Baran Lab Properties of Silicon Hafensteiner

Si vs. C Siliconium Ion - Si is less electronegative than C - Not believed to exist in any reaction in solution - More facile nucleophilic addition at Si center J. Y. Corey, J. Am. Chem. Soc. 1975, 97, 3237

- Pentacoordinate Si compounds have been observed Average BDE (kcal/mol) MeSiF4 NEt4 Ph3SiF2 NR4 C–C C–Si Si–Si C–F Si–F 83 76 53 116 135 - Lack of cation justified by high rate of bimolecular reactivity at Si C–O Si–O C–H Si–H Mechanism of TMS Deprotection 86 108 83 76 OTMS O

Average Bond Lengths (Å) C–C C–Si C–O Si–O 1.54 1.87 1.43 1.66 Workup

Si Si Silicon forms weak p-Bonds O O F F NBu4 p - C–C = 65 kcal/mol p - C–Si = 36 kcal/mol Pentavalent Silicon Baran Lab Properties of Silicon Hafensteiner

Nucleophilic addition to Si b-Silicon effect and Solvolysis F RO–SiMe3 RO F–SiMe3 SiMe3 Me H H vs. Me3C H Me3C H OSiMe O Li 3 H OCOCF H OCOCF MeLi 3 3 A B Me-SiMe3 12 kA / kB = 2.4 x 10 Duhamel et al. J. Org. Chem. 1996, 61, 2232 H H SiMe Me b-Silicon Effect 3 vs. Me3C H Me3C H

- Silicon stabalizes b-carbocations H OCOCF3 H OCOCF3 - Stabalization is a result of hyperconjugation 4 kA / kB = 4 x 10

SiR3 CR3 Evidence for Stepwise mechanism vs. Me3Si SiMe2Ph SiMe2Ph

A B Me3Si SiMe2Ph

*A is more stable than B by 38 kcal/mol * Me3Si SiMe2Ph Me3Si Jorgensen, JACS, 1986,107, 1496 Product ratios are equal from either starting material suggesting common intermediate cation Baran Lab Properties of Silicon Hafensteiner

Evidence for Rapid Nucleophilic Attack Extraordinary Metallation

Me SiMe3 SiMe3 Li Si t-BuLi Me SnCl4 Cl Me3Si Cl Me2Si Cl SiMe MeO OMe 3 OMe OMe Me2Si Cl vs. Gornowicz et al., J. Am. Chem. Soc. 1968, 90, 4478

SnCl 4 Cl Cation-Anion Harmony - Stabalization of a-anion and b-cation exemplified in MeO OMe OMe OMe regioselectivity of the hydroboration of alkynlsilanes Fleming et al., JCS Chem. Com. 1976, 182

SiMe3 SiR3 R BH - Organosilanes Stabilize C–M Bonds R SiMe 2 R d R 3 + BR2 - Metallation occurs a to silicon d BR H + 2 H - Hyperconjugation gives stability d- d

Zweifel et al., J. Am. Chem. Soc. 1977, 99, 3184 Me M Me Si R Me R Baran Lab Allylic and Vinylsilanes Hafensteiner

Silicon Migration Vinylsilane Reactivity - Conjugate addition can be followed by Si migration - React with electrophiles - Migration aptitude enhanced when Si has bulky R groups - 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 O Me O silyl group and olefin substituents TiCl Me 4 (i-Pr)3Si (i-Pr)3Si Vinylsilane Examples CH2Cl2

TiCl Et Et 4 Et OMe Et ClCH(OMe)2 SiMe OTiCl4 OTiCl4 3 OMe Me Me

Si(i-Pr)3 Si(i-Pr)3 (CH O) NH 2 n N SiMe3 A. I. Meyers, J. Org. Chem. 1998, 63, 5517 N N H TsOH H Me MeO C MeO C CO Me 2 Grieco et al. J. Chem. Soc. Chem. Comm., 1987, 185 2 2 ZrCl4 MeO C SiR3 R(i-Pr)2Si 2 Ar CH2Cl2 Ar R = i-Pr, Ph diasteromeric ratio 96:4, ~ 70% yeild Reactions with Silicon

