Recent Advances in Organosilicon Chemistry

Home , Brook rearrangement, Hiyama coupling, Organosilicon, Silenes, Silyl enol ether, Silyl ether

Liam Cox

SCI Annual Review Meeting December 2009 Contents

1. Silicon - basic properties, why Silicon?

2. Allylsilanes and related nucleophiles

3. Organosilanes in Pd-Catalysed cross-coupling

4. Brook rearrangement chemistry

5. Low coordination silicon compounds

6. Silicon Lewis acids

7. Silicon protecting groups

8. Using the temporary silicon connection

9. Biological applications

2 Silicon − Fundamental Properties

3 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

C−Si and H−Si bonds are polarised:

! ! ! ! Si C Si H

4 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 H Si cf C Me Me H H Me H

O O O O Si O Si Si O O O O O Si O 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.

2 F F 2 x F F F Si Si F F F 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 β-Positive Charge

Silicon is better at stabilising β-positive charge than is carbon.

This stabilisation effect is stereoelectronic in origin and often known as the β-Si- effect.1

Si Si

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

7 β-Silicon Effect E

empty empty p AO p AO !C-Si

1 "E !C-C "E2 "E1 > "E2

filled filled !C-Si MO !C-C MO Si C empty p AO

The higher energy σC-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 α-Negative Charge

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

Si R C R is more stable than

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

1. Empty 3d AOs allow pπ-dπ bonding. Si C

empty 3d AO filled sp3 HAO

2. Overlap between the filled orbital σ " of the metal-carbon bond and the ! Si-C Si Si (unfilled orbital) unfilled σ*C−Si orbital is energetically M favourable. The larger coefficient on M the silicon atom in the σ* MO further !M-C improves the orbital overlap. (filled orbital)

9 Stabilisation of α-Negative Charge

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

This effect is probably the most important mechanism for stabilising α-negative charge. 10 Bond Strengths and Bond Lengths

bond strength bond bond length (Å) (kJ mol−1)

Si−H 318 (in Me3SiH) 1.48

Si−C 318 (in Me4Si) 1.85

Si−O 452 (in Me3SiOMe) 1.66

Si−F 565 (in Me3SiF) 1.57

Key points:

1) Bonds to Si are approximately 25% longer than the same bonds to C; 2) Si−O and Si−F bonds are much stronger than Si−C and Si−H 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

SiMe3 allyltrimethylsilane

cheap and commercially available

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

LA LA LA O O O OH

SiMe3 R H R H R R

SiMe3 Nu

15 Mechanism

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

O LA OLA R H H H " R H !

SiMe3 SiMe3

reaction proceeds open T.S. through the γ-carbon (range of staggered reactive conformations need to be considered)

16 Mechanism

!* LUMO O LA R O LA R O LA H H R H

H H H H H H H H

HOMO Si Si Nu silyl group remote carbocation stabilised from reacting centre by "-Si effect

17 Enantioselective Allylation

18 Enantioselective Allylation of Aldehydes

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

OH 20 mol% 10 mol% TiF4 (S)-BINOL OH

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 Kobayashi:7 NH HN Nap 11 mol% Nap

NCbz 10 mol% Cu(OTf)2 NHCbz EtO EtO H SiMe3 O O 3 Å MS, 0 °C, CH2Cl2 73%, 88% e.e.

NTroc Troc SiMe3 NH EtO EtO EtO P H conditions as above EtO P O O 73%, 89% e.e. Nap = !-naphthyl 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 OH OH O SnBu3 R R R H BF3·OEt2, 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 H LB SiCl SiCl 3 SiCl3 R O 3

poor Nu LB good Nu

chair T.S. regenerate ensures catalyst predictable OSiCl 3 H LB syn / anti SiCl selectivity R R O 3 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 O P N N PhCHO 1 eq. OH

CH2Cl2, !78 °C, 6 h Ph SiCl3 72%, 83 : 17 e.r. syn/anti 98 : 2

PhCHO OH conditions as above Ph SiCl3 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%

N O N H O H P P H N N H N 5 N PhCHO OH

i Ph SiCl3 PrNEt2, CH2Cl2, !78 °C, 8-10 h 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 α-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

tBu O O tBu N S S O O O O O OMe N 2 N H Ph sulfoxides19 amine oxides17 pyridine N-oxides and related systems18

