Baran Lab

Properties of Silicon
Siliconium Ion

Hafensteiner

Si vs. C - Si is less electronegative than C

- More facile nucleophilic addition at Si center

- Not believed to exist in any reaction in solution

J. Y. Corey, J. Am. Chem. Soc. 1975, 97, 3237

- Pentacoordinate Si compounds have been observed

Average BDE (kcal/mol)

CC 83 CSi 76 CO 86 SiSi 53 SiO 108 CH 83 CF 116 SiF 135 SiH 76

MeSiF4 NEt4

Ph3SiF2 NR4

- Lack of cation justified by high rate of bimolecular reactivity at Si

Mechanism of TMS Deprotection

OTMS O

Average Bond Lengths ()

CC 1.54 CSi 1.87 CO 1.43 SiO 1.66

Workup
O

Silicon forms weak p-Bonds

p - CC = 65 kcal/mol p - CSi = 36 kcal/mol

Si
F NBu4

Si

Pentavalent Silicon

Baran Lab
Nucleophilic addition to Si
ROSiMe3 F RO

Properties of Silicon
b-Silicon effect and Solvolysis
FSiMe3 Me3C SiMe3 H H Me-SiMe3 A kA / kB = 2.4 x 1012 H Me3C H H SiMe3 vs. Me3C H vs. Me3C

Hafensteiner

Me H H B H

OSiMe3

O MeLi

Li

OCOCF3

OCOCF3

Duhamel et al. J. Org. Chem. 1996, 61, 2232

H H H Me

b-Silicon Effect
- Silicon stabalizes b-carbocations - Stabalization is a result of hyperconjugation SiR3 vs. CR3

OCOCF3 kA / kB = 4 x 104

OCOCF3

Evidence for Stepwise mechanism Me3Si SiMe2Ph SiMe2Ph

Me3Si

SiMe2Ph

*A is more stable than B by 38 kcal/mol *

Jorgensen, JACS, 1986,107, 1496

Me3Si

SiMe2Ph

Me3Si

Product ratios are equal from either starting material suggesting common intermediate cation

Baran Lab

Properties of Silicon
Extraordinary Metallation
SiMe3 SnCl4 Cl OMe vs. OMe Me3Si Cl

Hafensteiner

Evidence for Rapid Nucleophilic Attack

SiMe3

Me

t-BuLi

Li Me2Si Cl

Si Me SiMe3

MeO OMe

Me2Si Cl
Gornowicz et al., J. Am. Chem. Soc. 1968, 90, 4478

SnCl4 MeO OMe OMe

Cl OMe

Cation-Anion Harmony
- Stabalization of a-anion and b-cation exemplified in regioselectivity of the hydroboration of alkynlsilanes
SiMe3 dSiR3 R H BR2

Fleming et al., JCS Chem. Com. 1976, 182

Organosilanes Stabilize CM Bonds

- Metallation occurs a to silicon - Hyperconjugation gives stability

SiMe3

R2BH

R d+

BR H d+ 2 d-

Zweifel et al., J. Am. Chem. Soc. 1977, 99, 3184

Me Me Me

M Si R R

Baran Lab
Silicon Migration

Allylic and Vinylsilanes

Vinylsilane Reactivity

Hafensteiner

- Conjugate addition can be followed by Si migration - Migration aptitude enhanced when Si has bulky R groups

O Me TiCl4 (i-Pr)3Si CH2Cl2 (i-Pr)3Si

Me

- React with electrophiles - Regioselectivity governed by creation of b-carbocation - Elimination of SiR3 occurs with retention of initial double bond geometry due to principle of least motion - Limited rotation also prevents eclipsing interactions between silyl group and olefin substituents

