Post on 21-Jan-2016
February 5 2008Louis-Philippe Beaulieu
Complex-Induced Proximity Effect in Directed Ortho and Remote Metallation
Methodologies
Outline
2
1. Background Information
2. Complex-Induced Proximity Effect: The concept
Effect of Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
3. Directed Ortho Metallation: Seminal Work
4. Directed Ortho Metallation: Methodological Aspects
Arylsulfonamide DoM Chemistry
Enantioselective Functionalization of Ferrocenes Via DoM
Background Information
3
Complex-Induced Proximity Effect (CIPE): The Concept
4 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363
• The CIPE process requires kinetic removal of the β-proton in the presence of an α-proton which is ca. 10 pKa units thermodynamically more acidic
• The organolithium base is delivered with proper geometry to allow overlap between the HOMO of the β-C-H bond being broken and the LUMO of the π* orbital of the double bond
OiPr2N
HMe
H
s-BuLi OiPr2N
HMe
H
(LiBu)n OiPr2N
MeH
Li OiPr2N
MeH
MeMeI
O
iPr2N
H
CH2
MeH
(Li-Bu)n
FG
C H
+ (RLi)n
FG
C H
(LiR)n FG
C
Li
H
R
FG
C Li
E+
FG
C E
1 2 3 4 5
Complex-Induced Proximity Effect (CIPE): The Concept
5 Beak, P. et al. J.Am.Chem.Soc. 1986, 19, 356-363
Metallation Conditions Ratio 2:3
LDA-THF-HMPA 100:0
LDA-THF 40:60
HA
D
D
i) LDAii) H+
HA
+
D
DCO2Me CO2MeD CO2Me
1 2 3
• HMPA efficiently solvate cations and thus disrupts the oligomers of lithium base that constitute the preequilibrium complex
N
O
N
OBuLi
Li
N
O
N
OBuLi
OMe OMeLi
Bu
• In the case of the methoxy-substituted phenyloxazoline, no metalation occurs since the lithium base is complexed in a manner which holds the base away from the proton to be removed
CIPE : Kinetic Evidence for the Role of Complexes in the α’-Lithiations of Carboxamides
6
• The kinetics of the α’-lithiations in cyclohexane were determined by stopped-flow infrared spectroscopy• The interaction of ligands with sBuLi was investigated by cryoscopic measurements• Based on these investigations the reactive complex illustrated above was determined to have optimal reactivity
Beak, P. et al. J.Am.Chem.Soc. 1988, 110, 8145-8153
R
Li
Li
Li
RR
R
Li
LL
L
O Ar
N MeH
HH
R
Li
Li
Li
RR
R
Li
LL
L
O Ar
N MeH
HH
Ar N
O
Me
MeAr N
O
Me
Li
Ar = 2,4,6-triisopropylphenylL = 1 or TMEDAR = sBu
1 2
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
7
NBoc
s-BuLi
TMEDAN
OtBuO
Li
Me2SO4
N
OtBuO
Me
tBu tBu tBu
An orthogonal relationship between the lithio carbanion and the pi system of the amide is favorable:
• Allows for complexation of the lithium with the carbonyl oxygen•Relieves the possible repulsive interaction between the electron pairs of the carbanion and the pi system
Beak, P et al. Acc.Chem.Res. 1996, 29, 552-560
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
n R E+ E Time (h) Yield (cis:trans)
1 iPr Me3SnCl SnMe3 5 78: 0
1 iPr Me2SO4 Me 3 68:0
1 iPr PhMe2SiCl SiMe2Ph 4.5 43:0
2 tBu Me2SO4 Me 5 85:0
2 tBu PhMe2SiCl SiMe2Ph 5 50:10
8
NO
O
RR
sBuLi, TMEDAEt2O, -78C, 5h
n
NO
O
RRn
LiE+
NO
O
RRn
E
Beak, P. et al. J.Am.Chem.Soc. 2001, 123, 315-321
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
n R E+ E Time (h) Yield (cis:trans)
1 iPr Me3SnCl SnMe3 5 78: 0
1 iPr Me2SO4 Me 3 68:0
1 iPr PhMe2SiCl SiMe2Ph 4.5 43:0
2 tBu Me2SO4 Me 5 85:0
2 tBu PhMe2SiCl SiMe2Ph 5 50:10
9
NO
O
RR
sBuLi, TMEDAEt2O, -78C, 5h
n
NO
O
RRn
LiE+
NO
O
RRn
E
Beak, P. et al. J.Am.Chem.Soc. 2001, 123, 315-321
• The relative configuration of the stannane product was determined to be cis by X ray crystallography