Sakurai Reaction Examples of Addition to Carbonyls - Lewis acid catalzed addition of allysilanes to aldehydes and OH O acetals TiCl4 >95:5 Me3Si Me R OMe R H syn:anti OMe TiCl CH2Cl2 Me Me3Si 4 n-C H MeO n-C4H9 4 9 80% OH OH O Me Si TiCl4 3 R R R H OMe OMe CH Cl Me3Si TiCl4 Me 2 2 Me Me MeO n-C H n-C H 4 9 83% 4 9 Hyashi, Tett. Lett. 1983, 2865. ~65 : 35 Intramolecular Sakurai Reaction Conjugate Addition O H TMS O TMS OTMS OTMS O Me R H R H BF •Et O cat. O Me Si 3 2 LA H Me 3 75 % ene reaction OTiCl 4 Me O Me Me Si TMS TMS 3 H RCHO H Me3Si OTMS OTMS R R H O O 17 % R Fleming, Org. Reactions 1989, 37, 127-133 H Me SiMe3 Me OH EtAlCl2 R O O O R H CH2Cl2 78%

Markó et al. Tett. Lett.,1992, 33, 1799 Majetich, Tetrahedron 1987, 43, 5621 Baran Lab Brook Rearrangement Hafensteiner

Pioneering Work By A. G. Brook - Brook rearrangement can be used to access homoallylic enolate anions - Rearrangement of organosilyl alcohols under base catalysis - Retention at silicon and inversion at carbon O O Li (CH2)4 I R SiR3 R3Si Et NH Ph SiR R 2 Ph 3 Ph OH O Reich, J. Am. Chem. Soc. 1980, 102, 1423 Ph DMSO H OSiR O 3 Et2NH OLi SiR3 R Si R OLi 3 PhS PhS R R3Si Ph O Ph O Ph Ph H H H H N OSiR N LiO SiR3 3 [1,2]

Brook, Accts. Chem. Res. 1974, 7, 77-84 PhS O R PhS O R Examples of Brook Rearrangement Takeda, J. Am. Chem. Soc. 1993, 115, 9351 R Si O El 3 O E Takeda, Synlett. 1994, 178 R1 Takeda, Synlett. 1997, 255 Li R SiR3 R R OSiR3 O OLi OLi SiR3 PhS OLi R3Si R R PhS R R Moser, Tett. 2001, 57, 2065-2084 Moser, Tet. 2001, 57, 2065-2084 Baran Lab Peterson Olefination Hafensteiner

Pioneering Work By Peterson TMS H - Investigation aimed at finding a silicon analog to phosphorous H OMe O O OMe TMS OMe ylides H H H H - Same cyclic four-membered transition state can be envisioned 1. Li O H O H 2. SiO , benzene O R 2 R Si M R Si 3 R R1 3 OM R1

TMS H H O O OM O OMe R Si R3Si R H H H H 3 R 1 1. H2·Rh-Al2O3 R1 R O H O H 2. BF3·Et2O Peterson, J. Org. Chem. 1968, 33, 780-784 LA - Mg alkoxides are stable and do not breakdown to give olefin OH OH O O product TMS BF3•Et2O, TMS - Li, Na, and K alkoxides are reactive and breakdown to give olefin product MeOH MeOH - b-silyl-alcohols can be converted to olefins with dilute acid

OH 10% H2SO4 OH R OH OH R3Si OH R R3Si OMe R RT R SiMe3 OMe Whitmore et al., J. Am. Chem. Soc. 1947, 69, 1551 Ager, Org. Reactions 1990, 38, 1. Tamao Oxidation

Tamao Oxidation Representative Silanes - Conversion of organosilanes to corresponding alcohols - Pioneered by Tamao in 1984 (Tett. Lett. 1984, 25, 4249)