Vinylsilane Examples
Et TiCl4 Et Et OMe OMe

OTiCl4 Me Si(i-Pr)3
A. I. Meyers, J. Org. Chem. 1998, 63, 5517

OTiCl4 Me Si(i-Pr)3

Et

SiMe3

ClCH(OMe)2

N H

NH SiMe3 Me

(CH2O)n TsOH N H

MeO2C Ar

CO2Me

R(i-Pr)2Si

MeO2C ZrCl4 MeO C 2 CH2Cl2 Ar

SiR3

Grieco et al. J. Chem. Soc. Chem. Comm., 1987, 185

R = i-Pr, Ph diasteromeric ratio 96:4, ~ 70% yeild

Reactions with Silicon

Sakurai Reaction - Lewis acid catalzed addition of allysilanes to aldehydes and acetals Me3Si MeO OMe TiCl4 80% TiCl4 83% OMe Examples of Addition to Carbonyls O R H Me3Si Me TiCl4 CH2Cl2 TiCl4 Me CH2Cl2 R Me OH R Me ~65 : O Me Me3Si OTiCl4 Me Me3Si
Fleming, Org. Reactions 1989, 37, 127-133

OH >95:5 syn:anti OH R Me 35

n-C4H9

n-C4H9
O OMe R H Me3Si

Me3Si MeO

OMe

n-C4H9

n-C4H9

Hyashi, Tett. Lett. 1983, 2865.

Intramolecular Sakurai Reaction O R H TMS OTMS R LA H O H H ene reaction H R O TMS OTMS R H R OH O R H H R O H TMS OTMS TMS OTMS

Conjugate Addition O Me

BF3Et2O cat.

75 % Me Me3Si O

RCHO

17 % Me

Me O

SiMe3 EtAlCl2 CH2Cl2 78% O

Mark et al. Tett. Lett.,1992, 33, 1799

Majetich, Tetrahedron 1987, 43, 5621

Baran Lab

Brook Rearrangement
O R SiR3 Li (CH2)4 I

Hafensteiner

Pioneering Work By A. G. Brook

- Rearrangement of organosilyl alcohols under base catalysis - Retention at silicon and inversion at carbon R3Si OH Ph Ph Et2NH R3Si O Ph Ph H H N
Brook, Accts. Chem. Res. 1974, 7, 77-84

- Brook rearrangement can be used to access homoallylic enolate anions O R

Et2NH DMSO

Ph SiR3 Ph O H

Reich, J. Am. Chem. Soc. 1980, 102, 1423

O SiR3 R3Si Ph Ph H N O H LiO PhS R3Si R OLi R PhS O E R O R3Si R SiR3 O SiR3 R PhS

OSiR3 OLi R PhS R OLi

OSiR3 [1,2] PhS O R

Examples of Brook Rearrangement

O R SiR3 Li R1 El

Takeda, J. Am. Chem. Soc. 1993, 115, 9351 Takeda, Synlett. 1994, 178 Takeda, Synlett. 1997, 255

OSiR3 OLi PhS R R OLi

Moser, Tet. 2001, 57, 2065-2084

Moser, Tett. 2001, 57, 2065-2084

Baran Lab
Pioneering Work By Peterson

Peterson Olefination
O H O H OMe OMe H H 1. TMS Li

Hafensteiner

- Investigation aimed at finding a silicon analog to phosphorous ylides - Same cyclic four-membered transition state can be envisioned O R3Si M R R1 R3Si OM R R1

TMS O H H O H H

OMe

2. SiO2, benzene

OM R3Si R1 R

R3Si

H O R R1 H O H H 1. H2Rh-Al2O3 2. BF3Et2O

TMS O H H O H H

OMe

Peterson, J. Org. Chem. 1968, 33, 780-784

LA - Mg alkoxides are stable and do not breakdown to give olefin product - Li, Na, and K alkoxides are reactive and breakdown to give olefin product - b-silyl-alcohols can be converted to olefins with dilute acid OH R3Si R R 10% H2SO4 RT OH O TMS BF3Et2O, MeOH OH O TMS

MeOH

R R R3Si

OH

OH OMe

OH OH SiMe3 OMe

Whitmore et al., J. Am. Chem. Soc. 1947, 69, 1551 Ager, Org. Reactions 1990, 38, 1.