S O P Ph N Ph Ph2 Ph 2 H O P O S 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

160 °C, 24 h Si No Reaction Ph PhCHO

Si O 130 °C, 12 h Si PhCHO Ph Ph

85%

26 Strain-Induced Lewis Acidity

O Si O Si 90° (ideal for two groups occupying strain released apical and equatorial on coordination positions in a trigonal bipyramid)

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

RCHO, CH Cl , 2 2 OH N !10 °C, 20 h Si Cl R N 95-98% e.e.

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

28 Enantioselective Allylation of Imines

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

NHAr NHAr

Ph Ph Ph Ph

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

O MeSO3H, toluene, !78 °C CHO Ph Ph OH

88%, d.e. > 95%

Brønsted 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 Brønsted 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 reported.28

SiMe TBDPSO 3 H H OTBDPS TMSO O Et 10 mol% TMSOTf

CH2Cl2, 5 h, ! 78 °C CHO Et 81%, d.r. > 95:1

TMSOTf

SiMe3 TBDPSO Me O H RO H

H Et OTBDPS

Felkin-Anh control Markó28a 32 Allylsilanes in Multicomponent Reactions

PhCHO OTES 5 mol% BiBr3 R CH Cl , rt 2 2 R O Ph R = C5H11 SiMe3 70%, single diastereoisomer

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

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

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

34 Intramolecular Hosomi Sakurai Reaction

Under Lewis acid-activation, allylsilanes are good nucleophiles for conjugate addition reactions to α,β-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

BF3·OEt2 O OH O OH H CH2Cl2 SiMe2Ph !78 to !10 °C

81%, 98% d.e. H

BF3 O PhMe2Si H

chair-like T.S. with maximum H O number of substituents adopting H H pseudoequatorial positions 35 Reactions of Allylsilanes with other Electrophiles

Activated alkynes31

OH Ph Ph Ph Ph Si Si 1 mol% PPh3AuCl / AgSbF6 O R rt, CH Cl 2 2 R R = C6H13 71%, (Z):(E) 10:1

AuLn

HOR Ph Ph Ph Ph Ph Ph L Au Si LnAu Si n LnAu Si OR R R R

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 γ-terminus of the allylsilane to provide a cationic intermediate that collapses to provide an allyl fluoride (SE2’) product. OBz OBz OBz

SiMe3 "F " SiMe3 desilylation

F F

Cl N Selectfluor is the most commonly N 2 BF4 used electrophilic fluorine source. F 37 Stereoselective Electrophilic Fluorination of Allylsilanes

Substrate control:33

SiMe3 OBn OBn OBn Selectfluor 82% OBn F OBn F OBn 82 : 18

Auxiliary control:34

O O F O O Selectfluor Me3Si N O N O Bn Bn Bn Bn 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 F Bn Bn K2CO3, MeCN, !20 °C, 9 h

63%, 93% e.e.

Et Et N Ph N O O H H H H MeO N N OMe

Ph N N

(DHQ)2PYR 39 Electrophilic Fluorination of other Organosilanes

allenylsilanes36

PhMe Si H 2 H Selectfluor Cy · Bu Cy MeCN Bu F e.e. > 90% anti SE2' e.e. > 90% 47% allenylmethylsilanes37 Selectfluor F Me3Si NaHCO3, acetone · 99% Ph Ph

vinylsilanes38 Selectfluor C H C6H13 6 13 MeCN F SiMe3 45% (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 i OLA OLA Si Pr3 Nu i RCHO Si Pr3 R R RDS slow fast

O R

i Si Pr3

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 i OLA OLA Si Pr3 SiiPr i 3 RCHO Si Pr3 R R

