Thibaud Gerfaud
Literature Screening
JACS
Synthesis
February 2nd 2009
1
Oxidative Pd(II)-catalyzed C-H bond amination to Carbazole at ambient
temperature
James A. Jordan-Hore, Carin C. C. Johansson, Moises Gulias, Elizabeth M. Beck and Matthew J. Gaunt
H
Pd(II)
N R
Pd(IV)
N R
H
- Classical disconnection in C-N bond formation: C-X + NH (Pd(0) and Cu(I) couplings)
- This work: C-H + NH Pd(II) catalysis
- Interest: No prefunctionalization of the aryl group with an halide
- Carbazole motif present in a lot of natural products and medicines:
Cl
MeO
OH
HO
O
HO
HN
O
O
N
NH
HO
NH
HN
O
O
Cl
OH
carvidilol
rebeccamycin
Gaunt & al., JACS, 2008, 130, 16184-16186
2
Previous work on C-H amination:
- Via nitrenes, Rh catalysis
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Driver & al., JACS, 2007, 129, 7500-7501
- Allylic C-H amination, heterobimetallic catalysis
O
O
- S
Pd(OAc)2
S
Ph
Ph
(10 mol%)
Cr(III)(salen)Cl (6 mol%)
R
H
R
Ts
N
MeOC(O)NHTs
BQ, TBME
45°C, 72h
OMe
O
White & al., JACS, 2008, 130, 3316-3318
- Acetanilide amination, Pd catalysis
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Inamoto & al., Org. Lett., 2007, 9, 2931-2934
Gaunt & al., JACS, 2008, 130, 16184-16186
3
Mechanistic hypothesis:
C H
H
H
N
R
H
C
Pd(II)
H
Pd(II)
N
PdII
R
H
H
C
PdII
H
N
C
PdIV
[O]
N
R
-Pd(II)
C
N
R
R
Optimized reaction conditions:
H
N Bn
H
Pd(OAc) 5% mol.
N Bn
toluene, PhI(OAc)2 (1.2 eq.), rt, 1h
Yield : 96%
Gaunt & al., JACS, 2008, 130, 16184-16186
4
Scope of the reaction
H
N R1
H
Pd(OAc) 5-10% mol.
toluene, PhI(OAc)2 (1.2 eq.), rt
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N R1
H
N Bn
H
Pd(OAc) 5% mol.
N Bn
toluene, PhI(OAc)2, additive, rt
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Complex Isolation
Gaunt & al., JACS, 2008, 130, 16184-16186
5
Application to complex substrates
H
N
Pd(OAc) 20% mol.
OAc
O
OAc
AcO
OAc
OAc
N
toluene, PhI(OAc)2, 50ЎC
O
OAc
OAc
H
N
N-Glycosyl carbazoles
N iPr
N iPr
iPr
n-BuOH-H2O, 80ЎC
90% yield
CH2Cl2, rt
77% yield
I
72%
OAc
Pd(OAc)2 1% mol.
XPhos 2% mol., K3PO4
Pd(OAc) 10% mol.
I2, PhI(OAc)2
Tandem para-iodination, C-H amination followed by
Suzuki coupling to give highly functionalized cabazoles
Conclusion
- New Pd(II) catalyzed intramolecular C-H amination to form carbazoles
- Reaction occurs under mild conditions with a broad scope
- Rare exemple of reductive elimination from a high oxidation state transition
- A non polar solvent seems necessary to promote polynuclear palladacycles
- Useful in natural products synthesis
Gaunt & al., JACS, 2008, 130, 16184-16186
6
Direct Catalytic Asymmetric Synthesis of Cyclic Aminals From Aldehydes
Xu Cheng, Sreekumar Vellalath, Richard Goddard and Benjamin List
O
iPr
O
iPr
Cat. (10% mol.)
NH2
Cat:
NH
O
iPr
OHC
Toluene
P
O
O
iPr
OH
NH
NH2
Yield 86%, 99er (ee= 98%)
- Phosphoric acid catalyzed synthesis
- Stereogenic cyclic aminals: very common in drugs, catalysts and pharmaceuticals
HN
O
O
H2NO2S
O
O
O
S
H2NO2S
NH
N
O
NH
Cl
Cl
N
H
Aquamox
tBu
N
N
H
Thiabutazide
N
Physostigmine
H
N
H
MacMillan chiral auxiliary
- Common synthesis protocol for benzo(thia)diazines: use of an achiral catalyst and HPLC separation
List & al., JACS, 2008, 130, 15786-15787
7
Catalyst Screening:
O
O
Cat. (10% mol.)
NH2
NH
OHC
Toluene, 5A MS
-45°C, 24h
NH2
NH
Ar
F 3C
O
O
Ar=
P
O
Ar
CF3
OH
4a
4b
4c
O
4d
4e
Ph
O
Ph
O
P
OH
4f
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List & al., JACS, 2008, 130, 15786-15787
8
Scope of the reaction:
O
O
4d (10% mol.)