Tamao Oxidation
Tamao Oxidation
- Conversion of organosilanes to corresponding alcohols - Pioneered by Tamao in 1984 (Tett. Lett. 1984, 25, 4249) O CH2MgBr Me2Si CuI cat. O Si Me2 KHF2 TFA O 30% H2O2 OH 68% overall - Other substrates used and in all cases no Bayer-Villager seen O O O NaHCO3 F Si Me2 O RSiMe2Tol-p
Yoshida et al. J. Org. Chem. 1999, 64, 8709

Representative Silanes

RMe2Si

RMe2Si

RMe2Si

RMe2Si MeO

RMe2Si

SPh

RMe2Si

SPh

RSiPh3

Synthetic Example

1. BF3AcOH Me2Si O Ph Ph N O 2. 35% H2O2 NaHCO3 95% HO Ph N O

Weinreb et al. J. Org. Chem. 2002, 67, 4339

Baran Lab
Brook Rearrangement

Silicon in Synthesis
Cyanthin Tricyclic Core
O Me dysidiolide SiMe2Ph MeO OLi

Hafensteiner

PhMe2SiO Me OMe i-Pr O

i-Pr
HO HO O O OTBS O O O TBDPSO OH 1. BF3, 78C 2. PPTS, EtOH Me 6 steps Product H TBDPSO
Corey, Roberts, J. Am. Chem. Soc. 1997, 119, 12425 - 12431

0 C to rt 47%

PhMe2Si Me

OLi O OMe

PhMe2SiO Me O OMe

13 Steps

TMS OH

i-Pr
H

i-Pr

O OLi TBS TMS Me O OTBS SiMe3 i-Pr

i-Pr

80 C to 0 C 60%

Takeda et al. Org Lett. 2000, 2, 1907

Baran Lab
Brook Rearrangement
(+)-onocerin

Silicon in Synthesis
H OH TfO TMSCH2ZnBr OTf HO H Li O Pd(PPh3)4 O

Hafensteiner

O TMS

TMS O 1. MeAlCl2 15 min 2. TBAF

O O

TBS

Li -78 C O

OTBS

OH

0.5 equiv I2 O TfO OTf O CsF PhNTf2 O TBSO OTBS - Properties of silicon exploited - b-carbocation stabalization - a-anion stability O

HO

Mi, Schreiber, Corey, J. Am. Chem. Soc. 2002, 124, 11290-11291

Baran Lab
(+)-Tetronomycin
OH H H O H

Silicon in Synthesis
- Stabalization of b-cation MeO MeO HOH OMe R O O O
1 OH R

Hafensteiner

OH

OTBDPS

+MeO

OH

OTBDPS

OH H O H H R TMS H O H SiMe3 O H R1

- Key coupling step in convergent synthesis uses allysilane coupling reaction

OMe

H H PivO O H MeO TMS PivO OH OTBDPS OH H O OH H

OH

OTBDPS

BF3Et2O, 92%

HOH

OMe

OH OTBDPS H O O O

H PivO

Yoshi et al. J. Org. Chem. 1992, 57, 2888

Baran Lab

Silicon in Synthesis
O H TMS H D CO2Et 97% H H CO2Et 1. LiAlH4 2. PDC 72%, 2 steps TMS TMS Me3SI, NaH DMSO 60% O H HH H O 5% KOH 40%

Hafensteiner

()-Hirsutene
TMS

O H H H

1. H2 / Pt / C 2.

Sarkar et al. Tett. Lett., 1990, 31, 3461

()-Sarain A Core Scaffold

H 1. TiCl4 2. PCC 53% H

O N O H O HO O N OH Sarain A

PdCl2, CuCl O O2 76%

Silicon in Synthesis
()-Sarain A Core Scaffold
O O BnN OTHP 65% O NBn O BnN 1. o-DCB, 320 C 2. TsOH, MeOH 70%, 2 steps O BnN H Bn N H H OH H C H 4 9 NCO2Bn O TMS Li H 38% Al(i-Bu)2Me N Bn N

(+)-Pumiliotoxin A
OTHP H O C4H9 1. ()-pinene, 9-BBN 2. MeLi; TMSCl; HCl 3. ClCO2Me 4. MeMgBr; CuI 35%, 4 steps TMS H C4H9 Dibal-H; MeLi H C H 4 9 TMS Li H Al(i-Bu)2Me

