Recent Advances in Organosilicon Chemistry

Liam Cox
SCI Annual Review Meeting December 2009

Contents
1. 2. 3. 4. 5. 6. 7. 8. 9. Silicon - basic properties, why Silicon? Allylsilanes and related nucleophiles Organosilanes in Pd-Catalysed cross-coupling Brook rearrangement chemistry Low coordination silicon compounds Silicon Lewis acids Silicon protecting groups Using the temporary silicon connection Biological applications

Silicon Fundamental Properties

Silicon
Position in Periodic Table: Period 3, Group 14 (old group IV)

Electronegativity: 1.90 (Pauling scale) more electropositive than carbon (2.55) and hydrogen (2.2) metallic in character CSi and HSi bonds are polarised:

Si

Si

Silicon
Electron Configuration: 1s2, 2s2, 2p6, 3s2, 3p2

Four electrons in the valence shell and, like carbon, can form four covalent bonds (after hybridisation):
Me Me Si Me Me
O

cf

H H

C H

O O Si O O O Si O Si O O Si O O
5

Silicon
The availability of relatively low energy empty 3d AOs allows Si to attain higher coordination numbers (hypervalent silicon compounds). Electronegative substituents lower the energy of the 3d AOs, which facilitates the formation of hypervalent silicon compounds.

F F F Si F

2xF

F F Si F F F

hexafluorosilicate dianion

We will see later how the ability of Si to expand its valence state has ramifications on the mechanisms of many reactions proceeding at Si.
6

Stabilisation of -Positive Charge

Silicon is better at stabilising -positive charge than is carbon. This stabilisation effect is stereoelectronic in origin and often known as the -Sieffect.1

Si Si

Maximum stabilisation requires the CSi MO to align with the empty p AO on the adjacent carbocationic centre.

-Silicon Effect
E

!C-Si
"E1

empty p AO !C-C
"E1

empty p AO

"E2

> "E2

filled !C-Si MO Si empty p AO

filled !C-C MO C

The higher energy C-Si MO and the larger coefficient on the carbon in this MO (as a result of the more electropositive Si) lead to more effective orbital overlap and increased stabilisation.
8

Stabilisation of -Negative Charge

Carbanions with an -silicon group are more stable than their carbon analogues:
Si R

is more stable than

Si exerts a weak +I inductive effect through the -framework but this should destabilise -negative charge. This effect is over-ridden by a number of factors:

1. Empty 3d AOs allow p-d bonding.

Si empty 3d AO

C filled sp3 HAO

2. Overlap between the filled orbital of the metal-carbon bond and the unfilled *CSi orbital is energetically favourable. The larger coefficient on the silicon atom in the * MO further improves the orbital overlap.

Si M M

!"Si-C Si (unfilled orbital)

!M-C (filled orbital)

Stabilisation of -Negative Charge

3. Si is a relatively large atom (van der Waals radius ~2.1 ) and therefore readily polarised. Induced dipoles will also stabilise proximal negative charge.

Si

This effect is probably the most important mechanism for stabilising -negative charge.
10

Bond Strengths and Bond Lengths

bond bond strength (kJ mol1) 318 (in Me3SiH) 318 (in Me4Si) 452 (in Me3SiOMe) 565 (in Me3SiF) bond length ()

SiH SiC

1.48 1.85

SiO SiF

1.66 1.57

Key points: 1) 2) Bonds to Si are approximately 25% longer than the same bonds to C; SiO and SiF bonds are much stronger than SiC and SiH bonds.
11

Why Silicon?

12

Attractive Features of Organosilicon Chemistry

Organosilanes display many attractive properties:

compared with other organometallic reagents they are much more moisture- and air-stable readily prepared from a wide range of often cheap starting materials low toxicity rich and diverse chemistry that can usually be rationalised by understanding a relatively small number of fundamental properties of Silicon

13

Allylsilanes and Related Nucleophiles

14

Allyltrialkylsilanes
allyltrimethylsilane
SiMe3

cheap and commercially available not a strong nucleophile;1 thus reaction with aldehydes generally requires an external Lewis acid.2,3

LA
O R H R

LA O H SiMe3 R

LA O SiMe3 R

OH

Nu

15

Mechanism
Reaction proceeds through an anti SE2 reaction pathway.4,5

O R H

LA H R

OLA H H

" !
SiMe3

SiMe3

reaction proceeds through the -carbon

open T.S. (range of staggered reactive conformations need to be considered)

16

Mechanism
!* LUMO O R H H H H HOMO Si silyl group remote from reacting centre Si carbocation stabilised by "-Si effect Nu LA R O LA H R O LA H

17

Enantioselective Allylation

18

Enantioselective Allylation of Aldehydes

Use a chiral Lewis acid to differentiate the enantiotopic faces of the electrophile:6

20 mol% (S)-BINOL

OH OH

10 mol% TiF4

MeCN i) 10 mol% active catalyst

SiMe3 O OH

CH2Cl2, 0 C, 4 h
H

ii) TBAF, THF 90%, 94% e.e

Carreira
19

Enantioselective Allylation of Imines

Ph Ph HN Nap NHCbz EtO O 73%, 88% e.e.

Kobayashi:7
NH Nap NCbz EtO H O 11 mol%

10 mol% Cu(OTf)2 SiMe3 3 MS, 0 C, CH2Cl2

NTroc EtO EtO P O H

SiMe3 conditions as above

Troc NH EtO EtO P O

Nap = !-naphthyl

73%, 89% e.e.

20

Stereoselective Crotylation
Type II allylating agents8 have traditionally not been used widely to effect the stereoselective crotylation of aldehydes: reactions with crotylsilanes are particularly rare.9 The analogous reaction with crotylstannanes is usually syn-selective.10,11 Effective enantioselective variants have not been developed.9
(E) : (Z) 90:1
O R H OH SnBu3 R R OH

BF3OEt2, CH2Cl2, !78 C

syn

anti

R = Ph, syn:anti 98:2 (85%) R = Cy, syn:anti 94:6 (88%)

21

Allyltrichlorosilanes
Used on their own, allyltrichlorosilanes are poor allylating agents. However, their reactivity can be significantly increased when used in the presence of DMF,12 which acts as a Lewis base activator13 (remember, Si can expand its valence state). This observation opened up the possibility of using chiral Lewis bases to effect the enantioselective allylation of aldehydes using allyltrichlorosilanes.

LB SiCl3 poor Nu LB SiCl3 good Nu R

H O

LB SiCl3

OSiCl3 R

regenerate catalyst R

H O

LB SiCl3

chair T.S. ensures predictable syn / anti selectivity

syn

22

Chiral Phosphoramides
Denmark was the first to exploit chiral Lewis bases as catalysts for the enantioselective crotylation of aldehydes with allyltrichlorosilanes:14

N P N PhCHO SiCl3 1 eq.

O N OH Ph 72%, 83 : 17 e.r.

CH2Cl2, !78 C, 6 h

syn/anti 98 : 2

PhCHO SiCl3

OH conditions as above Ph 68%, 80 : 20 e.r.

syn/anti 2 : 98

23

Chiral Phosphoramides
Careful analysis of the mechanism of the reaction and consideration of the reactive transition state structures led to the development of improved catalysts based on a bis-phosphoramide scaffold:15,16
5 mol% H H PhCHO SiCl3
iPrNEt , 2

N P N

O N
5

O N P

N N

H H OH

CH2Cl2, !78 C, 8-10 h

Ph 82%, 92.8 : 7.2 e.r.

syn:anti 1 : 99

Aliphatic aldehydes are not good substrates for the reaction. Under the reaction conditions, rapid formation of the -chloro silyl ether occurs. Inclusion of HgCl2 as an additive improves the yield of the allylation; however enantioselectivity is compromised.15
24

Other Chiral Lewis Base Catalysts

N
tBu

O S O
2

O S O

tBu

O N

O N H

OMe

Ph

sulfoxides19 amine oxides17 pyridine N-oxides and related systems18

S O P Ph2 Ph2 P O S
Ph H N O Ph

formamides21

diphosphine oxides20
25

Strain-Induced Lewis Acidity

We have seen how the stereoselectivity of an allylation can be improved and predicted by forcing the reaction to proceed via a closed chair-like T.S. by making the Si atom more Lewis acidic. Another way of increasing the Lewis acidity of the Si centre is to include the Si atom in a small ring:22

Si Ph

160 C, 24 h PhCHO No Reaction

O Si Ph 130 C, 12 h PhCHO 85%

Si

Ph

26

Strain-Induced Lewis Acidity

Si O 90 (ideal for two groups occupying apical and equatorial positions in a trigonal bipyramid)

Si strain released on coordination

27

Leightons Allylsilanes
Leighton has introduced a range of allylsilanes in which the Si atom is contained within a five-membered ring. The long SiN and short CN bonds ensure the silacycle is still strained. The electronegative N and Cl substituents further enhance the Lewis acidity of the Si centre.23, 24
Br

RCHO, CH2Cl2, N Si N Cl !10 C, 20 h R

OH

95-98% e.e.

Br

reagents are crystalline, shelf-stable, and easy to prepare

28

Enantioselective Allylation of Imines

Leighton has recently used a related class of chiral -substituted allylsilane, readily prepared from the simple allylsilane by cross metathesis, in enantioselective imine allylation.25
Ph O Si N Me N Ph H OH Ph Cl N H Ph OH

NHAr Ph Ph 68%, 7:1 d.r., 96% e.e. Ph

NHAr

Ph 64%, >20:1 d.r., 96% e.e.

syn-selective

anti-selective

Of particular note in these examples, the choice of nitrogen substituent in the imine determines the diastereoselectivity of the reaction.26
29

More Allylsilane Chemistry

30

Substrate-Controlled Stereoselective Allylations in Ring Synthesis

Intramolecular allylation provides an excellent opportunity for generating rings. Since cyclisation frequently proceeds through well-defined transition states, levels of stereoselectivity can be excellent.
SiMe3 MeSO3H, toluene, !78 C CHO Ph Ph OH

88%, d.e. > 95%

Brnsted acids are not commonly used as activators for reactions involving allylsilanes owing to the propensity for these reagents to undergo protodesilylation. This was not a problem in this example however; indeed in this case, the use of Lewis acid activators led to a reduction in diastereoselectivity.27
31

Allylsilanes in Multicomponent Reactions

Lewis- or Brnsted acid-mediated reaction of alcohols or silyl ethers with aldehydes and ketones affords oxacarbenium cations. These reactive electrophiles react readily with allylsilanes. Both inter- and intramolecular variants have been 28 reported.
SiMe3 OTBDPS CHO TMSO Et 10 mol% TMSOTf CH2Cl2, 5 h, ! 78 C 81%, d.r. > 95:1 TBDPSO H O H Et

TMSOTf SiMe3 TBDPSO O H Et Me RO H H OTBDPS Felkin-Anh control

Mark28a
32

Allylsilanes in Multicomponent Reactions

OTES R R = C5H11 SiMe3 70%, single diastereoisomer PhCHO 5 mol% BiBr3 CH2Cl2, rt R O Ph

Ph O R I Si O R

Ph SiMe3 R II oxonia-Cope reveals a more reactive allylsilane O SiMe3 Ph

In this example, condensation of the TES ether with PhCHO generates oxacarbenium ion I. Further rearrangement to a second oxacarbenium II reveals an allylsilane, which undergoes cyclisation.28b
33

Vinylsilanes are Poor Nucleophiles

Allylsilanes are far more nucleophilic than vinylsilanes. In an allylsilane, the CSi bond can align with the developing -positive charge. In a vinylsilane, the CSi bond is initially orthogonal to the empty p AO. As a result, the CSi bond needs to undergo a 60 bond rotation before it can optimally stabilise the -positive charge. As a consequence, vinylsilanes are not much more nucleophilic than standard olefins.