NH2
Aldehyde
NH
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RCHO
Toluene, 5A MS
-45°C, 24h
NH2
NH
R
3
O
O
X
Aminobenzamide
X
6
4d (10% mol.)
5
NH2
1
2
4
3
NH2
NH
OHC
Toluene, 5A MS
-45°C, 24h
NH
3
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9
Conclusion:
- First enantioselective direct synthesis of aminals from aldehydes
catalyzed by chiral phosphoric acid
Ar
- Catalyst structure:
O
O
P
O
OH
Ar:
Ar
- Good aldehyde tolerance
- All investigated amides gave excellent enantioselectivities
- Methodology applied to different structures:
O
H2NO2S
O
O
O
H2NO2S
S
S
NH
NH
Cl
Cl
N
H
N
H
O
(R)-Cyclopenthiazide
Y: 72%, 91%ee
(R)-Thiabutazide
Y: 81%, 91%ee
O
H2NO2S
NH
O
O
H2NO2S
S
O
N
H
Cl
S
N
H
NH
NH
F3 C
H2NO2S
(S)-Aquamox
Y: 78%, 61%ee
Bn
(R)-Bendroflumethiazide
Y: 80%, 92%ee
F3 C
N
H
(R)-Penflutizide
Y: 74%, 90%ee
List & al., JACS, 2008, 130, 15786-15787
10
Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I)
Complex
Yao Du, Li-Wen Xu, Yohei Shimizu, Kounosuke Oisaki, Motomu Kanai and Masakatsu Shibasaki
O
O
F O
O
PPh2
N
OR4
CuOAc - Phosphine (5-10 mol %)
PinBH or (EtO)3SiH
Ph2P
R2
NH
O
F
R1
OR4
F
O
PPh2
O
PPh2
THF
R1
R2
R3
F
H
R3
O
(R)-Difluorphos
- Asymmetric -aminoacids: Mannich reaction is the most straighforward method
- Reaction was limited to the use of aldimines and iminoesters to form -amino acids
- Low reactivity of ketimines
- This work: expand the scope of previous work by the group
Shibasaki & al., JACS, 2008, 130, 16146-16147
11
Previous work by the same group:
O
O
Xy2P
OTMS
N
CuOAc- ligand (10 mol %)
(EtO)2Si(OAC)2 or (EtO)3SiF
Xy2P
NH
O
THF, 40°C, 20h
R1
R2
OBu
R1
OBu
R2
45-99%
77-97% ee
Shibasaki & al., JACS, 2007, 129, 500-501
- Method limited to acetate-derived enolates as donors
- New method required to achieve the catalytic asymmetric synthesis of -amino acids with a substituent at
the -position
Shibasaki & al., JACS, 2008, 130, 16146-16147
12
Catalytic Diastereoselective Reductive Mannich Reaction of Ketimines
O
O
O
PPh2
N
R1
OR4
R2
CuOAc (5 mol %)
PPh3 (10 mol %)
PinBH (1.6 eq.)
Ph2P
NH
R2
O
R1
OR4
THF, rt
R3
R3
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Shibasaki & al., JACS, 2008, 130, 16146-16147
13
Catalytic Asymmetric Reductive Mannich Reaction of Ketimines
O
O
O
PPh2
N
OEt
CuOAc (10 mol %)
(R)-Difluorphos (10 mol %)
(EtO)3SiH (2.8 eq.)
Ph2P
O
NH
R1
OEt
THF, -30 -50°C
R1
R3
R3
Conversion to 2,2,3-amino acids derivatives
O
Ph2P
NH
O
H2N
4M HCl aq.
EtOH, 50°C, 24h
O
OEt
OEt
NaHCO3 aq.
Cl
74%
Cl
Without any racemization and epimerization
Shibasaki & al., JACS, 2008, 130, 16146-16147
14
One-Pot Synthesis of -Siloxy Esters Using a Silylated Masked Acyl Cyanide
Hisao Nemoto, Rujian Ma, Tomoyuki Kawamura, Kenji Yatsuzuka, Masaki Kamiya and Masayuki Shibuya
TBS
O
CN
O
OR3
DMAP, Pyridine or PPY
H
R1
OTBS
R3OH
R1
R2
R2
One-Pot
CN
O
- -Hydroxycarboxylic acids or esters usually prepared in multiple steps by C-C bond formation using
carbanion chemistry
X
OH
Y
R1
CO2H
R1
Z
R2
R2
OH
O
Y
R1
HO
R2
OH
Y
Oxidation
R1
OR
R2
R1
R2
OR
-HY
CO2R
R1
R2
OH
Kirschning & al., Chem. Eur. J., 1999, 5, 2270
Nemoto & al., Synthesis, 2008, 23, 3819-3827
15
- Reminder on Passerini reaction:
O
OH
R5COOH
O
R5
O
hydrolysis
One-pot
R1
R2
H
N
R1
C
H 2N
R2
R6
N
CO2H
R1
R6
R2
O
R6
- One-pot reaction using MAC (Masked Acyl Cyanide)
TBS
O
XR3
One-Pot
H
R1
OH
CN
O
OTBS
hydrolysis
R1
R2
R2
CN
CO2H
R1
R2
O
MAC reagent
R3XH
O
R1
OTBS
TBS
O
R1
CN
R2
R2
NC
CN
HXR3
X = O or NR4
O
Nemoto & al., Synthesis, 2008, 23, 3819-3827
16
- Esters and tertiary amides which cannot be directly synthesized by Passerini reactions can be
synthesized using MAC reagents
- Amines can be used directly: no need to form an isonitrile
Scope of the reaction (selected examples)
H
R1
TBS
DMAP (0.1 eq.) or
Pyridine (1 eq.)
