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Silyl Anions in Organic Synthesis Christopher Clark Scheidt Group March 23, 2004
Transcript of Silyl Anions in Organic Synthesis › ... › 032304_ClarkSilylAnion.pdfSilyl Anions in Organic...
Silyl Anions in OrganicSynthesis
Christopher ClarkScheidt Group
March 23, 2004
"Normal" thoughts about silicon in organic synthesis
Protecting Groups
O
RR
SiMe3
R R
OH MeSiMe
MeCl
R NH2Cl O
OSiMe3 N
HO
OSiMe3
Allylation Agents
Cl3SiR H
O
R
OH
Lewis AcidsTrapping Reagents
O
R2CuLiMe3SiCl
OSiMe3
R
CO2CH3 Me3SiOTf CO2CH3
R
All of these utilize electrophilic character on the silicon
What about silyl anions? What can they do for YOU?Silyl anions can be roughly catagorized as synthetically useful and not-yet-synthetically useful
Synthetically useful silyl anions:
Me3SiLi HMPA complex
Si LiMe
Me
Si LiMe
Me
OMe
(RMe2Si)2CuCNLi2R = Ph, o-anisyl, furyl, Me
Ph3SiLi
Ph2MeSiLi
Other silyl anions:
SiKK
Si LiEtN
EtN
Compounds like these are interesting in terms of their physical properites, but have not found much use yet in organic synthesis due to difficulties in preparation.
Generation of early silyl anions
PhSiPh
PhH2N
Me
Li PhSiPh
PhLi Ph3Si SnMe3
NaPh Si NaPh
PhMe3SnNa
Kraus, C. A., Eatough, H. J. Am. Chem. Soc. 1933, 55, 5008
SiEt
EtEt
GePhPh
PhSi LiEt
Et
EtLi Ge Ph
Ph
PhKraus, C. A., Nelson, W. K. J. Am. Chem. Soc. 1934, 56, 195
PhMe
MeSi
PhPh
PhNa/KEther
MePh
MeK
PhSiPh
PhK
Benkeser, R. A., Severson, R. G. J. Am. Chem. Soc. 1951, 73, 1424
Si SiPh
PhPh
PhPh
PhNa/KEther 2 Si K
Ph
PhPh
LiEtNH2
Gilman, H., Wu, T. C., J. Am. Chem. Soc. 1951, 73, 4031
Improvements on early silyl anions by Gilman
Na/K is not an ideal reagent in any reaction, if it can be avoided, and lithium in THF also cleaves disilanes
Gilman, H. and Lichtenwalter, G. D., J. Am. Chem. Soc. 1958, 80, 608
Ph Si SiPh
Ph
Ph
PhPh Li
THF 2 Ph SiPh
PhLi
Si SiPh
Ph Ph
PhMeMe Li
THF 2 Me SiPh
PhLi
Ph Si SiMe
Me
Me
MePh Li
THF 2 Ph SiMe
MeLi
Proof of silyllithium formation used by Gilman and coworkers
Ph SiPh
PhLi Me Si
Me
MeCl Ph Si Si
Ph
Ph
Me
MeMe
What about TMSLi?