E H H H Si C!Si bond orthogonal to " bond H H

E bond rotation H Si Si H H H E

34

Intramolecular Hosomi Sakurai Reaction

Under Lewis acid-activation, allylsilanes are good nucleophiles for conjugate addition reactions to ,-unsaturated carbonyl compounds. Schauss used an intramolecular version of this reaction in a synthesis of the trans decalin scaffold found in the clerodane diterpenoid natural products.29,30

OH SiMe2Ph

BF3OEt2 CH2Cl2 !78 to !10 C 81%, 98% d.e.

O H

OH

BF3 PhMe2Si O H H H O H
35

chair-like T.S. with maximum number of substituents adopting pseudoequatorial positions

Reactions of Allylsilanes with other Electrophiles

Activated alkynes31
OH Ph Si R Ph 1 mol% PPh3AuCl / AgSbF6 rt, CH2Cl2 R = C6H13 AuLn HOR Ph LnAu Si OR Ph R 71%, (Z):(E) 10:1 Ph Si O Ph

Ph LnAu R Si

Ph LnAu

Ph Si

Ph

36

Reactions of Allylsilanes with Electrophilic Fluorine Sources

Regio- and stereoselective fluorination strategies
Allylsilanes react with electrophilic halogen sources. Of particular interest is the use of F+ electrophiles as a means for generating organofluorines in a controlled manner.32 As expected, fluorination occurs regiospecifically at the -terminus of the allylsilane to provide a cationic intermediate that collapses to provide an allyl fluoride (SE2) product.
OBz SiMe3 "F " F OBz SiMe3 desilylation F OBz

Cl N N F
37

2 BF4

Selectfluor is the most commonly used electrophilic fluorine source.

Stereoselective Electrophilic Fluorination of Allylsilanes

Substrate control:33
SiMe3 OBn Selectfluor 82% OBn F OBn 82 : 18 F OBn OBn OBn

Auxiliary control:34
O Me3Si Bn Bn N O Selectfluor O Bn Bn N O F O O

syn : anti = 1 : 2 (diastereoisomers separable)

38

Enantioselective Electrophilic Fluorination of Allylsilanes

Reagent control: Catalytic enantioselective fluorination of allylsilanes has
recently also been disclosed:35
SiMe3 F-N(SO2Ph)2 (NFSI) 10 mol% (DHQ)2PYR K2CO3, MeCN, !20 C, 9 h 63%, 93% e.e.
Et N H MeO O H N N N Ph (DHQ)2PYR
39

Bn

F Bn

Et Ph O H N H OMe

Electrophilic Fluorination of other Organosilanes

allenylsilanes36
PhMe2Si Bu e.e. > 90% Cy H Selectfluor MeCN Bu F e.e. > 90% 47% H Cy

anti SE2'

allenylmethylsilanes37
Me3Si Ph Selectfluor NaHCO3, acetone 99% Ph F

vinylsilanes38
C6H13 SiMe3

Selectfluor MeCN 45%

C6H13 F (Z):(E) = 4:1

40

[3+2] Annulation Approaches

41

Allylsilanes in Annulation Reactions

Allylation of aldehydes is a step-wise process, proceeding via a carbocationic intermediate. Normally, attack of an external nucleophile on the silyl group in this intermediate is rapid, leading to a homoallylic alcohol product.
LA SiiPr3 RCHO RDS R fast R O OLA SiiPr3 Nu slow R OLA

SiiPr3

However, if the second step of this allylation can be slowed down or disfavoured, alternative reaction pathways can be followed leading to different products. One of the easiest ways to redirect the allylation reaction is to replace the methyl substituents on the silyl group with bulkier groups. In this case, intramolecular trapping of a carbocationic intermediate provides ring products. 42

Allylsilanes in Annulation Reactions

Although the product outcome is rather substrate-dependent, a tetrahydrofuran product is particularly common.39 This outcome requires rearrangement of the initially formed cationic intermediate:

LA SiiPr3 RCHO R

OLA SiiPr3 R

OLA

SiiPr3

LA R SiiPr3

OLA

SiiPr3

43

Roushs Synthesis of Asimicin

Roush employed the [3+2] annulation of allylsilanes and aldehydes in the synthesis of the two tetrahydrofuran rings of asimicin.40

O OH HO 8 O TBDMSO 8 SiMe2Ph O CHO HO 9 asimicin PhMe2Si TBDMSO 9 O OTBDMS OTBDPS

44

Roushs Synthesis of Asimicin

R1 R1 SiMe2Ph CHO SnCl4, CH2Cl2, 4 MS, O PhMe2Si R2 0 C, 3.5 h, 80% PhMe2Si O R2 H

SiMe2Ph O H O H H H R2 SnCl4

d.r. > 20:1 R1 PhMe2Si O

The excellent diastereoselectivity of this reaction was attributed to the matched facial selectivity associated with using a chiral allylsilane (anti SE2) and SnCl4chelated chiral aldehyde reacting through a syn synclinal T.S. as proposed by Keck.41
45

[3+2] Annulation Route to Pyrrolidines

A 1,2-silyl shift of the silyl group in the initially formed carbocationic intermediate is sometimes unnecessary, as in Somfais synthesis of highly functionalised pyrrolidines where the sulfonamide functions as an internal nucleophile trap:42,43

O R H NHTs PhMe2Si SiMe2Ph R TsHN

OLA SiMe2Ph MeAlCl2, !78 C, CH2Cl2

SiMe2Ph HO OH KBr, AcOOH R N Ts

HO

SiMe2Ph

OH

stereospecific oxidation of Si!C bonds

Tamao-Fleming44

N Ts d.e. > 98:2

SiMe2Ph

46

Synthesis of Allylsilanes

47

Cross Metathesis Approach

Cross-metathesis provides an efficient route to -substituted allylsilanes.45 Allyltrimethylsilane is a Type I alkene according to Grubbs classification46 and homodimerises readily. The homodimer readily takes part in secondary cross-metathesis processes. Particularly good results are obtained with Type II olefins:45a
MesN 5 mol% O Me3Si 1 eq. EtO 3 eq. NMes Cl Ru O OEt Me3Si 40% O

(E) : (Z) 30:1

Cl
iPr

CH2Cl2, rt ref 45a

If the cross-metathesis product is required from an allylsilane and an alkene of similar reactivity, the best yields of product are obtained by employing the allylsilane in excess:45c
(E) : (Z) 92 : 8 OH Me3Si 4 eq. Ph 1 eq. 5 mol% Grubbs II CH2Cl2, 4 h, ! ref 45c Ph 86% OH SiMe3

48

A Silylsilylation Approach
i) Ph2Si O SiMe2Ph C6H13 2 mol% NC Pd(acac)2 8 mol% xylene, ! ii) nBuLi, THF, then KOtBu, 50 C 99.7% e.e.

C6H13 H SiMe2Ph 90%, 99.1% e.e.

Use of a temporary silyl ether connection47 enables an intramolecular bissilylation of the proximal olefin. In the second step, syn-specific Peterson48 of an intermediate oxesiletane unveils the allylsilane product.49

49

Mechanism
Ph2Si O SiMe2Ph R Si Pd(0) oxidative addition into Si!Si bond Ph O Si Pd Me Ph H Ph2Si R O O SiPh2 Si R

Si R

chair-like T.S., Me pseudoeq. minimises 1,3-diaxial int'ns Si R Ph2Si O SiPh2 R Si

syn-silasilylation of olefin
strain-induced Lewis acidity drives dimerisation R Si

Ph O Si H Me Ph H

Si R H

SiPh2

50

Mechanism
R O Si Ph2Si R O O SiR3 R' SiPh2 Si

syn-specific ring contraction

R H SiMe2Ph

syn-specific Peterson

O Ph2Si Nu

Ph2 Si

R Si
nBuLi,

SiPh2Nu O KOtBu Ph2Si R H O SiMe2Ph

51

Allenyl, Propargyl and Vinylsilanes

52

Allenylsilanes
Since the CSi bond can align with the nucleophilic -bond, allenylsilanes react in an anti SE2 fashion similar to allylsilanes.51 Chiral allenylsilanes can also be prepared enantioselectively, often by SN2 displacement of a propargyl mesylate by a silyl nucleophile, or in this example,52 by a Johnson orthoester Claisen rearrangement.
OH MeC(OMe)3 cat. EtCO2H xylenes, ! 99% e.e. SiMe2Ph 81%, 98% e.e. CHO TMSO Br
H O Me H Ar SiMe2Ph CO2Me

SiMe2Ph CO2Me

BF3OEt2, MeCN, "20 C O CO2Me

proposed reactive conformation

Br

78%, >20:1 d.r.

53

Propargylsilanes
Propargylsilanes also react in an SE2 fashion although anti selectivity is not as high as is observed with allyl- and allenylsilanes.51 Reaction with aldehydes, and related electrophiles, proceeds under Lewis- or Brnsted acid activation to afford allenyl alcohol products.

O Ph O

SiMe3 MeSO3H, CH2Cl2, !78 C Ph

ref 27

O OH

single diastereoisomer

54

Vinylsilanes
We have already explained why vinylsilanes are far less nucleophilic than allyl-, allenyl- and propargylsilanes. Nevertheless this class of organosilane still reacts with electrophiles with predictable regioselectivity. Panek used a stereodefined vinylsilane as a masked vinyl iodide in his synthesis of discodermolide. The trisubstituted vinyl iodide was unmasked upon treatment with NIS. This iododesilylation proceeded with complete retention of configuration.53
PMP O MeO O SiMe3 NIS MeCN, 95% MeO O O PMP O OMOM OTBS (+)-discodermolide I HO O H OH OH OH O O NH2 O O OMOM OTBS

55

Enantioselective Vinylation of Aldehydes

Shibasaki used vinyltrimethoxysilane as a starting reagent in an enantioselective vinylation of aldehydes in the presence of CuF2 and a chiral bis-phosphine.54

RCHO

i) CuF22H2O, DTBM-SEGPHOS, DMF, 40 C ii) TBAF

tBu

OH R 84-99% e.e.

Si(OMe)3

OMe O P P O OMe
tBu
2

tBu tBu

DTBM-SEGPHOS

56

Enantioselective Vinylation of Aldehydes

The likely nucleophile in this reaction is a vinylcopper reagent, which is generated in situ by transmetallation of a fluoride-activated vinylsilane intermediate.
activation CuF2 Si(OMe)3 Si(OMe)3 F transmetallation CuLn

The formation of the hypervalent silyl species is important as transmetallation from standard organosilanes to other vinyl metal species is less efficient.

Evans has since reported an enantioselective vinylation of aldehydes that proceeds in the presence of a chiral scandium catalyst directly from a vinylsilane nucleophile.55

57

Organosilanes in CrossCoupling Reactions

58

Disconnection
Pd-catalysed cross-coupling strategies require an electrophilic coupling partner, usually an organohalide or pseudohalide (sulfonate, phosphate, diazonium sp etc) and a nucleophilic coupling partner. Commonly used organometallic reagents include B, Sn, Zn, Cu, Mg, Zr and Si species.
R S

Pd catalyst R M

Pd catalyst

OTf

Reactions which employ organosilanes in this type of cross-coupling are commonly referred to as Hiyama couplings.1
59

Hiyama Coupling
Owing to the low polarisation of the CSi bond, organosilanes are relatively unreactive nucleophilic coupling partners for Pd(0)-catalysed cross-coupling reactions. As a result, reaction is usually performed in the presence of an activator, typically a fluoride source (TBAF, TASF etc). In the presence of an activator, reaction proceeds more readily owing to the in situ formation of a pentacoordinate siliconate species, which undergoes more rapid transmetallation.