• In this structure, the carbonyl group is nearly coplanar to the C-Sn bond. Assuming the reaction with Me3SnCl proceeds with retention of configuration, the proton that is nearly coplanar with the carbonyl group would be favored for removal
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
10
NN
LiiPr iPr
Li
(Et2O)n
N
tBuO O
+ prelithiation complex
1
2
C
N
tBuO O
Li
dPdT
= k2[C] eqn 1
k2Kc
Kc = [C] [2i-C][1i-C]
eqn 2
Since [2i] [1] or [C]: Kc = [C] [2i][1i-C]
eqn 3
Solving for [C] and substitution into eqn 1:
dPdT
= k2Kc [2i][1i] [2i][1i-C]
eqn 4
If Kc large:dPdT
= eqn 5k2[1i]
3
Beak, P. et al. J. Org. Chem. 1995, 60, 7092-7093
• The observation of a large intermolecular isotope effect (˃30) between 1 and 1-d4 suggests that the deprotonation is the rate-determinating step
• The large value for Kc indicates that the equilibrium lies heavily on the side of the complex C
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
11
Competitive Efficiency in Carbamate-Directed Lithiations: Comparison of Constrained Carbamates and Boc Amines
N
Boc
N
Boc
KA
KB
kA
kB
+ sBuLi/TMEDA
A
B
+ sBuLi/TMEDA
prelithiationcomplex A
prelithiationcomplex B
N
N
OtBuO
Li
OtBuO
Li
• The magnitudes of both the equilibrium constants and the rate constants can affect the competitive efficiencies of the reactions compared
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
Substrate Pseudo-1st Order Competitive Efficiency
Second Order Competitive Efficiency
Dihedral Angles(HA, HB)(º)
Distance from carbonyl oxygen (HA, HB)(Å)
1 136, 14820, 97
2.64, 3.882.41, 3.44
3 4 20, 127 2.48, 3.78
235 68 36, 70 2.57, 3.16
330 920 20, 127 2.69, 3.96
705 4800 10, 96 2.66, 3.72
fast 19000 28, 77 2.78, 3.7012
N
Boc
HB
HA
N
HB
HA
Boc
NO
O
iPriPrHB
HA
N
OO
HA
HB
tBu
tBu
NHB
HA Boc
N
OO
HA
HB iPr
iPr
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
13
N
Boc
i) sBuLi, (-)-sparteineEt2O, -78°C, 6h
ii) iPr2CO, -78°C, 3h 55%
N
Boc
iPr
OHiPr
99:1 er
SEMCliPr2NEt
CH2Cl250C, 72 h
76%
N
Boc
iPr
OSEMiPr
i) sBuLi, (-)-sparteineEt2O, -78°C, 24h
ii) Me3SnCl, -78°C, 3h 25%
N
Boc
iPr
OSEMiPrMe3Sn
1) TBAF, THF, , 4 d 47%
2) NaH, THF, , 16 h 51%
NO
O
iPriPr
Me3Sn
Synthesis of the trans-organostannane
NO
O
RR
Li NO
O
RR
Li N Li
OtBuO
Evaluation of the effect of restricting the position of the carbamate carbonyl group on the configurational stability of a dipole-stabilized organolithium
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
Stannane Diamine Temp (ºC) Time (h) Yield (%) cis:trans
cis TMEDA -78 4 57 >99:1
cis TMEDA -40 1 44 >99:1
cis none -78 6 69 >99:1
cis none -40 5 21 >99:1
trans none -78 5 56 <1:99
trans none -40 1 24 2:1
trans TMEDA -78 1 44 1:1
trans TMEDA -78 6.5 21 >99:1
14
NO
O
iPriPr
Me3Sn
nBuLi
Et2O, -78°Ctime
NO
O
iPriPr
Li
Me2SO4
-78°CN
OO
iPriPr
Me
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
15
NO
O
iPriPr
Me3Sn
nBuLi
Et2O, -78°CN
OO
iPriPr
Li
Me2SO4
-78°CN
OO
iPriPr
Me
HN
O
HHHH
LiO
iPriPrH
NO
O
iPr
iPrH
H
H
H
H
Li
H
cis trans
• The cis organolithium is more thermodynamically stable given the better chelating interaction between the carbonyl oxygen and the lithium than the trans configuration
• Additional stabilization results from the orthogonal relationship between pi system and the, anion which is more accessible in the cis configuration
CIPE: The Effect of Varying Directing-Group Orientation on Carbamate-Directed Lithiation Reactions
Solvent Temp (ºC) Time (h) Yield (%) e.r.