CH MgBr O 2 O Me2Si RMe2Si O RMe2Si O RMe2Si S

CuI cat. Si Me2

RMe2Si N KHF2 RMe Si SPh RMe Si SPh TFA MeO 2 2

O O 30% H2O2 F RSiMe2Tol-p RSiPh3 OH Si NaHCO3 Me2 Yoshida et al. J. Org. Chem. 1999, 64, 8709 68% overall

- Other substrates used and in all cases no Bayer-Villager Synthetic Example seen O O O

1. BF3·AcOH Me Si HO 2 N N 2. 35% H2O2 NaHCO Ph O 3 Ph O O 95%

Ph Weinreb et al. J. Org. Chem. 2002, 67, 4339 Baran Lab Silicon in Synthesis Hafensteiner

Brook Rearrangement Cyanthin Tricyclic Core

O PhMe2SiO

SiMe2Ph Me MeO OLi Me O

dysidiolide 0 °C to rt OMe i-Pr 47% i-Pr HO

HO O O OTBS OLi PhMe2SiO PhMe2Si O O Me Me O O TMS OH 13 Steps OMe OMe i-Pr i-Pr O H

TBDPSO O 1. BF3, –78°C OLi O OH 2. PPTS, EtOH TBS Me TMS Me OTBS 6 steps –80 °C to 0 °C SiMe i-Pr 60% i-Pr 3 Product H

TBDPSO Corey, Roberts, J. Am. Chem. Soc. 1997, 119, 12425 - 12431 Takeda et al. Org Lett. 2000, 2, 1907 Baran Lab Silicon in Synthesis Hafensteiner

Brook Rearrangement H OH O O TMS (+)-onocerin TfO TMSCH2ZnBr OTf Pd(PPh3)4 TMS HO H O O Li 1. MeAlCl2 15 min O TBS Li OTBS H 2. TBAF -78 °C OH O O

0.5 equiv I2

O O HO H TfO CsF TBSO Mi, Schreiber, Corey, J. Am. Chem. Soc. 2002, 124, 11290-11291

PhNTf2 OTf OTBS

O O - Properties of silicon exploited - b-carbocation stabalization - a-anion stability Baran Lab Silicon in Synthesis Hafensteiner

(+)-Tetronomycin - Stabalization of b-cation

–MeO OH MeO O H +MeO O H O OTBDPS OTBDPS H H H H O H OMe OH H R O O R1 R O O R1 O H H H H H H O TMS SiMe3 O - Key coupling step in convergent synthesis uses allysilane OMe coupling reaction

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

OH BF3•Et2O, 92% O H H H H O H OMe OH O H H O H H H OTBDPS PivO O O O Yoshi et al. J. Org. Chem. 1992, 57, 2888 Baran Lab Silicon in Synthesis Hafensteiner

O (±)-Hirsutene O H 5% KOH HH

TMS TMS 40% O H H H D H

97% 1. H / Pt / C CO Et CO Et 2 2 H 2 2. HH 1. LiAlH4 2. PDC 72%, 2 steps H H TMS TMS Sarkar et al. Tett. Lett., 1990, 31, 3461

H Me3SI, NaH H (±)-Sarain A Core Scaffold

DMSO H 60% H O O O 1. TiCl4 N N Sarain A 2. PCC OH 53% HO O H H PdCl2, CuCl

O O2 O H 76% H Silicon in Synthesis

(±)-Sarain A Core Scaffold (+)-Pumiliotoxin A O O 1. (–)-pinene, 9-BBN Bn O OTHP 2. MeLi; TMSCl; HCl H O NBn O N H TMS BnN OTHP C4H9 C4H9 BnN 3. ClCO2Me 4. MeMgBr; CuI 65% Dibal-H; 1. o-DCB, 320 °C 35%, 4 steps MeLi 2. TsOH, MeOH 70%, 2 steps H C4H9 O 1. Swern [O] O TMS H Bn H Bn H N 2. MgBr BnN BnN N Li Al(i-Bu)2Me 3. Ac O, TEA, DMAP H 2 H H 4. (TMS)2CNLi2Cu H O 27%, 4 steps H C H OH 4 9 NCO Bn N TMS 2 TMS O TMS H 38% 1. Na, NH , t-BuOH C H 3 O Li Al(i-Bu)2Me 4 9 2. LHMDS, TsCl, DMAP 3. Dibal-H KOH, MeOH 62%, 3 steps H2O 80% OH H H Bn C4H9 N TMS TsN (CH2O)n N NH H NBn C4H9 H TsN CSA HO HO TMS Weinreb et al., J. Org. Chem., 1991, 56, 3210 Overman et al., J. Org. Chem., 1985, 50, 3670 Baran Lab Silicon in Synthesis Hafensteiner