ArPdIIX Nu SiR3 SiR3 Nu

R3SiX +

Nu Pd Ar Ar

The substituents on the silyl group are also important. Silanes containing electronwithdrawing groups tend to be most useful: Me2FSi, MeF2Si (but not F3Si) are good, as are alkoxysilanes (Me2(RO)Si and Me(RO)2Si better than (RO)3Si).2
60

Recent Developments
Alkoxysilanes and silanols are particularly attractive coupling partners for Hiyama couplings. Reactions proceed efficiently in the presence of a fluoride source.1,3 Hiyama couplings under fluoride-free conditions are also possible. Denmark has made significant contributions to this field,1,4 showing that organosilanols undergo Pd-catalysed cross-coupling in the presence of a base.1,4
I R2 R1 Si 2 eq. base, r.t., DME OH [Pd(dba)2] R1 R2

61

Denmark Modifications
A range of bases can be employed including: NaOtBu, NaH and Cs2CO3. KOSiMe3 is a particularly mild alternative. In all cases, the reactive species is the corresponding silanolate. Mechanistic studies have revealed a different mechanistic pathway for this basemediated Hiyama coupling. Specifically, reaction does not require the formation of a pentavalent siliconate species, rather transmetallation proceeds in a direct, intramolecular fashion on an intermediate tetracoordinate PdII species:
ArPdIIX R Si OH B R Si O M MX R Si O Pd Ln intramolecular transmetallation
n

Ar

Si O reductive elimination Ar

R PdLn Ar

62

Effect of Silicon Substituents

Denmark has studied the effect of silicon substituents on the efficiency of Hiyama cross-coupling reactions.2 For fluoride-activated cross-couplings, the order of reactivity is: (CF3CH2CH2)MeSiOH > Me2SiOEt > Me2SiOH > Ph2SiOH > Et2SiOH > MeSi(OEt)2 > iPr SiOH > Si(OEt ) >> tBu SiOH 2 3 2 For TMSOK-activated cross-couplings, the order of reactivity is: Ph2SiOH > (CF3CH2CH2)MeSiOH > MeSi(OEt)2 > Me2SiOH > Si(OEt3) ~ Me2Si(OEt) >> iPr SiOH 2 Fluoride-activated cross-couplings tend to be faster and less sensitive to structural and electronic features of the substrates than base-mediated couplings.

63

Applications
The different activity of organosilanes can be exploited in sequential Hiyama coupling reactions:5
R1 I 2 eq. TMSOK 2.5 mol% [Pd(dba)2] dioxane, rt R1

RMe2Si

SiMe2OH

RMe2Si R2

R = 2-thienyl or benzyl

I 2 eq. TBAF

THF, rt

2.5 mol% [Pd(dba)2] R1

Lopez has recently applied this cross-coupling strategy to a highly stereoselective synthesis of retinoids.6

R2

64

Biaryl Synthesis
Hiyama couplings have been used to prepare biaryls, including, after optimisation, particularly challenging 2-aryl heterocycles:7
I MeO Si N Boc CF3 MeO CF3 N Boc

OH

5 mol% [Pd2(dba)3CHCl3] 2 eq. NaOtBu, 0.25 eq. Cu(OAc)2

toluene, 3 h, 4 h, 82%

Cl O Na Si O 5 mol% MeO PCy2 OMe

OMe

2.5 mol% [(allyl)PdCl]2 THF, 60 C, 8 h 77% OMe O

These couplings require careful optimisation of the reaction conditions. Choice of protecting group on the indole nitrogen, pre-forming the sodium silanolate prior to reaction, judicious choice of Pd catalyst and ligand, and in some cases the inclusion of a copper salt all need to be considered.7 65

All-Carbon Substituted Organosilanes for Hiyama Couplings

Although silanols, fluorosilanes and alkoxysilanes are the most commonly employed cross-coupling agents for Hiyama couplings, a range of latent silane coupling partners, which generate the reactive coupling agent in situ can also be used. These include, 2-pyridyl-, 2-thienyl, benzyl and allylsilanes:8

1.5 eq. N Si 5 mol% [Pd(PPh3)4] 1.5 eq. Ag2O THF, 60 C, 76% N

Yoshida has previously shown that 2-pyridylsilanes are useful alkenyl, alkynyl and benzyl transfer agents; however in this example, in the presence of a Ag(I) salt, the allyldimethylsilyl group functions as a 2-pyridyl transfer agent.8a
66

Ni-Catalysed Hiyama Reactions

Fu recently reported a Ni-catalysed variant of the Hiyama coupling between 2 alkyl halides and aryltrifluorosilanes.9 The inclusion of norephedrine as a ligand was important for obtaining good yields of product.
10 mol% NiCl2glyme 15 mol% ephedrine Br PhSiF3 12 mol% LiHMDS, 8 mol% H2O 3.8 eq. CsF, DMA, 60 C 88% Ph

O conditions as above N Cl O PhSiF3 Ph

O N O

86%

67

Hiyama Couplings in Pd-Catalysed Sequences

Prestat and Poli used a Pd-catalysed intramolecular allylic alkylation Hiyama crosscoupling sequence in their synthesis of a series of picropodophyllin analogues:10
Ar Si MeO2C O O O MeO2C 2.4 eq. TBAF 2.5 mol% Pd2(dba)3 THF, rt, 69% O O O HCO2H, THF, 0 C HO MeO2C O O quant. MeO2C O O O O Ar 1 mol% Pd(OAc)2 2 mol% dppe DMF, 60 C, 1.5 h, 59%
Ar = 2-thienyl

Si MeO2C

O O O O I

68

One-Pot Hiyama / Narasaka Coupling

Mioskowski exploited the different reactivity of differentially substituted vinylsilanes in a synthesis of stereodefined enones:11,12
1.0 eq. PhI Si EtO 1.3 eq. Hiyama with more reactive alkoxysilane Narasaka with remaining vinylsilane 3 eq. Ac2O 5 mol% [RhCl(CO)2]2 90 C, 24 h Si Ph 9 mol% ionic gel Pd cat. 1.4 eq. PS-TBAF dioxane, 60 C, 2 h filter through Celite Ph Si

83%

69

Direct Arylation of Cyclic Enamides

In contrast to standard Hiyama couplings, which employ halide coupling partners, this example uses CH activation to generate the vinyl-Pd transmetallation precursor. The AgF additive is proposed to play a dual role, activating the alkoxysilane towards transmetallation, and as an oxidant in regenerating Pd(II) at the end of the catalytic cycle.13 NHAc
Ag(0) O Pd(OAc)2 Ag(I) Pd(0) NHAc Ar O HN O Pd L Ar HOAc

HN

O Pd L OAc

O ArSi(OMe)3F activated arylsilane facilitates transmetallation

AcOSi(OMe)3 + F

70

Brook (and related) Chemistry

71

Brook Rearrangement
SiF and SiO bonds are notably stronger than SiH and SiC bonds. This difference in bond strength can be a strong driving force for chemical reactions, and has been particularly widely exploited to generate carbanions from alkoxides through the socalled Brook rearrangement:1
SiMe3

OH B R SiMe3 R

O SiMe3

1,2-Brook 1,2-retro-Brook R

The rearrangement is reversible. The position of the equilibrium depends on a number of factors including: i) solvent polarity, ii) anion-stabilising ability of the carbon substituents, and iii) strength of the oxygen-metal bond. Whilst the original report was of a [1,2]-rearrangement, the reaction is rather general. A range of [1,n]-silyl group to oxygen migrations have been reported and where investigated, been shown to proceed via intramolecular silyl group transfer.
72

Novel Silyl Enol Ether Synthesis

Treatment of acyl silanes with a copper alkoxide affords the corresponding copper enolate, which undergoes a 1,2-Brook rearrangement to afford the corresponding alkenylcopper species with high stereoselectivity. The use of DMF as solvent and a copper rather than alkali metal alkoxide is important to ensure smooth 1,2-silyl migration.2,3
O CuOtBu SiPh3 DMF SiPh3 Cu O 1,2-Brook O SiPh3

Cu

The generated alkenyl copper species is ripe for further elaboration:

Cl R 61% R = Me Cu

Ph3SiO R

OSiPh3

PhI, [Pd(PPh3)4] 71% R = PhCH2CH2 R

OSiPh3 Ph

regioselective synthesis from ketone using standard deprotonation chemistry would be difficult

73

One-Pot Synthesis of 2,3-Disubstituted Thiophenes

In this example from Xian, the inclusion of DMPU as a co-solvent was important to ensure a smooth 1,4-Brook rearrangement:4,5
Ph Br i) S SitBuMe2
tBuLi

ii) PhCHO, Et2O !78 C to !20 C

SitBuMe2

1,4-Brook

EtCHO THF, DMPU !20 C to 0 C

Ph OSitBuMe2 Et S 50% OH S

Ph OSitBuMe2

H O

Et

74

Retro Brook Rearrangements

When used in its reverse sense, the retro-Brook rearrangement provides a useful method for preparing organosilanes. Cox used a 1,4-retro-Brook rearrangement to generate stereodefined tetrasubstituted -halovinylsilanes, which serve as masked alkynes for oligoyne assembly. Intramolecular silyl group transfer allowed the incorporation of bulky silyl groups, which would be difficult to introduce by standard intermolecular trapping methods.6,7
Ph SnMe3
nBuLi

Ph

SnMe3

Ph

SnMe3 OH

THF Me3Sn O !78 C Li O Ph Si Ph tBu Ph F Ph Si Ph tBu 1,4-retro Brook Ph

SitBuPh2 Selectfluor F OH

SitBuPh2

SitBuPh2

SitBuPh2

F 10 mol% TBAF Ph

Ph

Ph

75

Anion Relay Chemistry

Organosilanes and Brook-type rearrangements have been employed to great effect in multicomponent synthesis. Recent work from Smith is particularly noteworthy:8
S
nBuLi,

O O

KOtBu

S R1

S M O

THF, !78 C

O S R1 S

SiMe2tBu S S 1,4-Brook

S OMe R1 Si* O S R1 OSiMe3 THF, !78 C to 0 C S S S

THF, !78 C

S SiMe2tBu

Si* S R1 d.r. 1.3 : 1 O S O S S

1,4-Brook THF !78 C SiMe3 Me3Si O S R1 S

SiMe2tBu S S

O H

Br Si* S R1 S O S S TBAF 37% (2 steps) O O OMe S S OH S S

ref 8d

OSiMe3

OH

76

Fluoride Activation of Latent Carbanions

Other carbanionic nucleophiles can be unmasked from organosilanes, often providing an alternative to using a strong base on the corresponding protonated precursor.9 Silylated 1,3-dithianes provide a nice illustration:8,9

ref 9c

SiMe3 S S H TBAF S S

SiMe3F H PhCHO

HO S S

Ph H

note: overall retention of configuration

cf:
H S S H
nBuLi

H S S Li PhCHO S S

H Ph OH

THF, !78 C

77

Fluoride-Mediated Carbanion Generation

Trifluoromethylation:
The formation of a thermodynamically stable SiF bond allows a range of organosilanes to be used as latent carbanions. For example, the Ruppert-Prakash reagent Me3SiCF3 is a useful source of the CF3 anion.10

Me3Si

CF3

Me Me

CF3 Si Me F E "CF3 "

CF3

78

Trifluoromethylation of Imines
Whilst the fluoride-mediated trifluoromethylation of carbonyl compounds is widespread, the corresponding reaction with imines has received less attention.10 Activated imines bearing electron-withdrawing substituents react readily with Me3SiCF3 in the presence of a fluoride source such as TBAF. Tartakovsky recently showed that trifluoromethylation of simple imines proceeds under acidic conditions under optimised conditions.11
Me3SiCF3 CF3CO2H, KHF2 MeCN, rt, 3 h Bn N Ph O O Me3SiCF3 , TBAF THF, 4 C, 18 h Ph F3C OH O 70% Bn N Ph O O 73% CF3 Bn N H

79

Trifluoromethylation of Imines
The authors proposed the reaction was mediated by HF, generated in situ from KHF2 and the Brnsted acid additive. CF3- anion transfer proceeds via a hypervalent silyl species, rather than the free CF3- anion, which would be quenched under the acidic reaction conditions.