Et2O -78 1 65 89:11
Et2O -78 2 53 82:18
Et2O -78 3 76 80:20
Et2O -78 5 33 65:35
Et2O -78 6.5 54 61:39
Et2O -78 8 20 55:45
Et2O/TMEDA -78 10 66 90:10
Et2O/TMEDA -40 1 50 46:54
16
nBuLi
Et2O, -78°C
Me2SO4
-78°CN SnMe3
BocN Li
OtBuO
N Me
Boc
(S)e.r. 95:5
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
17
Possible reaction pathways:
FG
C H
+ (RLi)n
FG
C H
(LiR)n FG
C
Li
H
R
FG
C Li
E+
FG
C E
1 2 3 4 5
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
18Beak, P. et al. J.Am.Chem.Soc, 1999, 121, 7553-7558
Possible reaction pathways:
H
HX Y
+D
DX Y
RLi H
LiX Y
+D
LiX Y
1 1-d2 4 4-d1
H
DX Y
RLi H
LiX Y
+D
LiX Y
1-d1 4 4-d1
Intramolecular effect Intermolecular effect
Kinetically enhanced metallation
Complex-induced proximity effect
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
19
Intramolecular isotope effect: kH/kD = [2-d1]/[2]
Ph N N
O
H
MeMe
D H i) 1.8 equiv sBuLi/TMEDA
THF, -78°Cii) CO2
N
NMe
Me
O
O
Ph
+
HN
NMe
Me
O
O
PhD
62%
kH/kD 20
1-d1 2-d12
Ph N N
O
H
MeMe
H H
Ph N N
O
H
MeMe
D D
i) 1.25-1.8 equiv sBuLi/TMEDA
THF, -78°Cii) CO2
6-60%
k'H/k'D 5-6
N
NMe
Me
O
O
Ph
+
HN
NMe
Me
O
O
PhD
2-d12
+
1-d2
1 1-d2 + 1
Intermolecular isotope effect: k’H/k’D = log([1]/[1]i) log([1-d2]/[1-d2]i)
• The relative concentrations of 1 and 1-d2 change as a function of time , and consequently so does the relative forward velocities
, assuming the reaction is first order in substrate
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
Substratek’H/k’D
IntermolecularkH/kD
Intramolecular
5-6 >20
>20 >30
>20 >20
20
Ph N N
O
H
MeMe
(D)HH(D)
O NiPr2
(D)H H(D)
O NHiPr2
(D)H H(D)
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
Substratek’H/k’D
IntermolecularkH/kD
Intramolecular
5-6 >20
>20 >30
>20 >20
21
Ph N N
O
H
MeMe
(D)HH(D)
O NiPr2
(D)H H(D)
O NHiPr2
(D)H H(D)
Limitations
Intramolecular isotope effect:
kH/kD = [2-d1]/[2]
• Precise determination of the isotope effect is complicated by the low occurrence of 2
• A different value of intra- and intermolecular kinetic isotope effect precludes a one-step mechanism
• Reaction pathway b, d or f might best describe the reaction profile
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
Substratek’H/k’D
IntermolecularkH/kD
Intramolecular
5-6 >20
>20 >30
>20 >20
22
Ph N N
O
H
MeMe
(D)HH(D)
O NiPr2
(D)H H(D)
O NHiPr2
(D)H H(D)
Limitations
Intramolecular isotope effect:
kH/kD = [2-d1]/[2]
• Precise determination of the isotope effect is complicated by the low occurrence of 2
Intermolecular isotope effect:
k’H/k’D = log([1]/[1]i) ([1-d2]/[1-d2]i)
• High conversions of 1 and very low conversions of 1-d2 complicate the determination of the isotope effect
• However qualitatively k’H/k’D would be large in value
CIPE: Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations
Substratek’H/k’D
IntermolecularkH/kD
Intramolecular
5-6 >20
>20 >30
>20 >20
23
Ph N N
O
H
MeMe
(D)HH(D)
O NiPr2
(D)H H(D)
O NHiPr2
(D)H H(D)
• Similar values of inter- and intramolecular kinetic isotope effects does not allow to distingsh between kinetically enhanced metallation and CIPE.
• However, if the deprotonations of all three substrates can be described similarly, then the two benzamide substrates may follow reaction pathway e.