CN
O
O
OMe
OTBS
R2
R1
MeOH
rt
CN
R2
O
R1
R2
Time
Yield
4-MeC6H4
H
5 min
96%
4-NCC6H4
H
2h
98%
(E)-MeCH=CH
H
2h
79%
Me3C
H
5h
30%
4-O2NC6H4
Me
0.5h
90%
4-MeC6H4
Me
24h
77%
Me3C
Me
48h
0%
Nemoto & al., Synthesis, 2008, 23, 3819-3827
17
- Electron density on aromatic rings did not influence the reaction
- Sterically hindered aldehydes and ketones are not good substrates for the reaction
- On cyclohexen-2-one; competition between 1,2 and 1,4 addition
O
TBSO
CN
H
TBSO
CO2Me
CO2Me
OTBS
OTBS
CN
CN
CN
32%
38%
Alcohol scope
TBS
O
CN
O
H
DMAP (0.1 eq.)
OR3
OTBS
R3OH
rt
H
CN
O
R3
Yield
i-Pr
90%
Bn
88%
Allyl
92%
Ph
93%
t-Bu
0%
- No reaction with hindered tert-butyl alcohol
Nemoto & al., Synthesis, 2008, 23, 3819-3827
18
Conclusion
- One-pot reaction to afford -siloxy esters
- A tertiary amine is necessary, in case of sterically hindered substrates DMAP can improve the yield
- Trialkylamines unsuitables for the reaction because of decomposition of the MAC reagents
- MAC reagents are the only acyl anions equivalents that allow one pot reactions to create -hydroxy
carbonyl compounds
Nemoto & al., Synthesis, 2008, 23, 3819-3827
19
A Concise Asymetric Total Synthesis of Aspidophytine
K. C. Nicolaou, Stephen M. Dalby and Uptal Majumber
Me
N
O
O
N
N
HO
O
MeO
O
N
H
OMe
Me
Haplophytine
Haplophyton cimicidium
- Isolated from Haplophyton cimicidium in 1953
- Structure disclosed in 1973
- Acid-mediated degradation lead to the right-hand constituent aspidophytine:
N
D
E
A
MeO
- First total synthesis: Corey 1999
C O
B
O
N
H
OMe
Me
Nicolaou & al., JACS, 2008, 130, 14942-14943
20
Retrosynthetic Analysis
N
N
D
E
A
A
C O
B
MeO
COO
O
N
C
B
MeO
N
H
H
OMe
OMe
Me
Me
TBSO
MeS
N
O
O
N
S
H
CO2TMSE
I
A
CO2TMSE
MeO
N
OMe
MeO
N
OMe
Me
B(OH)2
Me
B
Nicolaou & al., JACS, 2008, 130, 14942-14943
21
Synthesis of A
O
O
HN
I
a) NaH, TBSO
68%
O
O
TBSO
OBn
KHMDS,
O
N
89%
Br
Me
OBn
MeO
OBn
TBSO
N
b) LDA,
O
Me
CO2TMSE
4:1
CO2TMSE
66%
Me
1) H2, Pd(OH)2, 82%
2) NaBH4; NaIO4, 79%
I
O
I
O
H
PPh3I
TBSO
N
NaHMDS
CO2TMSE
O
TBSO
N
CO2TMSE
88%
A
Nicolaou & al., JACS, 2008, 130, 14942-14943
22
Fragment coupling and elaboration to Aspidophytine
TBSO
TBSO
N
N
O
MeO
MeO
69%
N
O
I
t-Buli, B(OMe)3, NH4Cl
N
CO2TMSE
PdCl2(dppf), Cs2CO3, H2O
B(OH)2
MeO
N
86%
OMe
OMe
CO2TMSE
Me
OMe
MeS
6-exo-trig cyclization
O
Tf2O, DTBMP
S
N
TBSO
H
MeO
TBSO
N
A
1) HF.py
H
MeO
MeO
2) NaH, CS2, MeI
MeO
N
CO2TMSE
83% (2 steps)
N
NaBH4
88%
MeO
N
CO2TMSE
Me
MeO
Me
N
CO2TMSE
Me
>95:5
n-Bu3SnH, AIBN
58%
N
N
Longest linear sequence: 12 steps
MeO
TBAF, THF
CO2TMSE
N
MeO
K3Fe(CN)6
t-BuOH / H2O
63%
Me
3:1
5% overall yield
O
H
MeO
O
N
H
OMe
Me
aspidophytine
Nicolaou & al., JACS, 2008, 130, 14942-14943
23
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24