R2 N R1 H HF

H N R1

R2

H N

R2

H CF3 Me Si Me Me F H F

R1

CF3

80

Low-Coordinate Silicon Compounds

81

Silylenes, Silenes and Related Species

Since Silicon lies immediately below Carbon in the Periodic Table, much effort has focused on preparing the Silicon analogues of carbenes, olefins and related unsaturated species.1

R C R silene Si

R R

R2C

R Si R silylene

dimerisation

R Si Si R

R R

disilene

Silenes, disilenes and silylenes and related low-coordinate Silicon species tend to be highly reactive; however this instability can be tempered by using sterically very bulky substituents and donor groups. Metal coordination offers another important stabilisation strategy.

82

Silylenes
Silylenes are the Silicon analogues of carbenes. They invariably possess singlet ground states and as a consequence of the vacant orbital on the Silicon, are highly electrophilic in character. In analogy with singlet carbenes, the chemistry of silylenes is typified by addition to bonds:
R Si Si R silacyclopropane silacyclopropene R R R Si R

Insertion reactions into bonds (e.g. OH, SiH, SiO) are also common. In these cases, reaction often proceeds via a nucleophilic addition-rearrangement mechanism.

83

Silylene Preparation
Silylenes have commonly been accessed by thermolysis- or photolysis-induced fragmentation or rearrangement processes. They dimerise readily to the corresponding disilene; however in the presence of a suitable trapping agent, such as cyclohexene, the silylene can react to afford the corresponding silacyclopropane. With bulky tert-butyl substituents on the silicon, this species exhibits sufficient stability for its application as a silylene transfer agent under metal catalysis.2
tBu tBu

tBu

tBu

Si Me3Si SiMe3

h!

tBu

Si

dimerisation

tBu

Si Si
tBu tBu

tBu

Si
tBu

AgX

Ag Si X

tBu tBu

silver silylenoid
84

Metal-Catalysed Silylene Transfer

In the presence of metal salts, commonly Ag(I) salts, silacyclopropanes react to afford a metal silylenoid species, (cf. metal carbenoids formed from diazo compounds and Rh or Cu species). The resulting silver silylenoid displays a rich chemistry that has been investigated in significant detail by Woerpel.2-4
tBu

ref 3

Si

tBu

tBu tBu

Bu

5 mol% AgOTf 20 mol% ZnBr2, HCO2Me

Si O OMe

Bu

87%, d.r. 76:24

tBu

tBu

Si Bu

tBu

OMe O H Bu

tBu

Si O OMe H

strain-induced Lewis acidity

regioselective insertion into C=O group

85

Application to 1,2,4-Triol Synthesis5,6

OH Bu 10 mol% Ag3PO4 OTIPS
tBu

OH Pr OH i) LiAlH4 (d.r. >99:1) ii) TBAF Si

Ph Bu 82% (2 steps)

Si

tBu

tBu tBu tBu tBu

O Ph

O Pr

Si Bu PrCHO, CuI
tBu tBu

OTIPS

Bu

89% d.r. 92:6:2

regioselective C=O insertion

PhCHO 25 mol% Sc(OTf)3 2 mol% CSA 2:1 PhMe:CH2Cl2 !78 C to 22 C O

tBu tBu

Si O Pr OTIPS

Si O Pr OTIPS
86

1,3-Brook

Bu 86%

Ph Bu

Mukaiyama aldol

Metal-Catalysed Silylene Transfer to Imines

Silylene transfer to imines is also possible.7 The mechanism of silaaziridine formation likely proceeds via nucleophilic addition of the imine nitrogen to the electrophilic silylenoid to provide an ylide which undergoes a 4-electrocyclisation to provide the strained product.

tBu

Si Ph NBn

tBu

tBu

tBu

Si Ph NBn

1 mol% AgOTf 80%

"

Ag Si TfO tBu
tBu

tBu

" 4!-electrocyclic Si Ph N Bn
87

tBu

Silaaziridines
Silaaziridines are sensitive to air and moisture; they can be isolated (with care) by distillation. More commonly, they are used directly in further transformations. They undergo ring-expansion reactions with aldehydes to afford the corresponding N,O-acetal resulting from insertion into the more ionic SiN bond.7
tBu iPr tBu tBu t Si Bu

Si
iPr

PhCHO 1 mol% AgOTf >95% (by NMR) Bn

O d.r. 91:9 Ph

NBn

In contrast, reaction with tert-butylisocyanide (a softer E+) proceeds via insertion into the more covalent SiC bond.7
tBu tBuN tBuNC, tBu

tBu

Si
iPr

23 C
iPr

Si tBu N Bn
88

NBn

>95% (by NMR)

Silaaziridines
Alkynes undergo regioselective insertion into the SiC bond under Pd-catalysis to provide an azasilacyclopentene ring-expanded product. Subsequent protodesilylation affords an allylic amine product.7
tBu

tBu

i)

Ph

NHBn
iPr

Si
iPr

[Pd(PPh3)4], 50 - 80 C ii) KOtBu, TBAF step ii 72% Ph

NBn

Pd(0) oxidative addition

tBu

protodesilylation

Pd Si tBu N
iPr

tBu tBu

step i Bn
tBu tBu

Si N Ph Bn N
iPr

Bn

Ph

H Ph

Si

90% reductive Pd(0) elimination

regioselective alkyne insertion

Pd

iPr

89

Silenes
Silenes are also reactive species. Traditionally, they have been generated by thermolysis processes:1
O R Si(SiMe3)3 180 C Brook R OSiMe3 Si(SiMe3)2

More recently, anionic approaches have allowed silenes to be generated under much milder conditions:1,8

SiMe3 Ph Si SiMe3 R OH

BuLi, 10 mol% LiBr

Ph

SiMe3 Si SiMe3 O

Peterson R

Si(SiMe3)Ph H

90

Silenes
Silenes are reactive species. For example, they react in a [2+2] cycloaddition fashion with carbonyl compounds, imines, alkenes and alkynes, whilst [4+2] cycloaddition pathways are (usually) observed with dienes and ,-unsaturated carbonyls.
Si(SiMe3)2Ph Ph OH BuLi 10 mol% LiBr Ph Si(SiMe3)Ph H Diels-Alder
ref 9

allylsilane chemistry
ref 10

Si

Ph SiMe3

Tamao-Fleming oxidation
ref 11

d.r. 74:20:6 45%

cycloadduct ripe for elaboration

91

Silicon Lewis Acids

92

Strong Lewis Acids

TMSOTf, and to a lesser extent TMSCl, are synthetically Lewis acids. Recent variants that exhibit increased Lewis acidity have been introduced. Of these, trialkylsilyl bistrifluoromethanesulfonamides (R3SiNTf2), developed by Ghosez1 and Mikami,2 are proving particularly useful. In light of their very high reactivity, R3SiNTf2 Lewis acids are most conveniently prepared in situ from the corresponding Brnsted acid and an allylsilane or related species:
HNTf2 SiR3 R3Si NTf2

(g)

93

Application3
OTMS 1.4 eq. O N Bn OAc OAc
tBu

O N Bn

OAc O
tBu

5 mol% HNTf2 CH2Cl2, 15 min, 0 C 90%

> 95 : 5

TMSNTf2 is formed in situ from the acid HNTf2 and silyl enol ether. The Lewis acid generates an N-acyl iminium species that is trapped in a diastereoselective fashion by the silyl enol ether. Reaction is 108 times faster than the TIPSOTf-catalysed process.

94

Even Stronger Lewis Acids

The effect of the counteranion on the strength of silyl Lewis acids was studied by Sawamura.4 Silyl borates of the form R3Si(L)BAr4, which contain a very weakly coordinating counteranion, were shown to be even more powerful Lewis acids than silyl bistrifluoromethanesulfonamides.
O Ph OTMS Ph 1 mol% LA toluene, !78 C 1h Et3Si(toluene) B(C6F5)4 TMSNTf2 TMSOTf OH O Ph

Ph 97% 12% 0%

Preparation:
toluene Et3SiH Ph3CB(C6F5)4 Et3Si(toluene) B(C6F5)4 Ph3CH

95

Lewis Base Activation of SiCl4

Whilst SiCl4 is a very weak Lewis acid, we have already seen how Lewis base additives can generate much more reactive Lewis acidic species:
LB SiCl4 SiCl4(LB) SiCl3(LB) Cl

In a nice illustration of this strategy, Takenaka recently used helical chiral pyridine N-oxide Lewis bases with SiCl4 in an efficient desymmetrisation of meso epoxides:5

N 10 mol% O Ph Ph SiCl4 , iPr2NEt, CH2Cl2 !78 C, 48 h Ph Cl O OSiCl3 Ph

77%, 93% e.e.

96

Strain-Induced Lewis Acidity

We have already seen how Leighton has used strain-induced Lewis acidity in enantioselective allylation reactions with allylsilanes. Using a similar concept, he has introduced a new class of Silicon Lewis acids for enantioselective synthesis using acyl hydrazones:6
d.r. ~ 2:1 Ph

The Lewis acid is readily prepared from pseudoephedrine and PhSiCl3 as an inconsequential 2:1 mixture of diastereoisomers.

O Si N Me N R R

Ph Cl

Me

NHBz H

Reaction with the acyl hydrazone generates an activated intermediate in which the faces of the electrophile are sterically differentiated.
Ph

H Ph O

N N Si O H Cl

Ph

NMe Me
97

Synthetic Application
d.r. ~ 2:1 NHBz N Ph
2

Ph 1.5 eq. Me OtBu

O Ph Si N Cl Me Ph
2

O Ph HN N OtBu

toluene, 23 C, 24 h 84%, d.r. 96 : 4, 90% e.e.

i) AcCl ii) TMSOTf, SiMe3

[3 + 2] cycloaddition of acyl hydrazones with tertbutyl vinyl ether proceeds with excellent enantioselectivity and diastereoselectivity to provide an aminal product that is primed for further reaction.6

iii) SmI2 NHAc NHBz Ph

2

> 20 : 1

56% (3 steps)

98

A More Active Leighton LA

Leighton has recently shown that replacing the Ph substituent in his 1st gen LA with an alkoxy group provides a more straightforward method for catalyst tuning. Moreover the more electron-withdrawing alkoxy group generates a more reactive activator, which allowed its application in an enantioselective Mannich reaction involving aliphatic ketone-derived acyl hydrazones.7,8

p-CF3-C6H4
NH N Ph
2

O 1.3 eq.

d.r. ~ 2:1 Ph O Si Me N Me Cl O
tBu

Ar(O)CHN NH Ph O OMe

Me

OTMS OMe

PhCF3 , 23 C, 30 min

Me 89%, 90% e.e.

99

Silyl Protecting Groups

100

Silyl Ethers as Alcohol Protecting Groups

Silyl ethers are important alcohol protecting groups. They are particularly useful because they can be cleaved with a fluoride source, which leaves other protecting groups intact. Moreover, the size of the substituents on the silyl group can be used to modulate their stability. Silyl ethers are usually formed by treating the alcohol with a silyl chloride or triflate. A base is invariably included to scavenge the acid by-product.

