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ASYMMETRIC PALLADIUM-CATALYZED ALKENE CARBOAMINATION
REACTIONS FOR THE SYNTHESIS OF CYCLIC SULFAMIDES
Chem. Eur. J. 2016, 22, 5919 – 5922 Zachary J. Garlets, Kaia R. Parenti, and John P. Wolfe
James Johnson Wipf Group Current Literature
2-11-17
James Johnson @ Wipf Group Page 1 of 19 3/4/2017
• Ethylene is produced from from petroleum and natural gas by thermal cracking. • Largest chemical produced organic compound.
• Alkenes used extensively in the polymer industry. • Carboamination
• Inexpensive starting materials are rapidly functionalized in a single step • Easily accessed heterocycles and amine building blocks (amino acids).
Alkene Difunctionalization: Carboamination
R RR1NR2R3
or R1R2RN
R3
RR2
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Intramolecular Palladium-Catalyzed Carboamination Reactions
XY
NHR
n
[Pd]Ar-Br
XY ∗∗
NR
n
RBase
NR
Ar
N
n R
Ar
NH
R1R2
R3 R4R5R6
ON
O
R R1H
H ArN
O
R R1H
H Ar
NR
O
NR
P
NH
OR1
R2
R3 RN NR1
O
R2 R3R5
R4
N NBoc
R
R1 R2
O NBoc
R1 R2
NAr
R2
R1 R3
R4
N
NRR1
R2
R3O
NRR1
R2N
NX R
Ar
R1
Ar1
R-BrAr-B(OH)2
NSOO
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Intermolecular Carboamination
Org. Lett. 2013, 15, 2502-2505; ACS Catal., 2016, 6 (10), pp 7183–7187
N
O
O
OR1
R
R2
R3
NiCl2(PMe3)2 (10 mol%)Zn dust (5 eq.)
toluene, 100 °C, 12 h N
O
R1R
R2
R3
20 examples 21-90%
RR1
N SO2PhPhO2S
F
SO2Ph
Cu(CH3CN)4BF4 (2.5 mol%)
OH
N
O 1.6 mol%
PhCN, 60 °C
SO2NR
R1SO2Ph
O NH
O
OR
O
R1
OH
HN
O
OR
R1O
[Cp*Co(CO)I2] (10 mol%)AgSbF6 (20 mol%)CsOAc (25 mol%)K3PO4 (25 mol%)
TFE, 3Å MS40 °C, 22 h
17 examples 30-88%
CbzHN BF3K
R
CbzN
RR1R1
Cu(OTf)2 (20 mol%)1,10-phen (25 mol%)
MnO2 (255 mol%)
DCE, 105 °C, 24 h35 examples 35-78%
O
H
NHNs
R1R3
N
NH
O
t-BuRN
Ns
R2
R3
R1
R2
O
HFe(phen)3(SbF6)3
DME, Na2HPO4-10 °C, 12 h
17 examples 50-88%2:1 dr to >20:1 dr; 87-96% ee
O
NHTf
R1R3 N
TfCHCl3, 2,6-lutadine
455 nm LEDs, rt, 24 h28 examples 35-77%
1.7:1 dr to 16:1 dr
N
Mes
PhBF4-
R5
R6
R7
R2
OR1R2
R3
R6R7
R54-MeO-PhSH
OAr
X
RO2SHN
Br R1
R2
R3 ONSO2R
X
Ar
R1R2
R3H
H
Pd2(dba)3 (2.5 mol%)CPhos (5 mol%) or L
LiOtBu
toluene:t-Amyl-OH110 °C, 24 h
OMePCy2L20 example 20-94%
dr 19:1 to 49:1; 63-73 % ee
Cat.
Cat. 5 mol%Cat. (20 mol%)
Cat.