Hexamethyldisilane will not cleave in the presence of an alkali metal, so other procedures must be employed
Si SiMe
MeMe
Me
MeMe 2 Si Li
Me
MeMeLi
THF
Me3SiBr Na/Hg SiMe
MeMe Hg Si
Me
MeMe Li 2 Si Li
Me
MeMe Hg
Drawback: Need to use mercury
Hengge, E., Holtschmidt, N. J. Organomet. Chem. 1968, 12, P5
Si SiMe
MeMe
Me
MeMe MeLi
HMPA Si LiMe
MeMe Si Me
Me
MeMe
Drawback: Need to use HMPA PO
NMe2NMe2Me2N
Still, W. C., JOC, 1976, 41, 3063
Great, so I can make and fragment disilanes. Is this really useful?Yes! These TMSLi can be added to organic coumpounds much like organocuprate reagents
O
Me
MeMe
TMSLi, HMPAEt2O, –20 oC
OHSiMe3
Me
MeMe
Still, W. C., JOC, 1976, 41, 3063
O
TMSLi, HMPATHF, –78 oC
OLi
SiMe3
MeOH
TMSCl
MeI
O
SiMe3
OSiMe3
SiMe3
O
SiMe3
Me
99%
99%
97%
Utility of aryl groups on silicon for synthesis
Tamao-Fleming oxidation
R1 R2
SiMe2X
X = F, Cl, Br, OR
KF, HOOHor
MCPBA if X = F R1 R2
OH
100% retention
Brook rearrangement
R1 R2
OH
SiR3
BaseR1 R2
OSiR3
H
Aryl groups on silicon speed up this process greatly
Useful for umpolung processes
Aryl groups can be removed from silicon underacidic conditions
Phenyldimethylsilyl group can be thought of as amasked hydroxyl group
NMR studies of silyl anion stucture
Olah, G. A., Hunadi, R. J. J. Am. Chem. Soc. 1980, 102, 6989Buncel, E., Venkatachalam, T. K., Eiasson, B., Edlund, U. J. Am. Chem. Soc. 1985, 107, 303
How is charge delocalized in phenylated silyl anions?
C Li
H Li
For correspoding carbanions, there is a substantialresonance stabliization as can be seen in 13C NMR
Si Li
Si
H Li
For the silyl anions, this charge delocalization isreduced by a factor of four to ten.
Si Li Si Li
δ+
δδ+
δδ−δ−
Instead, one sees π-polarization of the phenyl rings, which results in a stabilization of the negative charge on silicon. Resonance stabilization would put partial negative charge on the ortho carbon and partial positive charge on the meta cabon on the phenyl rings. The opposite is observed by 13C NMR.
Silyl cuprates as improved silyl anions (Fleming's reagent)
Ager, D. J., Fleming, I., Patel, S. K. J. Chem. Soc., Perkin Trans. 1. 1981, 2520
Si Cl
Me
MeLi
THF Si Li
Me
Me0.5 eq. CuX
(PhMe2Si)2CuXLi2
This reagent is much more reactive for conjugate additions than the silyllithium
O
COOCH3
(PhMe2Si)2CuILi2
OCu
COOCH3PhMe2Si
MeI
O
COOCH3PhMe2Si
Me
In addition, it is much more tolerant of various funtionalities
X= I, CN
O
MeMe
Me
(PhMe2Si)2CuILi2THF, -23 oC, 4 hr
68%
O
MeMe
MeSiMe2Ph
Phenyldimethylsilyl groups as α,β-unsaturation of ketone protecting groups
Ager, D. J., Fleming, I., Patel, S. K. J. Chem. Soc., Perkin Trans. 1. 1981, 2520
Application to the syntheses of carvone and jasmone
O
COOCH3PhMe2Si
MeEthylene glycol
TsOH, 95%COOCH3PhMe2Si
MeOO
1. MeLi2. H3O+
88%O
Me
Me
MeOH
PhMe2Si
CuBr2, (PhCO2)2
72%
O
Me
MeOH
Me
1. Ac2O2. FVP
O
Me
Me
Carvone
O
Me
(PhMe2Si)2CuLi
O
Me
SiMe2Ph
TMSClTEA, 82%
OSiMe3
Me
SiMe2Ph
1. BuCHO, TiCl42. TsOH, PhH 76%
O
Me
SiMe2PhBu
H2, Pd/C99%
O
Me
SiMe2Ph
pentylPhNMe3Br3
91%
O
Me
pentyl
Jasmone
Limitations of the Tamao-Fleming OxidationDesilylation of the phenyl group can be problematic
R1 R2
Si MeMe H+ or Br2
R1 R2
Si MeMeBr or H H
X-
R1 R2
Si MeMeBr or H H
XR1 R2
Si MeMe
The T-F oxidation requires a heteroatom on the silicon to proceed. The easiest way todo this is either to protonate or brominate the phenyl group off the silicon
Standard conditions (and their problems):
1. AlCl3, HCl (g). This is very incompatible with acid-sensitive functionality and inconvenient.
2. HF gas. Also incompatible with acid-sensitive functionality, and using HF gas is very dangerous!
3. HBF4 diethyl ether complex. Also incompatible with acid-sensitive functionality.
4. Bromine. Incompatible with olefins in the substrate.
X
Proposed (but unsuccessful) improvements in silyl anions
Include electron-donating functional groups on the phenyl ring?