R1R2R3SiCl or R1R2R3SiOTf R OH base, B R

R1 Si O

R2 F source R3 R OH

BHCl or BHOTf

101

Formation of Silyl Ethers

New methods for forming silyl ethers that avoid the formation of HXamine salts have been developed. For example, Vogel has introduced silyl methallylsulfinates as silylating agents for alcohols, phenols and carboxylic acids.1 The reaction proceeds under mild and non-basic reaction conditions. Volatile by-products (SO2 and isobutene) facilitate work-up:
1.1 eq. OH O OEt O S Et3SiO O OEt quant (1H-NMR)

OSiEt3

20 C, CH2Cl2, < 5 min

1.5 eq. OH Ph

O S

OSitBuMe2

Ph

OSitBuMe2

20 C, 7 h, CH2Cl2 quench excess reagent with MeOH to generate volatiles side-products quant (1H-NMR)

102

Formation of Silyl Ethers

The dehydrogenative coupling of a silane with an alcohol is an attractive method for silyletherification since the only by-product is H2. Ito and Sawamura have developed one of the best reagent systems for effecting this type of silyletherification.2a
C8H17 OH C8H17 2 mol% CuOtBu 2 mol% DTBM-xantphos Et3SiH, 22 C, 19 h, toluene 95% OSiEt3 C8H17 C8H17

HO

Et3SiO

99 : 1

PAr2 O DTBM-xantphos =

PAr2 Ar =

tBu

OMe
tBu

Under the optimised conditions, a range of silanes can be employed, although poor results are observed with very hindered silanes such as iPr3SiH. Excellent levels of selectivity are observed in the selective silylation of 1 over 2 alcohols. A related Au(I)xantphos catalyst system has also been developed.2b
103

Modifying Reactivity by Silylation

Silylation can be used to modify the reactivity of a range of reagents:

tBuMe

2SiPPh2

5 mol% [(dppp)Rh(cod)]ClO4 5 mol% dppp, Et3N 1,4-dioxane!H2O 10:1 60 C, 2 d 77% PPh2

In this example from Oestreich, the silyl phosphine functions as a masked phosphinide in a Rh(I)-catalysed phosphination of cyclic enones.4

104

Modifying Reactivity by Silylation

Carreira has introduced silanolates as hydroxide equivalents in an Ir-catalysed enantioselective synthesis of allylic alcohols:5
i) 3 mol% [Ir(cod)Cl]2 6 mol% phosphoramidite ligand 2 eq. Et3SiOK, CH2Cl2, rt Ph ii) TBAF 88%, 97% e.e.

O Ph O OtBu

OH

ligand =

O P N O

Ph Ph

tBuMe

and iPr3SiOK could also be used if the the desired product is a alcohol that is protected as a more robust silyl ether.
2SiOK

105

Modifying Activity by Silylation

Proline derivatives have emerged as powerful organocatalysts for mediating a range of transformations. Diarylprolinol silyl ethers, introduced by Hayashi and Jrgensen, have been used particularly widely, for example in this recent example of a direct enantioselective -benzoylation of aldehydes.6
OSitBuMe2 N H 20 mol% O H Ph Ph

1.5 eq. BzOOBz THF, rt, 20 h then NaBH4 OH OBz 77%, 92% ee

The silyl protecting group in this class of organocatalyst generates a sterically bulky substituent off the pyrrolidine and is important for achieving high levels of asymmetric induction.
106

New Silyl Protecting Groups

Crich has introduced the 3-fluoro-4-silyloxy-benzyl ether protecting group. The group is readily introduced and can be removed by treatment with TBAF in THF under microwave irradiation.7 The electron-withdrawing fluoro substituent imparts enhanced stability to acid and the oxidative reaction conditions used to remove PMB protecting groups, which allows these two types of benzyl ethers to be used as orthogonal alcohol protecting groups.
TBAF, THF w, 90 C 74% OPMB O OR Ph O O HO OPMB O OR

Ph O

O O

Ph DDQ CH2Cl2-H2O 80% O

O O

OH O OR

R = adamantyl

F OSitBuPh2

F OSitBuPh2
107

Chiral Silylating Agents in Kinetic Resolutions

Oestreich has used a chiral silane to effect the kinetic resolution of racemic 2 alcohols.9 Silylation proceeds with retention of configuration at the silicon centre. The silane resolving agent can be recovered (retention of configuration) from the silyl ether by treatment with DIBALH.
N 5 mol% CuCl 10 mol% PAr3 5 mol% NaOtBu toluene, 25 C Ph 1.0 eq. OH 96% e.e. H Si tBu 0.6 eq. N H Si tBu Ph OH 98%, 96% e.e. DIBALH Ph N 56% conversion d.r. = 86:14 N

O Si tBu

Ph

OH

84% e.e.

78%, 71% e.e.

108

Catalytic Enantioselective Silylation of Triols

Imidazole is commonly used as a nucleophilic catalyst (as well as an acid scavenger) in silylation reactions involving silyl chlorides. Hoveyda and Snapper have developed a chiral imidazole catalyst for the enantioselective silylation of alcohols.10 They recently extended this strategy to the desymmetrisation of meso 1,2,3-triols:11,12
tBu

MeN OH HO OH N

H N N H O 20 mol% TESCl, DIPEA THF, !78 C, 48 h

tBu

tBu

OH TESO OH

H N

H MeN N Et Cl Si Et Et N H H H O O H O R O

Me
tBu

85%, > 98% e.e.

109

Silyl Linkers for Solid-Supported Synthesis

Silyl groups have been used as traceless linkers for solid-supported synthesis.14 Tan showed that a tert-butyldiarylsilyl linker exhibited increased stability to acids than previously used diisopropylsilyl-based linkers.14a
P Br i)
tBuLi,

PhH, rt

tBu

ii) Cl

P Cl N O N Cl

Si H

Ph

H Si Ph tBu O

P = polystyrene resin

tBu

Si

Ph Cl

R i) solid-supported chemistry R' OH ii) TASF, rt, < 1 h P

OH
tBu

Si O R

Ph
110

Temporary Silicon Connection

111

Silyl Tethers
Silyl groups have been used widely to tether two reacting species. Subsequent reaction can then occur in an intramolecular fashion and therefore benefit from all the advantages associated with intramolecular processes. Cleavage of the tether post reaction provides a product of an overall net intermolecular process.1

R FG1 X FG2

R Y

form silyl tether

R FG1 Si FG2

reaction

R X'

R Y'

remove tether

Si
112

Silyl Ether Connection in Intramolecular Allylation2

SiMe3 Et Si O O O TMSOTf, 2,6-DTBMP CH2Cl2, !78 C OTMS O >95:5 H2O2, KF, KHCO3, O Et Et Si Et 21:1

1. silyl ether links allylsilane to aldehyde 2. highly stereoselective intramolecular allylation 3. subsequent stereospecific (retention of configuration) oxidative cleavage of silyl tether provides a stereodefined 1,2,4-triol

THF-MeOH

OH

OH

OH

113

Tandem Silylformylation-CrotylationOxidation Route to Polyketides4

ref 4a
Si O
iPr

Rh(acac)2(CO)2 CO, PhH, 60 C intramolecular silylformylation

iPr

Si

O H

intramolecular crotylation

H2O2, KF, OH
iPr

OH

THF-MeOH 40 C C!Si oxidation and diastereoselective protonation

O
iPr

Si

62%

15 : 1 (major: all minor diastereoisomers)

114

Diastereoselective Oxidative Coupling of Bis-Silyl Enol Ethers5

O Si R R O O CAN, NaHCO3 MeCN, !10 C O

d/l : meso
R = Me R = iPr 29% 57% 2.4 : 1 10 : 1

isolated yield of d/l diastereoisomer

The R substituents in the silyl tether were important in governing the yield and diastereoselectivity of the reaction. Unsymmetrical bis-silyl enol ethers can also be used.
115

Origins of Diastereoselectivity
R Si R O O R R Si O O

d/l
R ! Si R increase size of R increase size of ! O " O decrease size of "

meso

destabilise T.S. leading to meso

116

Silyl-Tethered Tandem Ring-Closing Metathesis6

HO EtO2C O TBSO OTBS Roush H

O H O HO H H H

O TBSO

ref 7

OAc

(!)-cochleamycin A

117

Formation of Metathesis Precursor

OEt EtO S S R1 OH 10 mol% NaH, hexane 81% R1 R2 PivO

Si O

Si

HO

Note the use of silyl acetylides8 as an alternative to silyl chlorides or silyl triflates for silyletherification
R1

Si O O

R2

10 mol% NaH, hexane 68%

118

Double RCM - Protodesilylation Synthesis of (E,Z)-1,3-Diene

R2 R2 O R1 O Si O

Si O R1

Grubbs II

TBAF

Double RCM generates an intermediate bicyclic siloxane. Subsequent fluorideinduced protodesilylation provides the stereodefined (E,Z)-1,3-diene.
HO R1

R2 HO H (E)

(Z)

61% over two steps

119

Biological Applications of Organosilanes

120

Bioactive Organosilanes
In spite of the similarity of Silicon and Carbon, silicon-containing organic compounds are relatively rare in biological chemistry research programmes. However, bioactive organosilanes are known and in some cases have been commercialised:

N N N HO N N Si N N O N Si N
F

F N Si N N

flusilazole antifungal agent ($$$)

Pc4 (photodynamic agent for application in cancer treatment)

Si

Ph Si

OH N
EtO silafluofen insecticide ($$$)

OPh

muscarinic receptor agonist

121

Silanediols as Protease Inhibitors

Proteases are enzymes that catalyse the hydrolysis of a peptide bond. Aspartic acid proteases and metalloproteases both catalyse the addition of a water molecule to the amide carbonyl group. Molecules that mimic the hydrated form of the hydrolysing amide bond have therefore been used as inhibitors of these two classes of enzymes.
O N H O R2 HO
2 OH R

O O H3N

R2

H2O protease

R1

R1 HO Si R1

N H O
2 OH R

R1

peptide chain

Silanediols have recently come to the fore as potentially useful isosteres of the tetrahedral intermediate in this type of hydrolysis reaction. Providing their propensity to oligomerise to siloxanes can be controlled (e.g. by steric blocking), they are potentially very attractive stable hydrate replacements since they are neutral at physiological pH.1,2 122

Silanediol Inhibitors of AngiotensinConverting Enzyme (ACE)

Sieburth prepared the silanediol analogue of a known ACE inhibitor.1b

O Ph O H N Bn O N CO2H Ph O H N

HO Si Bn

OH N O CO2H

known ACE inhibitor IC50 1.0 nM

IC50 3.8 nM

Significantly, the inhibitory activity of the silanediol analogue compared favourably with the keto lead. The synthesis of the silanediol is noteworthy.

123

Silanediol Synthesis
H N O Ph Si Bn O Ph N CO2tBu TfOH Ph O H N H Bn Ph Si O N CO2tBu

Ph

! 2 PhH

Ph O

H N

F Si Bn NaOH HO Si Bn

F N O CO2H

Ph NH4OH HF(aq) HN

O Si O Bn N CO2H

Ph O

H N

OH N O CO2H

124

Some Conclusions

125

The chemistry of organosilicon compounds is rich and diverse and finds application in many aspects of modern organic synthesis. Most of it, however, can still be rationalised by considering the basics: electronegativity: Si is more electropositive than C and H size: Si is a relatively large and polarisable atom compared with C, H, O etc

electron confign: 1s2, 2s2, 2p6, 3s2, 3p2 posn in Periodic Table: Period 3, therefore capable of expanding its valence state

stereoelectronics: CSi bond is good at stabilising -positive charge bond strengths: SiO and SiF bonds are significantly stronger than SiC and SiH bonds.

