H
1.5 eq PPh3
2 eq NEt3
O
+
Cl
NO2
H
CH3CN
r.t.
O
Bn
N
Me
PNP
Ph
71%
+
PNP
N
Ph
PPh3
Me
20%
O
O
4
R
Bn
1
N
R3
R
H
R2
4
R
N
R3
R1
H
2
R
Improvement by Tuning Counter Ion
N
Me
Bn
PPh3
2 eq NEt3
O
H + Cl
NO2
Ph
CH3CN
r.t.
H
Me
Bn
N
PNP
Ph
Additives
yields
No
71%
Bu4NI
86%
Bu4NBr
78%
NaI
52%
KI
61%
Pyrrole Synthesis
1
N
R
R
3
O
2
R
+
R5
Cl
R4
Et
N
H
Cl
H
Me
N
COOEt
Me
1.5 eq. PPh3
Bu4NI
2 eq. Base
CH3CN
r.t. to 80 oC
R2
R3
Ph
N
H
R1
N
NO2
R5
R4
OMe
N
H
Et
H
S
N
70%
H
61%
Et
N
S
Me
Bn
N
H
Me
NO2
82%
H
Et
N
52%
OEt
Ph
Et
N
H
Me
N
75%
N
62%
59%
CF3
Comparing with the method through Münchnone intermediate:
No regioselectivety problem, Much more broader diversity
50%
Synthesis of Lukianol A
O
OMe
O
PMP
a) Toluene
r.t. 2h
H +
PMP MeO
H2N
H
O
b)
EtO2C
Cl
PPh3, DBU
PMP
DMB O
N
OEt
a, b
PMP
H
PMP
O
N
OEt
PMP
65 %
c, d
HO
PMP = 4-MeOC6H4
DMB =2,4-(MeO)2C6H3
PMP
N
OH
O
HO
O
Lukianol A
(a) anisol, TFA/CH2Cl2, 400C, 2h, 85%. (b) p-MeOC6H4COCH2Br, K2CO3, acetone, reflux, 92%. (c) (i) KOtBu,H2O,
Et2O, 00C-rt; (ii) Ac2O, NaOAc, reflux (d) BBr3, CH2Cl2, -780C-rt, 63% (over two steps).
Conclusion
 Amido
esters and pyrroles.
R1
R5

R2
N R
3
O
Pd
R1
R4
O
R3
Pd
N OR
R2
R1
Pyrroles from Wittig reaction.
R3
R4
 Chiral
NR1
O
+
R2 R5 Cl
PPh3 R2
Base
R3
R1
N R5
Bromsted acid.
O
OH
+
Substrate
R NH
P
Chiral pool
LnM R'
Tunable
catalyst
R4
R3
N COOR
R2
Synthesis of Secondary Amines:
A Tandem
Hydroboration-Aminaton Pathway
The Steric-Royal Chemistry
JACS, 2004, 126, 9200-9201.
JACS 2009, 131, 5024-5025.
Metal Catalyzed Amination
R1
R2
NH2
+
X
Pd/BINAP
NaOtBu
m-xylene, 100oC
R2
R1
N
H
J. Hartwig et. al. J. Am. Chem. Soc. 1994, 5969
S. L. Buchwald et. al. Angew. Chem. Inter. Ed. 1995, 1348
Though widely applied in organic synthesis, the harsh reaction condition
and strong bases used limited the functionality tolerance
An Alternative Route: Chan-Evans-Lam Reaction
R1
B(OH)2
+
R2
H
N
Cu(oAc)2/base
R3
R1
DCE/r.t.
R3
N
R2
Lam, et. al. Tetrahedron Lett. 1998, 2941
Evans, et. al. Tetrahedron Lett. 1998, 2937
Chan, et. al. Tetrahedron Lett. 1998, 2933
Room temperature reaction with milder base
Catalytic route with oxidant also been discovered
Reactions involving alkyl boranes are rare, and require
higher reaction temperature
Reaction with Secondary Boranes
Cu(oAc)2/base
+
BX2
NH2
N
H
slovent, r.t.
Solvent
bsae
yield
BF3K
DCE
K2CO3
5%
BPin
DCE
K2CO3
75 %(at 90 0C)
BCat
DCE
K2CO3
65%
BCat
benzene
K2CO3
80%
BCat
benzene
Cs2CO3
32%
Boranes
A One-Pot Hydroboration-Amination Pathway
1% Rh(COD)2BF4
2% DPPB
+
removal of solvent
BCat
HBcat
THF, r.t. 1h
BCat
+
NH2
2 eq. Cu(oAc)2
K2CO3
benzene, r.t. 8h
N
H
80% base on styrene
Diversity
R2
Rh cat.
THF, r.t.
Br
H
+ ArNH2
R1
benzene, r.t.
N
55%
HN
HN
H
N
Cl
83%
85%
O
HN
R1
Br
O
72%
68%
NO2
Cl
HN
H
N
HN
HN
O
O
O
62%
86%
64%
NH
R2
Cl
Br
H
N
Cu(oAc)2
K2CO3
R2
+ HBCat
R1
Ar
BCat
52%
O
56%
But, No Retention of ee
BCat
Cu(OAc)2
K2CO3
+ PhNH2
Ph
NH
benzene, r.t.
3% ee
Changing solvent, adding ligands, varying temperature, etc
Nothing helps.
Switching to Another Strategy
NHR2
Ar
Cu cata./ chiral ligand
BCat
+
Ar
R1
R1
R2NH2
conditions
BCat
Ar
But, I need a catalytic reaction condition
R1
Searching for An Oxidant
20% Cu(OAc)2.
BCat
+
PhNH2
Ph
benzene, K2CO3, oxidant
Oxidant
Yield (%)
AgOAc
21
O2
4
DDQ
-
tBuOOtBu
57
oxone
-
(PhCOO)2
50
NHPh
Ph
Ligands Screening
20% Cu(OAc)2.
24% ligand
BCat
+
Ph
PhNH2
NHPh
*
Ph
benzene, K2CO3, (tBuO)2
ligand
Yield
ee
R,R-DPEN
-
-
R,R-pyBOX
-
-
R,R-DACH
-
-
Spartein
23
3
35
76
-
-
CF3
F3C
MeN
NMe
S-MOP
Conclusion

Substituted amines could be synthesized from simple
alkenes and primary amines through a tandem one-pot
reaction

Reaction proceeds under milder reaction conditions and
with great functionality tolerance

Asymmetric amination is still ongoing
Acknowledgement
Prof. Bruce Arndtsen
Prof Cathleen Crudden
The Arndtsen Group And The Crudden Group