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Wolfe Group Chemistry
N NH
O CN 2 mol% [Pd2(dba)3]6 mol% (S)-Siphos-PE
NaOtBu
xylenes, 115 °C
Ar-Br
N N
O CN
Ar56-89% (77-95% ee)
NHBoc
RR
R1-BrPd2(dba)3 (2.5 mol%)
(R)-Siphos-PE (7.5 mol%)NaOtBu
BocN
RR
R1
toluene, 90 °C23 examples 61-80%
72-94% ee
NR1
H H
O2S NHPMP
R-OTfPd(OAc)2 (4 mol%)CPhos (10 mol%)
LiOtBu
tBuOH, 82 °C, 16 h9 examples 45-89%
5:1 to 13:1 dr
NR1
H H
O2S NPMP
H
R
NHH
C4H9
BnO
NH H
TMSC4H9
BnO
OtBuO OtBuO
Br TMSPd2(dba)3P(2-furyl)3
NaOtBu, xylenes140 °C
68% >20:1 dr
1) TFA2) PMBNCO N
H H
C4H9
BnO
NHOPMP
72%
Pd2(dba)3PCy3•HBF4
NaOtBu, toluene110 °C
91% >20:1 dr
NH H
C4H9
BnO
NOPMP
Et
NH
N
NH
H H
C4H9C4H9
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Cyclic Sulfamides N N
O2S
F
N OO
NHAc
Active against gram-positivemethicillin and vancomycin
resistant bacteria
N SO2
N
ON
O
OMe
O
Low µM inhibitionof norovirusus N
NSO2N F
O
HOβ-secretase-1 inhibitor
• Biologically active • Enantioselective synthesis usually multi-step starting from amino acids
• Only one previous asymmetric metal-catalyzed synthesis
NH2
OH
O
5 steps
N SO2
NBnO
R
SN N
O O
t-But-BuHN NH
S
R
O OPd2(dba)3 (2.5 mol%)10 mol% L
toluene, 65 °C, 3 h14 examples, 66-98%
90-93% ee
O
OP N
Ph
PhLOrg. Lett., 2013, 15 (4), pp 796–799
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Anti-aminopalladation
Chem. Eur. J. 2014, 20, 8782 – 8790
N SBnO
NH
Anti-aminopalladation
ArOTfPd(OAc)2 (2 mol%)Ru-Phos(5 mol%)
LiOtBu N NSBn
O
Bn
Ar
PhCF3, 100 °C14 examples51 to 92 %
BnO
O
D
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Optimization of Cyclization with Ar-OTf
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Syn vs Anti-aminopalladation
N SBnO
NH
DSyn-aminopalladation Anti-aminopalladation
PhBrPd(OAc)2 (2 mol%)
C-Phos(5 mol%)NaOtBu N N
SBnO
Bn
DPh
PhCF3, 100 °C90%, >20:1 dr
BnO
ON NSBn
O
Bn
DPh
OPhBr
Pd(OAc)2 (2 mol%)X-Phos(5 mol%)
NaOtBu
toluene, 100 °C47%, 4:1 dr
Mechanism highly solvent and ligand dependent Chem. Eur. J. 2014, 20, 8782 – 8790
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Title Paper
James Johnson @ Wipf Group 13
N St-BuO
NH
Syn-aminopalladation
BnO
N NSt-Bu
O
Bn
DAr
O
Ar-BrPd2(dba)3 (1 mol%)
(S)-Siphos-PE (5 mol%)NaOtBu
xylenes120 °C, 18 h
Chem. Eur. J. 2016, 22, 5919 – 5922
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Optimization of Protecting Groups
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Reaction Scope
NS
N
O OBnt-Bu
96% (93:7 er)
NS
N
O OBnt-Bu N
SN
O OBnt-Bu
Ph
X = Br 95% (94:6 er)X = I 75% (75:25 er)
NMe2
85% (95:5 er)
NS
N
O OBnt-Bu
N ON
SN
O OBnt-Bu
75% (96:6 er)
NS
N
O OBnt-Bu N
SN
O OBnt-Bu
74% (92:8 er) 74% (90:10 er)
NS
N
O OBnt-Bu
CF3
OMe
OMe
O
OPh
O NS
N
O OBnt-Bu
69% (90:10 er)
NS
N
O OBnt-Bu
NS
N
O OBnt-Bu
72% (92:8 er)
58% (68:32 er)
NS
N
O OBnt-Bu
F
NBn77% (88:12 er)
F3C21% (62:38 er)
NS
N
O OBnt-Bu
34% (95:5 er)
NS
N
O OBnt-Bu
44% (94:6 er)TMS OMe
89% (94:6 er)
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• Olefin substitution not tolerated
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Anti-aminopalladation
Syn-aminopalladation
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Deuterium Labeling Studies
• EWD groups decrease dr • anti-aminopalladation pathway
• Addition of water (4b) improved yield. • No effect on dr or er
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Deprotection
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Conclusions
• Developed enantioselective Pd-catalyzed alkene carboamination with good to high enantio selectivity
• Example of controlling syn vs anti-aminopalladation
• Expansion to intermolecular variant?
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