126

References

127

General References and introductory section

References

For a useful introduction to organosilicon chemistry: Organic Synthesis: The Roles of Boron and Silicon (Oxford Chemistry Primers series), S. E. Thomas, 1991. 1: J. B. Lambert et al., Acc. Chem. Res. 1999, 32, 183-190. Allylation and related nucleophiles 1. (a) H. Mayr et al., Angew. Chem. Int. Ed. Engl., 1994, 33, 938-957; (b) H. Mayr et al., J. Chem. Soc., Chem. Commun. 1989, 91-92. General reviews: (a) S. E. Denmark et al., Chem. Rev., 2003, 103, 2763-2794; (b) Y. Yamamoto et al., Chem. Rev., 1993, 93, 2207-2293; (c) W. R. Roush In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Volume 2, Chapter 1.1, pp 1-53. (d) I. Fleming In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Volume 2, Chapter 2.2, pp 563-593; (e) J. W. J. Kennedy et al., Angew. Chem. Int. Ed., 2003, 42, 4732-4739; (f) I. Fleming et al., Chem. Rev., 1997, 97, 2063-2192; (g) I. Fleming et al., Org. React., 1989, 37, 57-575; (h) L. Chabaud et al., Eur. J. Org. Chem., 2004, 3173-3199. Note that additives, such as fluoride, which activate the allylsilane, have occasionally been used. In these cases, the nucleophile may be an allyl anion, see: (a) A. Hosomi et al., Tetrahedron Lett., 1978, 3043-3046; (b) T. K. Sarkar et al., Tetrahedron Lett., 1978, 3513-3516; (c) for the use of Schwesinger bases to activate silyl nucleophiles: M. Ueno et al., Eur. J. Org. Chem., 2005, 1965-1968. (a) M. J. C. Buckle, et al., Org. Biomol. Chem., 2004, 2, 749-769; (b) S. E. Denmark et al., J. Org. Chem., 1994, 59, 5130-5132; (c) S. E. Denmark et al., Helv. Chim. Acta, 1983, 66, 1655-1660. For computational investigations on the Lewis acid-mediated reaction of allyltrialkylsilanes with aldehydes: (a) L. F. Tietze et al., J. Am. Chem. Soc., 2006, 128, 11483-11495; (b) P. S. Mayer et al., J. Am. Chem. 128 Soc., 2002, 124, 12928-12929; (c) A. Bottoni et al., J. Am. Chem. Soc., 1997, 119, 12131-12135.

2.

3.

4.

5.

References
Allylation and related nucleophiles (contd) 6. D. R. Gauthier Jr. et al., Angew. Chem. Int. Ed. Engl., 1996, 35, 2363-2365. Note the enantioselective allylation of allylstannanes has been used much more widely, see for example: G. E. Keck et al., Tetrahedron Lett., 1993, 34, 7827-7828 and references therein. H. Kiyohara et al., Angew. Chem. Int. Ed., 2006, 45, 1615-1617. For the classification of allyl metals: (a) R. W. Hoffmann, Angew. Chem. Int. Ed. Engl., 1982, 21, 555-566; (b) ref 4c. (a) K. Ishihara et al., J. Am. Chem. Soc., 1993, 115, 11490-11495; (b) S. Aoki et al., Tetrahedron, 1993, 49, 1783-1792. G. E. Keck et al., J. Org. Chem., 1994, 59, 7889-7896. For a review on stereoselective allylation: Y. Yamamoto, Acc. Chem. Res., 1987, 20, 243-249. S. Kobayashi et al., J. Org. Chem., 1994, 59, 6620-6628. Lewis base activation of silyl nucleophiles has been recently reviewed, see: J. Gawronski et al., Chem. Rev., 2008, 108, 5227-5252. S. E. Denmark et al., J. Org. Chem., 2006, 71, 1513-1522. S. E. Denmark et al., J. Org. Chem., 2006, 71, 1523-1536. For reviews on chiral Lewis base-catalysed allylations: S. E. Denmark et al., Chem. Commun., 2003, 167170.

7. 8.

9.

10. 11. 12. 13.

14. 15. 16.

129

References
Allylation and related nucleophiles (contd) 17. 18. (a) J. F. Traverse et al., Org. Lett., 2005, 7, 3151-3154; (b) V. Simonini et al., Synlett, 2008, 1061-1065.. (a) A. V. Malkov et al., Angew. Chem. Int. Ed., 2003, 42, 3674-3677; (b) R. Hrdina et al., Chem. Commun., 2009, 2314-2316; (c) for a review on chiral N-oxides in asymmetric synthesis: A. V. Malkov et al., Eur. J. Org. Chem., 2007, 29-36. (a) P. Wang et al., Org. Biomol. Chem., 2009, 7, 3741-3747; (b) A. Massa et al., Tetrahedron: Asymmetry, 2009, 20, 202-204. (a) V. Simonini et al., Adv. Synth. Catal., 2008, 350, 561-564; (b) S. Kotani et al., Tetrahedron, 2007, 63, 3122-3132. K. Iseki et al., Tetrahedron, 1999, 55, 977-988. K. Matsumoto et al., J. Org. Chem., 1994, 59, 7152-7155. (a) K. Kubota et al., Angew. Chem. Int. Ed., 2003, 42, 946-948; (b) X. Zhang et al., Angew. Chem. Int. Ed., 2005, 44, 938-941. Related agents for enantioselective crotylation have also been reported: (a) B. M. Hackman et al., Org. Lett., 2004, 6, 4375-4377; (b) N. Z. Burns et al., Angew. Chem. Int. Ed., 2006, 45, 3811-3813. J. D. Huber et al., Angew. Chem. Int. Ed., 2008, 47, 3037-3039. J. D. Huber et al., J. Am. Chem. Soc., 2007, 129, 14552-14553. P. J. Jervis et al., Org. Lett., 2006, 8, 4649-4652.

19.

20.

21. 22. 23.

24.

25. 26. 27.

130

References
Allylation and related nucleophiles (contd) 28. (a) J. Pospsil et al. Angew. Chem., Int. Ed., 2006, 45, 3357-3360; (b) Y. Lian et al., J. Org. Chem., 2006, 71, 7171-7174; (c) F. Peng et al., J. Am. Chem. Soc., 2007, 129, 3070-3071; (d) M. Pham et al., J. Org. Chem., 2008, 73, 741-744; (e) P. R. Ullapu et al., Angew. Chem. Int. Ed., 2009, 48, 2196-2200; (f) J. T. Lowe et al., Org. Lett., 2005, 7, 3231-3234; (g) Y. Zhang et al., Org. Lett., 2009, 11, 3366-3369. S. A. Rodgen et al., Angew. Chem. Int. Ed., 2006, 45, 4929-4932. B. D. Stevens et al., J. Org. Chem., 2005, 70, 4375-4379. S. Park et al., J. Am. Chem. Soc., 2006, 128, 10664-10665. For a review of this area: M. Tredwell et al., Org. Biomol. Chem., 2006, 4, 26-32; for a nice recent application: S. C. Wilkinson et al., Angew. Chem. Int. Ed., 2009, 48, 7083-7086. S. Purser et al., Chem. Eur. J., 2006, 12, 9176-9185. M. Tredwell et al., Org. Lett., 2005, 7, 1267-1270. T. Ishimaru et al., Angew. Chem. Int. Ed. Engl., 2008, 47, 4157-4161 and references therein. (a) L. Carroll et al., Org. Biomol. Chem., 2008, 6, 1731-1733; (b) L. Carroll et al., Chem. Commun., 2006, 4113-4115. M. C. Pacheco et al., Org. Lett., 2005, 7, 1267-1270. B. Greedy et al., Chem. Commun., 2001, 233-234.

29. 30. 31. 32.

33. 34. 35. 36.

37. 38.

131

References
Allylation and related nucleophiles (contd) 39. see for example: (a) R. H. Bates et al., Org. Lett., 2008, 10, 4343-4346; (b) G. C. Micalizio et al., Org. Lett., 2000, 2, 461-464. J. M. Tinsley et al., J. Am. Chem. Soc., 2005, 127, 10818-10819. G. E. Keck et al., J. Am. Chem. Soc., 1995, 117, 6210-6223. M. Dressel et al., Chem. Eur. J., 2008, 14, 3072-3077. Isocyanates have also been used to trap -carbocations resulting in heterocyclic ring products: A. Romero et al., Org. Lett., 2006, 8, 2127-2130. For reviews on the oxidation of CSi bonds: (a) I. Fleming, Chemtracts: Org. Chem., 1996, 9, 1-64; (b) G. R. Jones et al., Tetrahedron, 1995, 52, 7599-7662. (a) S. Bouzbouz et al., Adv. Synth. Catal., 2002, 344, 627-630; (b) P. Langer et al., Synlett, 2002, 110-112; (c) F. C. Engelhardt et al., Org. Lett., 2001, 3, 2209-2212; (d) ref 25; (e) H. Teare et al., Arkivoc, 2007, part x, 232-244; (f) A. D. McElhinney et al., Heterocycles, 2009, 49, 417-422. A. K. Chatterjee et al., J. Am. Chem. Soc., 2003, 125, 11360-11370. For reviews on the use of the temporary Silicon connection: (a) L. R. Cox, S. V. Ley, In Templated Organic Synthesis; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000; Chapter 10, pp 275-375; (b) M. Bols et al., Chem. Rev., 1995, 95, 1253-1277; (c) L. Fensterbank et al., Synthesis, 1997, 813-854; (d) D. R. Gauthier Jr. et al., Tetrahedron, 1998, 54, 2289-2338.

40. 41. 42. 43.

44.

45.

46. 47.

132

References
Allylation and related nucleophiles (contd) 48. For reviews on the Peterson olefination: (a) L. F. van Staden et al., Chem. Soc. Rev., 2002, 31, 195-200; (b) D. J. Ager, Org. React. 1990, 38, 1-223; (c) D. J. Ager, J. Chem. Soc., Perkin Trans. 1, 1986, 183-194; (d) D. J. Ager, Synthesis, 1984, 384-398; for a recent application of this reaction in the synthesis of vinylsilanes: J. Mc Nulty et al., Chem. Commun., 2008, 1244-1245. (a) M. Suginome et al., Chem. Eur. J., 2005, 11, 2954-2965; (b) W. R. Judd et al., J. Am. Chem. Soc., 2006, 128, 13736-13741. For other interesting synthetic approaches to allylsilanes: (a) L. E. Bourque et al., J. Am. Chem. Soc., 2007, 129, 12602-12603; (b) R. Shintani et al., Org. Lett., 2007, 9, 4643-4645; (c) N. J. Hughes et al., Org. Biomol. Chem., 2007, 5, 2841-2848; (d) R. Lauchli et al., Org. Lett., 2005, 7, 3913-3916. For a review on vinyl-, propargyl- and allenylsilicon reagents in asymmetric synthesis: M. J. Curtis-Long et al., Chem. Eur. J., 2009, 15, 5402-5416. (a) R. A. Brawn et al., Org. Lett., 2007, 9, 2689-2692; (b) see also: W. Felzmann et al., J. Org. Chem., 2007, 72, 2182-2186. A. Arefelov et al., J. Am. Chem. Soc., 2005, 127, 5596-5603. This paper also provides a powerful illustration of Paneks chiral allylsilane reagents in stereoselective synthesis. Note judicious choice of solvent can be important for controlling the stereoselectivity of this type of iododesilylation: E. A. Ilardi et al., Org. Lett., 2008, 10, 1727-1730. D. Tomita et al., J. Am. Chem. Soc., 2005, 127, 4138-4139; For another example of transmetallation of organosilanes to organocopper reagents: J. R. Herron et al., J. Am. Chem. Soc., 2008, 130, 16486-16487. D. A. Evans et al., J. Am. Chem. Soc., 2006, 128, 11034-11035.