Directed Ortho Metallation: Seminal Work
24
Oi) nBuLi
Et2O, -78°C, 20hii) CO2
O
CO2
+
O O O
19% 40%
DMG
(RLi)n or(RLi)nLm DMG
(RLi)n
nH
-(RH)n DMG
nLi
E+DMG
E
DMG = Directed Metallation Group
Bebb, R.L. et al. J.Am.Chem.Soc. 1939, 61, 109-112
Seminal Discovery (1939)
Mechanism
Directed Ortho Metallation: Directed Metallation Groups
25Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4464-4466
N
O
+i) nBuLi (1 equiv)
THF, -100°Cii) MeIDMG
N
O
+
DMG
Me
Me
DMG = SO2NMe2,SO2NHMe, CON(iPr)2, CONEt2, CONHMe, CH2NMe2
CONEt2
DMG
i) sBuLi/TMEDA
THF, -100°Cii) MeOD
CONEt2
DMG
D
DMG = p-SO2NEt2, p-SO2NHMe, p-CO2H, p-CH2NMe2, m-CH3, p-CH3, o-Cl, m-Cl, p-Cl
Beak, P. et al. J.Org.Chem. 1979, 44, 24, 4463-4464
OCO2NR2
SO2tBu SOtBu
CONR2 CON R
SO2NR2 SO2N-R
CO2-
OMOM
N-Boc N-COtBu
(CH2)nNR2, n = 1,2
F
NR2
N
OIncreasingDMG Power
Beak, P. et al. Angew.Chem.Int.Ed. 2004, 43, 2206-2225
Directed Ortho Metallation: Methodological Aspects
26
CONEt2
OMe
i) sBuLi/TMEDAii) TMSCl
CONEt2
OMe
TMS
i) sBuLi/TMEDAii) ClCONEt2
CONEt2
OMe
TMS
CONEt2i) sBuLi/TMEDAii) ClCONEt2
CONEt2
OMe
TMS
CONEt2Et2NOC
i) sBuLi/TMEDAii) MeI
(78%)
(66%)(74%)(94%)
CONEt2
OMe
TMS
CONEt2Et2NOC
Me
Snieckus, V. et al. J.Org.Chem. 1989, 54, 4372-4385
Iterative DoM Reactions: The "Walk-Along-The-Ring" Sequence
Directed Ortho Metallation: Methodological Aspects
27 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526
Silyl Group Functionalization : ipso-Halodesilylation Reactions
Compd Hal+/solvent/temp X Yield (%)
2 ICl/CH2Cl2/rt Cl 86
2 NCS/MeCN/reflux Cl 70
2 Br2/CH2Cl2/0°C-rt Br 92
3 ICl/CH2Cl2/rt Cl 71
3 NCS/MeCN/reflux Cl 65
3 Br2/CH2Cl2/0°C-rt Br 78
4 ICl/CH2Cl2/rt Cl 66
4 NCS/MeCN/reflux Cl NR
4 Br2/CH2Cl2/0°C-rt Br 77
DMG
TMS
DMG
X
R
Hal+
2, 3, 4 5, 6, 7
2, 5: DMG = OCONEt2; 3, 6: DMG = CONEt2; 4, 7: DMG = SO2NEt2
Directed Ortho Metallation: Methodological Aspects
28 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526
Silyl Group Functionalization : ipso-Borodesilylation Reactions
DMG R Yield (%)
CONEt2 H 76
N-cumyl amide H 95
OCONEt2 H 85
OCONEt2 6-TMS 89
SO2NHEt H 90
R
DMG
TMS
i) BX3 (1.2 equiv) CH2Cl2, rt, 2h
ii) Pinacol (4 equiv), EtOAc
X = Cl, Br
R
DMG
B
O
O
Directed Ortho Metallation: Methodological Aspects
29 Snieckus, V. et al. Org.Let. 2005, 7, 13, 2523-2526
Silyl Group Functionalization : in situ ipso-Borodesilylation and Suzuki Cross-Coupling Reactions
DMG ArX Yield (%)
PhBr 76 (80)
3-Br-Py 83(58)
PhBr 76
R
DMG
TMS
BX3 (1.2 equiv) CH2Cl2, rt, 2h
R
DMG
BX2
ArX
Pd(PPh3)4Na2CO3
R
DMG
Ar
CONEt2
TMS
OCONEt2
TMS
OCONEt2
TMS
TMS
Directed Ortho Metallation: Methodological Aspects
30
OCONR2
R'i) RLi, -78°C
ii) RT
OH
CONR2
1) PG
2) RLi3) E+
OPG
CONR2
R' R'
Anionic Rearramgement
Snieckus, V. et al. J.Org.Chem. 1983, 48, 1935-1937
Snieckus, V. et al. J.Am.Chem.Soc. 1985, 107, 6312-6315
OCONEt2
R
OCONEt2
R
Et2NOCi) sBuLi/TMEDA
ii) MeI
OMe
R
Et2NOC CONEt2i) sBuLi/TMEDA
ii) RTii) MeI/K2CO3
i) sBuLi/TMEDA
ii) MgBr2
ii) Allyl bromide
OMe
R
Et2NOC CONEt2 6N HCl
OH
R
HO2CO
O OH
R
O
O
NH
OHO2C
Ph
R = H ochratoxin BR = Cl ochratoxin A
R = HR = Cl
R = H (89%)R = Cl (77%)