O BnN

H Bn N H H

1. Swern [O] 2. MgBr 3. Ac2O, TEA, DMAP 4. (TMS)2CNLi2Cu 27%, 4 steps

O O TMS C4H9 KOH, MeOH H2O 80%

TMS 1. Na, NH3, t-BuOH 2. LHMDS, TsCl, DMAP 3. Dibal-H 62%, 3 steps OH H Bn N TsN H H TsN TMS
Weinreb et al., J. Org. Chem., 1991, 56, 3210

H NBn N HO

C4H9 (CH2O)n CSA HO NH

TMS C4H9

Overman et al., J. Org. Chem., 1985, 50, 3670

Baran Lab
Prostoglandins

Silicon in Synthesis

Hafensteiner

- Fleming contributed greatly to the field of organosilicon chemistry TMS O 05C Cl Cl 70% TMS O Cl Cl MeO2C OAc 1. O3 2. Me2S 47%, 2 steps O

OH OAc CO2Me

MeOCH2Cl SnCl4 78% O MeO 1. H2O2AcOH O 2. ZnAcOHH2O 62%, 2 steps MeO O Cl Cl

Fleming, J. Chem. Soc. Chem. Comm., 1977, 79 - 80 Fleming, J. Chem. Soc. Chem. Comm., 1977, 81

()-Linaridial
TMS TiCl4 ClCH2SMe 77% H

Loganin
TMS O Cl Cl ClSO2NCO 1. NaNO2, Ac2O OAc MeO2C 2. NaOAc 3. CH2N2 61%, 4 steps OAc ClO2SN OTMS H OH TMS OAc O

SMe 1. Raney Ni 2. CH2Br2, Zn, TiCl4 H

1. KNH(CH2)3NH2 2. Hydroboration/ [O]

Baran Lab
()-Linaridial
OH H 1. Swern [O] 2. NaH CN OMe (OEt)2P O OMe

Silicon in Synthesis
CN OMe OMe H O 1. O3; Zn / HCl 2. Wittig Ph3P 1. Dibal-H 2. 1M HCl, THF CHO CHO H 2 : 1 TMS 50% O O

Hafensteiner

TMS

EtAlCl2 53% O

Tokoroyama et al. Tett. Lett., 1987, 28, 6645

()-a-Acoradiene
O Li O O P(OMe)2 61% O
Yamamoto et al. J. Org. Chem., 1990, 55, 3971

Baran Lab
Hydrosilation

Hydrosilation
Reduction with Silanes

Hafensteiner

- Metal and radical catalyzed addition to alkenes and alkynes - Metal catalysis is done at room temperature and best yields obtained with trichloro and methyldichlorosilanes - Addition of methyl grignard converts chlorosilanes to TMS H Cl3SiH SiCl3 R R H2PtCl6 H Cl3SiH Cl3Si R R H2PtCl6
Chalk; Harrod; J. Am. Chem. Soc. 1965, 87, 16

- Catalysis needed for convenient rates - Catalysts include TBAF, protic and Lewis acids, Wilkinson's cat, silatrane O O H Si N OO HO H

Attar-Bashi et al. Organometallic Chem. 1976, 117, C87

Silanes and Dehalogenation

- Organohalides can be reduced with various organosilanes - Radical mechanism of hydrodehalogenation - Reactivity of halide I > Br > Cl > F - Reactions are fast and clean often giving quantitative yields -Common Silanes S(i-Pr) H Si (i-Pr)S S(i-Pr) SMe H Si MeS SMe Et Si Et H Et

-Cr(CO)6 with light gives 1,4 reduction of dienes

Germanes and Dehalogenation

- Organohalides can also be reduced with various organogermanes - Can be used catalytically with PPh3 for reduction of CX bond - Reactivity of halide I > Br > Cl > F - Solid support methods can be used - Similar reactivity to silanes - Furanylgermane reduces CX bond under mild conditions -"Common" Germanes GeCl2PPh3 O GeH 3 P (CH2)nEt2GeH

- Common Radical Intiators AIBN Dibenzoylperoxide

- Phenylsilane is also used - Reactions with phenylsilane are refluxed neat with a radical initiator