49.

50.

51.

52.

53.

54.

55.

133

References
Organosilanes in metal-catalysed cross-coupling chemistry 1 For some recent reviews: (a) S. E. Denmark et al., Chem. Eur. J., 2006, 12, 4954-4963; (b) S. E. Denmark et al., Acc. Chem. Res., 2008, 41, 1486-1499; (c) S. E. Denmark, J. Org. Chem., 2009, 74, 2915-2927; (d) T. Hiyama et al., Top. Curr. Chem., 2002, 219, 61-85.; (e) S. E. Denmark et al., Acc. Chem. Res., 2002, 35, 835-846. S. E. Denmark et al., J. Org. Chem., 2006, 71, 8500-8509. S. E. Denmark et al., J. Am. Chem. Soc., 2004, 126, 4865-4874. S. E. Denmark et al., J. Am. Chem. Soc., 2004, 126, 4876-4882. S. E. Denmark et al., J. Am. Chem. Soc., 2005, 127, 8004-8005. J. Montenegro et al., Org. Lett., 2009, 11, 141-144. (a) S. E. Denmark et al., J. Org. Chem., 2008, 73, 1440-1455; (b) S. E. Denmark et al., J. Am. Chem. Soc., 2009, 131, 3104-3118. (a) T. Nokami et al., Org. Lett,. 2006, 8, 729-731; (b) L. Li et al., Org. Lett., 2006, 8, 3733-3736; (c) K. Hosoi et al., Chem. Lett., 2002, 138-139; (d) K. Itami et al., J. Am. Chem. Soc., 2001, 123, 5600-5601; (e) B. M. Trost et al., Org. Lett., 2003, 5, 1895-1898; (f) S. E. Denmark et al., J. Am. Chem. Soc., 1999, 121, 58215822; (g) Y. Nakao et al., J. Am. Chem. Soc., 2005, 127, 6952-6953. N. A. Strotman et al., Angew. Chem. Int. Ed., 2007, 46, 3556-3558. M. Vitale et al., J. Org. Chem., 2008, 73, 5795-5805.

2 3 4 5 6 7

9 10

134

References
Organosilanes in metal-catalysed cross-coupling chemistry (contd) 11. 12. C. Thiot et al., Eur. J. Org. Chem., 2009, 3219-3227. For other examples of Hiyama-type cross-coupling reactions in tandem processes: (a) S. E. Denmark et al., J. Am. Chem. Soc., 2007, 129, 3737-3744; (b) C. Thiot et al., Chem. Eur. J., 2007, 13, 8971-8978; (c) S. E. Denmark et al., J. Org. Chem., 2005, 70, 2839-2842. H. Zhou et al., Angew. Chem. Int. Ed., 2009, 48, 5355-5357. For other relevant papers: (a) Mechanistic study on the Pd-catalysed vinylation of aryl halides in H2O: A. Gordillo et al., J. Am. Chem. Soc., 2009, 131, 4584-4585; (b) Hiyama couplings using phosphine-free hydrazone ligands: T. Mino et al., J. Org. Chem., 2006, 71, 9499-9502; (c) Hiyama coupling in oligoarene synthesis: Y. Nakao et al., J. Am. Chem. Soc., 2007, 129, 11694-11695.

13. 14.

135

References
Brook Chemistry 1 (a) A. G. Brook, J. Am. Chem. Soc., 1058, 80, 1886-1889; (b) A. G. Brook et al., J. Am. Chem. Soc., 1959, 81, 981-983; (c) A. G. Brook et al., J. Am. Chem. Soc., 1961, 83, 827-831. A. Tsubouchi et al., J. Am. Chem. Soc., 2006, 128, 14268-14269. For other examples of 1,2-Brook rearrangements: (a) Y. Nakai et al., J. Org. Chem., 2007, 72, 1379-1387; (b) R. B. Lettan, II et al., Angew. Chem. Int. Ed., 2008, 47, 2294-2297; (c) R. Baati et al., Org. Lett., 2006, 8, 2949-2951. N. O. Devarie-Baez et al., Org. Lett., 2007, 9, 4655-4658. For other uses of Brook rearrangements: (a) R. Unger et al., Eur. J. Org. Chem., 2009, 1749-1756; (b) Y, Matsuya et al., Chem. Eur. J., 2005, 11, 5408-5418; (c) M. Sasaki et al., Chem. Eur. J., 2009, 15, 33633366. (a) S. M. E. Simpkins et al., Org. Lett., 2003, 5, 3971-3974; (b) S. M. E. Simpkins et al., Chem. Commun., 2007, 4035-4037; (c) M. D. Weller et al., C. R. Chimie, 2009, 12, 366-377. For other examples of retro Brook rearrangements: (a) Y. Mori et al., Angew. Chem. Int. Ed., 2008, 47, 1091-1093; (b) A. Nakazaki et al., Angew. Chem. Int. Ed., 2006, 45, 2235-2238; (c) S. Yamago et al., Org. Lett., 2005, 7, 909-911. (a) A. B. Smith III et al., Chem. Commun., 2008, 5883-5895; (b) A. B. Smith III et al., J. Org. Chem., 2009, 74, 5987-6001; (c) N. O. Devarie-Baez et al., Org. Lett., 2009, 11, 1861-1864; (d) A. B. Smith III et al., Org. Lett., 2007, 9, 3307-3309.

2 3

4 5

136

References
Brook Chemistry (contd) 9. (a) A. DeglInnocenti et al., Chem. Commun., 2006, 4881-4893; (b) M. M. Biddle et al., J. Org. Chem., 2006, 71, 4031-4039; (c) V. Cere et al., Tetrahedron Lett., 2006, 47, 7525-7528. For a review on the use of this reagent: R. P. Singh et al., Tetrahedron, 2000, 56, 7613-7632. V. V. Levin et al., Eur. J. Org. Chem., 2008, 5226-5230.

10. 11.

137

References
Low coordination silicon compounds 1 2 For a recent overview: H. Ottosson et al., Chem. Eur. J., 2006, 12, 1576-1585. (a) A. K. Franz et al., Acc. Chem. Res., 2000, 33, 813-820; (b) for mechanistic studies: T. G. Driver et al., J. Am. Chem. Soc., 2003, 125, 10659-10663; (c) T. G. Driver et al., J. Am. Chem. Soc., 2004, 126, 999310002. (a) J. Cirakovic et al., 2002, 124, 9370-9371; (b) see also: A. K. Franz et al., Angew. Chem. Int. Ed., 2000, 39, 4295-4299. See also: (a) T. G. Driver et al., J. Am. Chem. Soc., 2002, 124, 6524-6525; (b) P. A. Cleary et al., Org. Lett., 2005, 7, 5531-5533; (c) B. E. Howard et al., Org. Lett., 2007, 9, 4651-4653; (d) K. M. Buchner et al., Org. Lett., 2009, 11, 2173-2175. T. B. Clark et al., Org. Lett., 2006, 8, 4109-4112. For other examples of silylene transfer to alkynes: (a) W. S. Palmer et al., Organometallics, 2001, 20, 36913697; (b) T. B. Clark et al., J. Am. Chem. Soc., 2004, 126, 9520-9521. Z. Nevrez et al., Org. Lett., 2007, 9, 3773-3776. (a) M. B. Berry et al., Tetrahedron Lett., 2003, 44, 9135-9138; (b) M. B. Berry et al., Org. Biomol. Chem., 2004, 2, 2381-2392. (a) A. S. Batsanov et al., Tetrahedron Lett., 1996, 37, 2491-2494; (b) M. J. Sanganee et al., Org. Biomol. Chem., 2004, 2, 2393-2402. (a) N. J. Hughes et al., Org. Biomol. Chem., 2007, 5, 2841-2848; (b) J. D. Sellars et al., Tetrahedron, 2009, 65, 5588-5595.

5 6

7 8

10

138
11 J. D. Sellars et al., Org. Biomol. Chem., 2006, 4, 3223-3224.

References
Silicon Lewis acids 1 2 3 4 5 6 7 8 B. Mathieu et al., Tetrahedron Lett., 1997, 38, 5497-5500. A. Ishii et al., Synlett, 1997, 1145-1146. R. B. Othman et al., Org. Lett., 2005, 7, 5335-5337. K. Hara et al., Org. Lett., 2005, 7, 5621-5623. N. Takenaka et al., Angew. Chem. Int. Ed., 2008, 47, 9708-9710. S. Shirakawa et al., J. Am. Chem. Soc., 2005, 127, 9974-9975. G. T. Notte et al., J. Am. Chem. Soc., 2008, 130, 6676-6677. For other applications of this class of Lewis acids: (a) K. Tran et al., Org. Lett., 2008, 10, 3165-3167; (b) F. R. Bou-Hamdan et al., Angew. Chem. Int. Ed., 2009, 48, 2403-2406.

139

References
Silicon Protecting Groups 1 2 3 X. Huang et al., Chem. Commun., 2005, 1297-1299. (a) H. Ito et al., Org. Lett., 2005, 7, 1869-1871; (b) H. Ito et al., Org. Lett., 2005, 7, 3001-3004. For other silyletherification approaches that do not employ silyl halides or triflates: (a) disilanes: E. Shirakawa et al., Chem. Commun., 2006, 3927-3929; (b) vinylsilanes: J.-W. Park et al., Org. Lett., 2007, 9, 4073-4076; (c) aminosilanes: J. Beignet et al., J. Org. Chem., 2008, 73, 5462-5475; (d) alkynylsilanes: J. B. Grimm et al., J. Org. Chem., 2004, 69, 8967-8970. V. T. Trepohl et al., Chem. Commun., 2007, 3300-3302. I. Lyothier et al., Angew. Chem. Int. Ed., 2006, 45, 6204-6207. H. Gotoh et al., Chem. Commun., 2009, 3083-3085 and references therein. D. Crich et al., J. Org. Chem., 2009, 74, 2486-2493. For the development of very bulky silyl protecting groups for stabilising oligoynes: W. A. Chalifoux et al., Eur. J. Org. Chem., 2007, 1001-1006. (a) S. Rendler et al., Angew. Chem. Int. Ed., 2005, 44, 7620-7624; (b) B. Karatas et al., Org. Biomol. Chem., 2008, 6, 1435-1440; (c) S. Rendler et al., Chem. Eur. J., 2008, 14, 11512-11528. Y. Zhao et al., Nature, 2006, 443, 67-70. Z. You et al., Angew. Chem. Int. Ed., 2009, 48, 547-550.

4 5 6 7 8

10 11

140

References
Silicon Protecting Groups (contd) 12 For an overview of stereoselective silylation of alcohols in kinetic resolutions and desymmetrisations: S. Rendler et al., Angew. Chem. Int. Ed., 2008, 47, 248-250 and references therein. For the use of chiral silyl ethers in diastereoselective synthesis: M. Campagna et al., Org. Lett., 2007, 9, 3793-3796. (a) C. M. DiBlasi et al., Org. Lett., 2005, 7, 1777-1780; (b) A. Ohkubo et al., J. Org. Chem., 2009, 74, 28172823; (c) T. Lavergne et al., Eur. J. Org. Chem., 2009, 2190-2194. For an application of fluorous silyl ether protecting groups in natural product synthesis: Y. Fukui et al., Org. Lett., 2006, 8, 301-304.