R = H (59%)R = Cl (42%)
R = H (55%)R = Cl (38%)
R = H (50%)R = Cl (49%)
Aspergillus ochraceus and Penicillium viridicatum
Fungal toxic metabolites from strains of
Directed Ortho Metallation: Methodological Aspects
31
Remote Aromatic Metalation
• X-ray crystal structure data for N,N-Diisopropyl 2-phenyl-6-(1’-naphtyl)benzamide shows an approximately orthogonal amide carbonyl with respect to the central aromatic ring
CONiPr2
BuLi or LDAN
O
iPr
iPr Li
H
Ar1
Ar2
OH
Ar1
Ar2
BCl3
OHO
MeO
OMeMe
CONEt2iPrO
i) sBuLi/TMEDA THF/ -78°C
ii) B(OnBu)3CONEt2
iPrO
B(OnBu)2
PdCl2(dppf)2K3PO4/DMF/RT
MeO
iPrO
OMe
CONEt2iPrO
MeO
iPrO
OMe
I
(50%)
(94%)
i) LDA/THF 0°C RT
ii) BCl3/CH2Cl2 0°C
(58%)
Dengibsinin
Snieckus, V. et al. J.Org.Chem. 1991, 56, 1683-1685
N-Cumyl Benzamide, Sulfonamide and Aryl o-Carbamate DMG
32 Snieckus, V. et al. Org.Let. 1999, 1, 8, 1183-1186
O2S
NH
Ph
Me Me
OMeN
O
Ph
Me MeTMS
OH
TMS
1) TFA2) 10% NaOH/ EtOHO
MeN
O
Ph
Me Me
i) sBuLi/TMEDA THF, -78°C, 2h
ii) -78°C rt
OHMeN
O
Ph
Me Me(82%)
TFE
reflux / 11h
OH
NHMe
O
NH
O
Ph
Me Me
TMS
TFA, rt, 15 min (83%)
NH2
O
E orBF3·OEt2CH2Cl2, rt, 2 h (86%)
TMS
TFA, rt, 15 min (82%)
O2S
NH2
TMS
i) sBuLi/TMEDA THF, -78°C, 2h
ii) TMSCl
(87%)
(79%)
(70%)
N-Cumyl Arylsulfonamide DoM Chemistry
33
SNH
Ph
O O
E
E = TMSTFA, rt, 10 min
(85%)
SNH2
O O
TMS
E = Hi) NaH, DMF 0°C RT
ii) EtI (91%)
SNEt
Ph
O O
i) sBuLi, THF, -78°Cii) TMSCliii) 10:1 TFE/AcOH
(72%)
SNHEt
O O
TMSCl
E = ICu powderDMF, 105°C, 25h
SNH
Ph
O O
)2
E =OH
Ph PhTFA, rt, 10 min
NHS
OO
Ph Ph
(99%)
E = CHO
NS
OO
PhOH
PDC, DMF
(67%)N
SO
O
PhO
Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206
N-Cumyl Arylsulfonamide DoM Chemistry
34 Snieckus, V. et al. J.Org.Chem. 2007, 72, 3199-3206
SEt2NOCO O
NH
Ph
R
i) nBuLi/TMEDA THF, -78°C, 1h
ii) I2
SEt2NOCO O
NH
Ph
RI
R = Ph (53%)R = OMe (62%)
Pd(PPh3)4, PhB(OH)22M Na2CO3, DME
90°C, 24h
R = Ph (76%)R = OMe (82%)
SEt2NOCO O
NH
Ph
RPh
1) TFA, rt, 10 min2) AcOH, reflux 12h3) HCl
R = Ph (79%)R = OMe (83%)
RPh
S
HN O
OO
NS
OO
O N
O
Me
OHHH
-O2C+R3N
SNH
Ph
O O
I+,XCoupl
1
+CONEt22
I+,XCoupl
3
Merck carbapenem-typeantibacterial agents
Arylsulfonamide DoM Chemistry
35Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891
SO2NEt2R
iPr2Mg (2.25 equiv)5 mol% [Ni(acac)2]
Et2O / rtR
H
Entry R Yield (%)
1 H (74)
2 2-Me (74)
3 3-Me (94)
4 4-Me (56)
5 2-CONEt2 60(64)
6 4-CONEt2 58(67)
7 2-N(Me)Ph 53
8 4-N(Me)Ph 18
9 2-OMe (97)
10 2-OCH2Ph 68
11 2-OiPr 59
12 3-OMe (91)
13 4-OMe (18)
14 2-TMS (48)
15 4-TMS (76)
16 2-(p-MeO-C6H4) 90
17 4-(p-MeO-C6H4) 85
Arylsulfonamide DoM Chemistry
36Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891
SO2NEt2R
iPr2Mg (2.25 equiv)5 mol% [Ni(acac)2]
Et2O / rtR
H
Entry R Yield (%)
1 H (74)
2 2-Me (74)
3 3-Me (94)
4 4-Me (56)
5 2-CONEt2 60(64)
6 4-CONEt2 58(67)
7 2-N(Me)Ph 53
8 4-N(Me)Ph 18
9 2-OMe (97)
10 2-OCH2Ph 68
11 2-OiPr 59
12 3-OMe (91)
13 4-OMe (18)
14 2-TMS (48)
15 4-TMS (76)
16 2-(p-MeO-C6H4) 90
17 4-(p-MeO-C6H4) 85
• Large ortho substituents and para-substituted electron-donating groups promote lower yields
Arylsulfonamide DoM Chemistry
37Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891
SO2NEt2R
iPr2Mg (2.25 equiv)5 mol% [Ni(acac)2]
Et2O / rtR
H
Entry R Yield (%)
1 H (74)
2 2-Me (74)
3 3-Me (94)
4 4-Me (56)
5 2-CONEt2 60(64)
6 4-CONEt2 58(67)
7 2-N(Me)Ph 53
8 4-N(Me)Ph 18
9 2-OMe (97)
10 2-OCH2Ph 68
11 2-OiPr 59
12 3-OMe (91)
13 4-OMe (18)
14 2-TMS (48)
15 4-TMS (76)
16 2-(p-MeO-C6H4) 90
17 4-(p-MeO-C6H4) 85
• Large ortho substituents and para-substituted electron-donating groups promote lower yields
• Groups ortho to the sulfonamide that are capable of metal coordination enhance the yield significantly
SO2NEt2R
iPr2Mg (2.25 equiv)5 mol% [Ni(acac)2]
Et2O / rtR
H
OMe OMe
R = 4-N(Me)Ph (77%)R = 4-OMe (87%)
Arylsulfonamide DoM Chemistry
38 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891
Entry
R R’ Yield (%)
1 2-OMe Me (60)
2 2-OMe Ph 52
3 4-OMe Ph 79
4 2-(p-MeO-C6H4) Ph 65
5 4-(p-MeO-C6H4) Ph 72
6 2-Me Ph (69)
7 4-Me Ph (80)
8 2-TMS Ph (73)
9 4-TMS Ph (84)
SO2NEt2R
R'MgX (4.5 equiv)5 mol % [Ni(acac)2] / dppp
PhMe / refluxR
R'
• Electronic effects seem to have little influence on the yields of products
SO2NEt2X
MeO-C6H4-ZnCl[Pd(PPh3)4]
THF / reflux
SO2NEt2MeO
PhMgBr[Ni(acac)2]
dppp
PhMe / reflux
Ph
MeO
a: 2-I (85%)b: 4-Br (89%)
a: 2-MeO-C6H4 (65%)b: 4-MeO-C6H4 (72%)
Arylsulfonamide DoM Chemistry
39 Snieckus, V. et al. Angew.Chem.Int.Ed. 2004, 43, 888-891
L2NiX2
2 MgX2
2 RMgX
L2NiR2
R-R
Ar-SO2NEt2
L2NiAr
SO2NEt2
L2NiAr
RL2NiR'
R
1
2
3
4
5
RMgX
MgXSO2NEt2
Ar-SO2NEt2
Ar-SO2NEt2
Ar-R
• The reduction of 6 by [D7]iPr2Mg and the regiospecific cross-coupling of aryl sulfonamides with aryl Grignard reagents suggest that the cross-coupling reaction proceeds through the catalytic cycle of the Corriu-Kumada- Tamao reaction
SO2NEt2
TMS
OMe
OMe
2.25 equiv [D7]iPr2Mg5 mol% [Ni(acac)2]
Et2O / rt
D
TMS
OMe
OMe
6 7
Arylsulfonamide DoM Chemistry
40 Snieckus, V. et al. Synlett 2000, 9, 1294-1296
Me
SO2NHEti) nBuLi (2.1 equiv)THF, 0°C 30 min
ii) I2 (1.1 equiv)THF, -78°C 30 min
Me
SO2NHEt
I
1) [(PPh3)2PdCl2] (2 mol%) CuI (1 mol %) (1.2 equiv) rt, 2h
2) K2CO3 (0.1 equiv) MeOH, rt, 10 min
TMS
Me
SO2NHEt
50% aq. KOH18-crown-6CH2Cl2
Br (equiv) Me
SO2N
EtGrubbs I (10 mol %)0.002 M CH2Cl2
Me
NEtSO O
OO O
Toluene80°C, 2h
Me
NEtSO O
O
O
O
H
(86%) (84%)
(63%)
(40%)
(61%)
Enantioselective Functionalization of Ferrocenes Via DoM
41 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686
Entry E+ E Yield (%) ee (%)
1 TMSCl TMS 96 98
2 MeI Me 91 94
3 Et2CO Et2C(OH) 45 99
4 Ph2CO Ph2C(OH) 91 99
5 ClCH2OCH3 CH2OCH3 62 81
6 I2 I 85 96
7 (PhS)2 PhS 90 98
8 (PhSe)2 PhSe 92 93
9 Ph2PCl Ph2P 82 90
10 B(OMe)3 B(OH)2 89 85
N
N
H
H
(-)-sparteine (1.2 equiv) -78°C, Et2O
i) nBuLi (1.2 equiv)
ii) E+
FeCONiPr2
E
FeCONiPr2
Enantioselective Functionalization of Ferrocenes Via DoM
42 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686
Entry E+ E Yield (%) ee (%)
1 TMSCl TMS 96 98
2 MeI Me 91 94
3 Et2CO Et2C(OH) 45 99
4 Ph2CO Ph2C(OH) 91 99
5 ClCH2OCH3 CH2OCH3 62 81
6 I2 I 85 96
7 (PhS)2 PhS 90 98
8 (PhSe)2 PhSe 92 93
9 Ph2PCl Ph2P 82 90
10 B(OMe)3 B(OH)2 89 85