Rahman, N. A., Fleming, I., Zwicky, A. B. J. Chem. Res., Miniprint 1992, 2401
Si
Me
Me
ClRO Li, THF0 oC
SiRO
Me
Me
Si
Me
Me
OR
R = Me, 10%R = i-Pr, 72%
Li, THF0% Si
Me
Me
LiRO
Methyl phenyl ethers are reduced to phenoxides under these conditions, but the reasons why lithium will not reduce these
disilanes is unclear. What about other electron donating groups?
Me Si
Me
Me
Cl Li, THF0 oC
Me Si
Me
Me
Si
Me
Me
Me Li, THFreflux
Me Si
Me
Me
HO
90%
OMe
Si
Me
Me
Cl Li, THF0%
OMe
Si
Me
Me
Si
Me
Me
O Me
Improvements by Corey
Lee, T. W., Corey, E. J. Org. Lett. 2001, 3, 3337
OMe
Li
Cl Si Si
Me
Me
Me
Me
Cl
THF, 93%Si Si
Me
Me
Me
Me
OMe MeOMeLi
4:1 THF-HMPA0.15 M
-50 oC, 5h
Si
Me
Me
OMe
Li
Other anions made by this procedure:
Si
Me
Me
Li
Me
Me
Si
Me
Me
Li
Me
Me
OMe
Si
Me
Me
Li
These anions are unstable at temperatures above -30 oC, but the cuprates are stable at 0 oC, meaning they can be used in synthesis effectively
Reactions with Corey's improved silanes
Lee, T. W., Corey, E. J. Org. Lett. 2001, 3, 3337
Si
Me
Me
OMe
CuCNLi2
2
Me
Me
Me
OBz
Me
Me
Me
Si
Me Me
MeO
-50 oC, 16 h80%
Me OBz
Si
Me
Me
OMe
CuCNLi2
2
-50 oC, 10 h72%
Si
Me Me
MeO
Me
OSi
Me
Me
OMe
CuCNLi2
2
-50 oC, 20 min80%
O
Si
Me
MeOMe
Tamao-Fleming oxidation using Corey's silanes
Lee, T. W., Corey, E. J. Org. Lett. 2001, 3, 3337
Ph Si
Me Me
MeO
1.2 eq NBSTHF, 23 oC2.5h
Ph Si
Me Me
Br
2.5 eq TFATHF, 23 oC3.5h
Ph Si
Me Me
OCOCF3
KF, KHCO3,H2O2, THF-MeOH23 oC, 18h, 72% overall
Ph OH
KF, KHCO3,H2O2, THF-MeOH23 oC, 12h, 80% overall
Application of Corey's silanes to total synthesis
MeMe
MeO
COOCH3
Eunicinone A
RMe
R = E,E-farnesyl
OBz Si Si
Me
Me
Me
Me
OMe MeO
MeLi, CuCNHMPA-THF-50 oC, 70%
RMe
Si
Me Me
MeO
NB
OO O
HS
OO
tol
HMe
HN
50 mol%
2-bromoacrolein, CH2Cl2-78 oC, 85% y, 97% ee
endo:exo >98:2
RMe
Si
Me Me
MeO
BrCHO
1. NaBH4
2. NaOMe
RMe
Si
Me Me
MeO
O
1. 3 N LiOH2. TFA, CH2Cl2; KF, KHCO3
HOOH, THF3. cat. CSA, THF 62%
OMe
OMe
RMe
OH
OO
Lee, T. W., Corey, E. J. J. Am. Chem. Soc. 2001, 123, 1872
Me
MeHO
Conclusions
• Silyl anions can be effectively used in the synthesis of complex naturalproducts, as seen by the work of Fleming and Corey.
• The utility of the phenyldimethylsilyl group as a masked hydroxyl grouphas only begun to be explored with the advent of better silyl groups.
• Silyl anions can be synthesized easily in the lab, but the need forHMPA in the synthesis of more interesting anions limits the use of thismethodology on the industrial scale.