13

14

15

141

References
Use of the temporary Silicon connection 1 For reviews on the use of the temporary Silicon connection: (a) L. R. Cox, S. V. Ley, In Templated Organic Synthesis; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000; Chapter 10, pp 275-375; (b) M. Bols et al., Chem. Rev., 1995, 95, 1253-1277; (c) L. Fensterbank et al., Synthesis, 1997, 813-854; (d) D. R. Gauthier Jr. et al., Tetrahedron, 1998, 54, 2289-2338. J. Beignet et al., J. Org. Chem., 2008, 73, 5462-5475. For another recent example where a temporary Silicon connection was used with allylsilanes: J. Robertson et al., Org. Biomol. Chem., 2008, 6, 2628-2635. (a) J. T. Spletstoser et al., Org. Lett., 2008, 10, 5593-5596; see also: (b) S. J. OMalley et al., Angew. Chem. Int. Ed., 2001, 40, 2915-2917; (c) M. J. Zacuto et al., J. Am. Chem. Soc., 2002, 124, 7890-7891; (d) M. J. Zacuto et al., Tetrahedron, 2003, 59, 8889-8900; (e) P. K. Park et al., J. Am. Chem. Soc., 2006, 128, 2796-2797. C. T. Avetta, Jr., et al., Org. Lett., 2008, 10, 5621-5624. S. Mukherjee et al., Org. Lett., 2009, 11, 2916-2919. T. A. Dineen et al., Org. Lett., 2004, 6, 2043-2046. J. B. Grimm et al., J. Org. Chem., 2004, 69, 8967-8970. For other recent examples where temporary Silicon connections have been usefully employed in synthesis: (a) C. Rodrguez-Escrich et al., Org. Lett., 2008, 10, 5191-5194; (b) Q. Xie et al., J. Org. Chem., 2008, 10, 5345-5348; (c) C. Cordier et al., Org. Biomol. Chem., 2008, 6, 1734-1737; (d) F. Li et al., J. Org. Chem., 2006, 71, 5221-5227; (e) T. Gaich et al., Org. Lett., 2005, 7, 1311-1313.

2 3

5 6 7 8 9

142

References
Biological applications 1 (a) S. McN. Sieburth et al., Eur. J. Org. Chem., 2006, 311-322; (b) J. Kim et al., J. Org. Chem., 2005, 70, 5781-5789. L. Nielsen et al., J. Am. Chem. Soc., 2008, 130, 13145-13151.

Silyl Enol Ethers Silyl enol ethers, ketene acetals and related species are important nucleophiles. For some recent examples of their use: 1 Lewis base-mediated Mukaiyama aldol reactions: 1 2 3 4 5 6 7 2 S. E. Denmark et al., J. Am. Chem. Soc., 2007, 129, 14684-14865. S. E. Denmark et al., J. Am. Chem. Soc., 2006, 128, 1038-1039. S. E. Denmark et al., J. Am. Chem. Soc., 2005, 127, 3774-3789. S. E. Denmark et al., J. Org. Soc., 2005, 70, 5235-5248 S. E. Denmark et al., J. Org. Soc., 2005, 70, 10823-10840. S. E. Denmark et al., J. Org. Soc., 2005, 70, 10393-10399. M. Hatano et al., Org. Lett., 2007, 9, 4527-4530.

Enantioselective synthesis of quaternary stereogenic centres: 1 2 3 K. Mikami et al., J. Am. Chem. Soc., 2007, 129, 12950-12951. A. H. Mermerian et al., J. Am. Chem. Soc., 2005, 127, 5604-5607. S. E. Denmark et al., J. Am. Chem. Soc., 2007, 129, 14684-14865.

143

References
Silyl Enol Ethers contd 3. Enantioselective protonation of silyl enol ethers: 1 2 4. T. Poisson et al., Angew. Chem. Int. Ed., 2007, 46, 7090-7093. A. Yanagisawa et al., Angew. Chem. Int. Ed., 2005, 44, 1546-1548.

Enantioselective synthesis of quaternary stereogenic centres: 1 2 3 K. Mikami et al., J. Am. Chem. Soc., 2007, 129, 12950-12951. A. H. Mermerian et al., J. Am. Chem. Soc., 2005, 127, 5604-5607. S. E. Denmark et al., J. Am. Chem. Soc., 2007, 129, 14684-14865.

5.

Silyl enol ethers as oxyallyl cation precursors: W. K. Ching et al., J. Am. Chem. Soc., 2009, 131, 45564557. Silyl enol ethers as the ene component of enyne cyclisations: B. K. Corkey et al., J. Am. Chem. Soc., 2007, 129, 2764-2765. Alkylation of silyl enol ethers: E. Blanger et al., J. Am. Chem. Soc., 2007, 129, 1034-1035. Silyl enol ethers and related species in conjugate addition reactions: 1 2 T. E. Reynolds et al., Org. Lett., 2008, 10, 2449-2452. N. Takenaka et al., J. Am. Chem. Soc., 2007, 129, 742-743.

6.

7. 8.

9.

Applications of (tristrimethylsilyl)silyl enol ethers: 1 2 M. B. Boxer et al., J. Am. Chem. Soc., 2007, 129, 2762-2763. M. B. Boxer et al., Org. Lett., 2008, 10, 453-455.

144

References
Silyl Enol Ethers contd 10. Silyl enol ethers in Claisen Rearrangements: D. Craig et al., Chem. Commun., 2007, 1077-1079.

145

References
Silanes as reducing agents Silanes are important reducing agents. For some recent applications: 1 Hydrosilylation of Aldehydes and Ketones 1 2 3 Silver-catalysed hydrosilylation of aldehydes: B. M. Wile et al., Chem. Commun., 2006, 41044106. Enantioselective hydrosilylation of ketones: (a) L. Zhou et al., Chem. Commun., 2007, 29772979; (b) N. S. Shaikh et al., Angew. Chem. Int. Ed., 2008, 47, 2497-2501. Hydrosilylation of ketones: (a) S. Des-Gonzlez et al., J. Org. Chem., 2005, 70, 4784-4796; (b) Z. A. Buchan et al., Angew. Chem. Int. Ed., 2009, 48, 4840-4844 (interesting application in intramolecular aglycone delivery). New catalysts and mechanistic studies: (a) N. Schneider et al., Angew. Chem. Int. Ed., 2009, 48, 1609-1613; (b) S. Rendler et al., Angew. Chem. Int. Ed., 2008, 47, 5997-6000; (c) V. Comte et al., Chem. Commun., 2007, 713-715; (d) V. Csar et al., Chem. Eur. J., 2005, 11, 2862-2873.

Amide reduction: 1 2 Practical synthesis of 2 and 3 amines: S. Hanada et al., J. Org. Chem., 2007, 72, 75517559. Chemoselective amide reduction in the presence of ketones and esters: H. Sasakuma et al., Chem. Commun., 2007, 4916-4918.

Dehydration of amides to nitriles: 1 2 S. Zhou et al., Chem. Commun., 2009, 4883-4885. S. Zhou et al., Org. Lett., 2009, 11, 2461-2464.

146

References
Silanes as reducing agents (contd) 4. 5. Reductive amination: O.-Y. Lee et al., J. Org. Chem., 2008, 73, 8829-8837. Conjugate reduction of enones: (a) H. Otsuka et al., Chem. Commun., 2007, 1819-1821; (b) S. Chandrasekhar et al., Org. Biomol. Chem., 2006, 4, 1650-1652; (c) S. Rendler et al., Angew. Chem. Int. Ed., 2007, 46, 498-504. Reduction of alkyl halides: J. Yang et al., J. Am. Chem. Soc., 2007, 129, 12656-12657. Cleavage of alkyl ethers: J. Yang et al., J. Am. Chem. Soc., 2008, 130, 17509-17518. Reduction of propargylic alcohols: Y. Nishibayashi et al., Angew. Chem. Int. Ed., 2006, 45, 4835-4839. Hydrosilylation of alkenes and alkynes: 1. Alkenes: (a) V. Gandon et al., J. Am. Chem. Soc., 2009, 131, 3007-3015; (b) E. Calimano et al., J. Am. Chem. Soc., 2008, 130, 9226-9227; (c) F. Buch et al., Angew. Chem. Int. Ed., 2006, 45, 2741-2745. Alkynes: (a) G. Berthon-Gelloz et al., J. Org. Chem., 2008, 73, 4190-4197; (b) T. Matsuda et al., Chem. Commun., 2007, 2627-2629; (c) B. M. Trost et al., J. Am. Chem. Soc., 2005, 127, 17644-17655; (d) C. Menozzi et al., J. Org. Chem., 2005, 70, 10717-10719; (e) C. S. Aric et al., Org. Biomol. Chem., 2004, 2, 2558-2562; (f) B.-M. Fan et al., Angew. Chem. Int. Ed., 2007, 46, 1275-1277.

6. 7. 8. 9.

2.

147

References
Miscellaneous 1. For recent applications of (Me3Si)3SiH in radical chemistry: 1 2 3 2. L. A. Gandon et al., J. Org. Chem., 2006, 71, 5198-5207. A. Postigo et al., Org. Lett., 2007, 9, 5159-5162. C. Chatgilialoglu, Chem. Eur. J., 2008, 14, 2310-2320.

Silylmetallation: 1 2 3 4 For an overview of the silylmetallation of alkenes: S. Nakamura et al., Chem. Eur. J., 2008, 14, 1068-1078. Silylboranes in the synthesis of siloles: T. Ohmura et al., J. Am. Chem. Soc., 2008, 130, 1526-1527. Silylboration of alkynes: T. Ohmura et al., Chem. Commun., 2008, 1416-1418. Silylzincation of alkynes: G. Auer et al., Chem. Commun., 2006, 311-313.

3.

Organo[2-hydroxymethyl)phenyl]dimethylsilanes for Rh-cat. conjugate addition reactions: Y. Nakao et al., J. Am. Chem. Soc., 2007, 129, 9137-9143. Rh-cat enantioselective 1,4-addition of silylboronic esters: C. Walter et al., Angew. Chem. Int. Ed., 2006, 45, 5675-5677. Rh-cat. arylation of tertiary silanes: Y. Yamanoi et al., J. Org. Chem., 2008, 73, 6671-6678. Rh-cat. coupling of 2-silylphenylboronic acids with alkynes for benzosilole synthesis: M. Tobisu et al., J. Am. Chem. Soc., 2009, 131, 7506-7507. Si-based benzylic 1,4-rearrangement / cyclisation reaction: B. M. Trost et al., Org. Lett., 2009, 11, 511-513.

4.

5. 6.

7.

148

References
Miscellaneous (contd) 8. Pd-cat. intramolecular coupling of 2-[(2-pyrrolyl)silyl]aryl triflates through 1,2-silicon migration: K. Mochida et al., J. Am. Chem. Soc., 2009, 131, 8350-8351. Synthesis of tetraorganosilanes by Ag-catalysed transmetallation between chlorosilanes and Grignard reagents: K. Murakami et al., Angew. Chem. Int. Ed., 2008, 47, 5833-5835. Synthesis of (arylalkenyl)silanes by Pd-cat. allyl transfer from silyl-substituted homoallylic alcohols to aryl halides: S. Hayashi et al., J. Am. Chem. Soc., 2007, 129, 12650-12651. Use of cyclopropyl silyl ethers as homoenols: application to the synthesis of 7-ring carbocycles: O. L Epstein et al., Angew. Chem. Int. Ed., 2006, 45, 4988-4991. Accelerated electrocyclic ring-opening of benzocyclobutenes under the influence of a -silicon atom: Y. Matsuya et al., J. Am. Chem. Soc., 2006, 128, 412-413. Enantioselective synthesis of silanols: K. Igawa et al., J. Am. Chem. Soc., 2008, 130, 16132-16133.

9.

10.

11.

12.

13.

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