• The (S) absolute configuration was established by single-crystal X-ray crystallographic analysis
• Since the sp2-hybridized ferrocenyl carbanions are configurationally stable, the enantioselective induction must occur at the deprotonation and not the electrophile substitution step
• On this basis, the configurational outcome of the other 1,2-disubstituted ferrocenes was assigned to be S
• The enantiomeric excess was determined by comparison with racemic products generated by deprotonation with nBuLi using chiral HPLC
N
N
H
H
(-)-sparteine (1.2 equiv) -78°C, Et2O
i) nBuLi (1.2 equiv)
ii) E+
FeCONiPr2
E
FeCONiPr2
Enantioselective Functionalization of Ferrocenes Via DoM
43 Snieckus, V. et al. J.Am.Chem.Soc. 1996, 118, 685-686
FeCONiPr2
EE = TMS
i) nBuLi, -78°C, THF
ii) Ph2COFe
CONiPr2
TMS
OH
Ph Ph
(72%)
Pd(PPh3)4 (2 mol %)aq. Na2CO3 (6 equiv)DME, reflux, 48h
B(OH)2
OMeMeO
FeCONiPr2
OMeMeO
+FeCONiPr2
E = I
(31% 96% ee)(67%)(1.6 equiv)
Enantioselective Functionalization of Ferrocenes Via DoM
44 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631
Entry E+ E Yield (%) ee (%)
1 Ph2CO Ph2C(OH) 92 94
2 Et2CO Et2C(OH) 45 91
3 Bu3SnCl Bu3Sn 58 82
4 Ph2PCl Ph2P 53 97
5 (PhS)2 PhS 71 89
6 (PhSe)2 PhSe 82 71
7 I2 I 70 89
8 MeI Me 71 92
N
N
H
H
(-)-sparteine (4.2 equiv) -78°C, Et2O
i) nBuLi (4.2 equiv)
ii) E+ (6 equiv)
FeCONiPr2
E
FeCONiPr2
CONiPr2 CONiPr2
Enantioselective Functionalization of Ferrocenes Via DoM
45 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631
Entry ee 1 (%) R E+ E Yield (%)
dl : meso
ee (%)
1 0 TMS TMSCl TMS 86 51:49 72
2 a TMS TMSCl TMS 75 84:16 91
3 97 Ph2P Ph2PCl Ph2P 45 >95:5 98
4 89 PhS (PhS)2 PhS 60 99:1 97
FeCONiPr2
R
N
N
H
H
(-)-sparteine (4.2 equiv) -78°C, Et2O
i) nBuLi (4.2 equiv)
ii) E+ (6 equiv)
FeCONiPr2
R
FeCONiPr2
CONiPr2 CONiPr2
+
R
E
dl meso
CONiPr2
E
a CSP HPLC enantiomeric resolution was not feasible, [α]23578 +67.5 (c 0.54, CHCl3)
Enantioselective Functionalization of Ferrocenes Via DoM
46 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631
FeCONiPr2
CONiPr2
X
B(OH)2
OMeMeO
PhBr (1.3 equiv)
X = I X = SnnBu3
Pd(PPh3)4 ( 10 mol%)aq. Na2CO3 (6 equiv)DME, reflux, 5 d
(1.6 equiv)
PdCl2(dppf) (30 mol %)CuO (8 equiv)DMF, 150°C, 18 h
FeCONiPr2
CONiPr2
Ph
FeCONiPr2
CONiPr2
FeCONiPr2
CONiPr2
FeCONiPr2
CONiPr2
I
+ +
MeO OMe
(20%, 89% ee) (70%) (35%) (51%)
Enantioselective Functionalization of Ferrocenes Via DoM
47 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631
Ph Ph
OAc
+ CH(CO2Me)2
[Pd(3-C3H5)Cl]2 (2.5 mol%)AcOK (4 mol %)BSA (3 equiv)Dimethyl malonate (3 equiv)DCM, rt, 10h
FeCONiPr2
PPh2
CONiPr2Ph2P
(10 mol%)
Ph Ph
MeO2C CO2Me
(96%, 84% ee (R))
Tsuji-Trost allylation
Applications in asymmetric synthesis
Enantioselective Functionalization of Ferrocenes Via DoM
48 Snieckus, V. et al. Org.Lett. 2000, 2, 5, 629-631
Asymmetric alkylation of benzaldehyde
H
O
+ Et2Zni) 5 mol %
solvent, rt, 2-3 dii) HCl/H2O
FeCONiPr2
R
CONiPr2Et
OH
*
Entry R ee of ligand
Solvent Yield (%) ee (%)
1 Ph2C(OH) 96 Hexane 98 61(S)
2 Ph2C(OH) 96 PhMe 98 12(R)
3 Ph2C(OLi) 95 PhMe 70 47(S)
4 Et2C(OH) 90 Hexane 37 60(S)
5 2,4-di(MeO)Ph 89 PhMe 43 90(S)