Prostoglandins - Fleming contributed greatly to the field of organosilicon chemistry OH 1. O TMS TMS OAc 3 O O O OAc 0–5°C MeO C 2. Me2S 2 47%, 2 steps Cl CO2Me Cl Cl 70% Cl

MeOCH2Cl SnCl4 78% Fleming, J. Chem. Soc. Chem. Comm., 1977, 79 - 80 Fleming, J. Chem. Soc. Chem. Comm., 1977, 81 O O 1. H2O2–AcOH O 2. Zn–AcOH–H O Cl (±)-Linaridial 2 Cl MeO 62%, 2 steps MeO TMS H TiCl4 Loganin ClCH2SMe TMS TMS 77% O O O SMe OAc 1. Raney Ni Cl 2. CH2Br2, Cl Zn, TiCl4 ClSO NCO 2 OH H H 1. NaNO2, Ac2O 1. KNH(CH2)3NH2 OAc OAc 2. NaOAc 2. Hydroboration/ [O] 3. CH N MeO2C 2 2 ClO SN 61%, 4 steps 2 OTMS Baran Lab Silicon in Synthesis Hafensteiner

( )-Linaridial ± CN OMe O O TMS OH OMe 1. O3; Zn / HCl H 1. Swern [O] H 2. Wittig 2. NaH TMS CN OMe Ph3P EtAlCl2 (OEt)2P OMe 50% 53% O 1. Dibal-H 2. 1M HCl, THF O O O CHO CHO

H 2 : 1 : 2

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

(±)-a-Acoradiene

O O O Li P(OMe)2

61% O Yamamoto et al. J. Org. Chem., 1990, 55, 3971 Baran Lab Hydrosilation Hafensteiner

Hydrosilation Reduction with Silanes - Metal and radical catalyzed addition to alkenes and alkynes - Catalysis needed for convenient rates - Metal catalysis is done at room temperature and best yields - Catalysts include TBAF, protic and Lewis acids, Wilkinson's cat, obtained with trichloro and methyldichlorosilanes silatrane - Addition of methyl grignard converts chlorosilanes to TMS H O O HO Cl3SiH SiCl H R R 3 H Si N H2PtCl6 O O H Attar-Bashi et al. Organometallic Chem. 1976, 117, C87 Cl3SiH Cl Si R 3 R Silanes and Dehalogenation H2PtCl6 - Organohalides can be reduced with various organosilanes Chalk; Harrod; J. Am. Chem. Soc. 1965, 87, 16 - Radical mechanism of hydrodehalogenation - Reactivity of halide I > Br > Cl > F -Cr(CO)6 with light gives 1,4 reduction of dienes - Reactions are fast and clean often giving quantitative yields Germanes and Dehalogenation -Common Silanes - Organohalides can also be reduced with various organogermanes S(i-Pr) SMe Et - Can be used catalytically with PPh for reduction of C–X bond H H H 3 Si Si Si - Reactivity of halide I > Br > Cl > F (i-Pr)S S(i-Pr) MeS SMe Et Et - Solid support methods can be used - Similar reactivity to silanes - Furanylgermane reduces C–X bond under mild conditions - Common Radical Intiators Dibenzoylperoxide -"Common" Germanes AIBN - Phenylsilane is also used GeCl •PPh GeH P 2 3 O (CH2)nEt2GeH - Reactions with phenylsilane are refluxed neat with a radical 3 initiator