Enantioselective Functionalization of Ferrocenes Via DoM
49 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382
Entry E+ E Yield (%) 2
Yield (%) 3
ee (%) 3
1 MeI Me 87 99 96(R)
2 DMF CH2OCH3a 75 80 95(R)
3 TMSCl TMS 69 99 95(R)
4 Ph2PCl Ph2P N.D. 61 N.D.
5 (MeS)2 MeS 89 99 88(R)
6 ICH2CH2I I 72 99 96(R)b
Fe
EtN
O
Ph
Me MeFe
EtN
O
Ph
Me Me
i) 1.2 equiv nBuLi/(-)-sparteine 6:1 Et2O:PhMe/ -78°C
ii) E+
CF3CH2OH
reflux, 5-12 h
E
Fe
NHEt
O
E
1 2a-f 3a-f
a Product aldehyde was reduced with NaBH4 to give the corresponding alcohol, which was methylated using NaH/MeIb Absolute stereochemistry was established by single crystal X-ray analysis
Enantioselective Functionalization of Ferrocenes Via DoM
50 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382
Fe
NHEt
O
TMS i) 2.2 equiv nBuLi/TMEDA THF, -78°C -10°C
ii) I2 (32%)
Fe
NHEt
O
TMS
I
TBAF
THF, rt Fe
NHEt
OI
(89%, 94% ee)
Latent Silicon Protection Route
Enantioselective Functionalization of Ferrocenes Via DoM
51 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382
Fe
NHEt
O
E i) NaH, DMF 0°C rt
ii) R-XFe
EtN
O
IR
1 2a (R = Me, 90%)2b (R = allyl, 77%)
2a (R = Me)
1) BH3SMe2
THF, reflux
2) 10% NaOHreflux(76%)
Fe
EtN
IR
4
(E = I)
2b (R = allyl)
Pd(PPh3)4 (3 mol %)NEt3 (12 equiv)
MeCN, 95°C, 48 h(47%)
Fe
NEt
O
5
i) 2.6 equiv TF2O 6.0 equiv Py -40°C 0°C, 1.5 h
ii) MeOH, rt, 12 hiii) NH4Cl
Fe
E
3a-c
CO2Me
Entry E Yield (%) ee (%)
1 Me 50(92) 96
2 TMS 49(92) 93
3 I 26(94) 96
Enantioselective Functionalization of Ferrocenes Via DoM
52 Snieckus, V. et al. Adv.Synth.Catal. 2003, 345, 370-382
Fe
EtN
O
Ph
Me Me Fe
EtN
O
Ph
Me Me
i) nBuLi/(-)-sparteine (1.2 equiv) 6:1 Et2O:PhMe/ -78°C
ii) DMF
CHO1) TMSCH2MgCl (2.5 equiv.) Et2O, rt
2) NH4Cl3) NaH, THF, reflux
Fe
EtN
O
Ph
Me Me
1) CF3CH2OH reflux, 10.5 h
2) NaH, DMF3) Allyl bromide
(89 %) (61 %) (90%)
Fe
NEt
O
1) Grubbs I (16 mol %) CH2Cl2, reflux
2) Pd/C/H2 MeOH (73%, 91% ee)
Fe
NEt
O
i) sBuLi (1.2 equiv) TMEDA 1:1 Et2O: THF, -78°C
ii) Ph2PCl (87%)
Fe
NEt
OPPh2
Conclusion
53
• Thinking beyond thermodynamic acidity leads to new synthetic methodologies for remote functionalization
• CIPE provides a heuristic model to discover new modes of C-H activation
• The involvement of CIPE in directed ortho and remote metallation allows the synthesis of complex aromatic systems with ease
• Combination of several methodologies to DoM and DreM expands the versatility of this synthetic strategy