O i R LA OLA Si Pr3

R i Si Pr3

43 Roush’s 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 OTBDPS HO OTBDMS

8 TBDMSO

O 8 SiMe2Ph

O CHO

HO O 9 PhMe Si asimicin 2 TBDMSO 9

44 Roush’s Synthesis of Asimicin

1 R SiMe2Ph d.r. > 20:1 O SnCl R1 4 H R1 O H PhMe2Si SiMe2Ph H H R2 H O CHO

SnCl4, CH2Cl2, 4 Å MS, O 0 °C, 3.5 h, 80% O

PhMe2Si PhMe2Si R2 R2

The excellent diastereoselectivity of this reaction was attributed to the matched facial selectivity associated with using a chiral allylsilane (anti SE2’) and SnCl4- chelated 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 Somfai’s synthesis of highly functionalised pyrrolidines where the sulfonamide functions as an internal nucleophile trap:42,43

O OLA PhMe Si SiMe Ph R 2 2 R SiMe Ph H 2 MeAlCl2, !78 °C, CH2Cl2 NHTs TsHN

SiMe2Ph

HO OH HO SiMe2Ph KBr, AcOOH

R stereospecific oxidation N R of Si!C bonds N Ts OH Ts SiMe Ph Tamao-Fleming44 2 d.e. > 98:2

46 Synthesis of Allylsilanes

47 Cross Metathesis Approach

Cross-metathesis provides an efficient route to γ-substituted allylsilanes.45 Allyl- trimethylsilane is a Type I alkene according to Grubbs’ classification46 and homo- dimerises readily. The homodimer readily takes part in secondary cross-metathesis processes. Particularly good results are obtained with Type II olefins:45a

MesN NMes Cl Ru (E) : (Z) 30:1 5 mol% Cl O O i Pr OEt Me Si Me Si 3 3 EtO CH2Cl2, rt O 1 eq. 3 eq. ref 45a 40%

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 OH 5 mol% Grubbs II Me Si Ph Ph SiMe3 3 CH2Cl2, 4 h, ! 4 eq. 1 eq. ref 45c 86% 48 A Silylsilylation Approach

SiMe2Ph 2 mol% NC Ph2Si Pd(acac)2 8 mol% xylene, ! C6H13 O C6H13 H ii) nBuLi, THF, t then KO Bu, 50 °C SiMe2Ph 99.7% e.e. 90%, 99.1% e.e.

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

49 Mechanism

SiMe2Ph Ph2Si R O R O SiPh2 Si Si

Ph2Si O Pd(0) oxidative addition into Si!Si bond R

Ph O Si Pd Si chair-like T.S., Me pseudoeq. Me R minimises 1,3-diaxial int'ns Ph Si H R syn-silasilylation of olefin

Ph2Si O Ph strain-induced O SiPh O H Lewis acidity drives 2 Si Si O SiPh2 dimerisation Me R Ph R H H R Si Si

50 Mechanism

R O SiPh2 Si Si O SiR3 Ph2Si O R R' syn-specific ring syn-specific contraction R Peterson H

SiMe2Ph

R SiPh2Nu Ph2 Si O Ph Si O Si n t 2 BuLi, KO Bu R Ph2Si H O

O SiMe2Ph Nu

51 Allenyl, Propargyl and Vinylsilanes

52 Allenylsilanes

Since the C−Si bond can align with the nucleophilic π-bond, allenylsilanes react in an 51 anti SE2’ fashion similar to allylsilanes. 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 H cat. EtCO2H SiMe2Ph · xylenes, ! CO2Me

SiMe2Ph 99% e.e. 81%, 98% e.e.

CHO TMSO Br H Ar BF3·OEt2, MeCN, "20 °C O · SiMe2Ph O Me H CO2Me CO2Me

proposed reactive conformation 78%, >20:1 d.r. Br

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 Brønsted acid activation to afford allenyl alcohol products.

· O O MeSO3H, CH2Cl2, !78 °C SiMe3 Ph O Ph OH

ref 27 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 O O OMOM OTBS MeO O OH O

O OH O NH SiMe3 2 PMP HO OH NIS H MeCN, 95% O O O OMOM OTBS MeO (+)-discodermolide

55 Enantioselective Vinylation of Aldehydes

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

i) CuF ·2H O, DTBM-SEGPHOS, RCHO 2 2 OH DMF, 40 °C

ii) TBAF R Si(OMe)3 84-99% e.e. tBu OMe O t P Bu 2 P tBu O OMe t Bu 2 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 CuF 2 transmetallation Si(OMe)3 Si(OMe)3 CuLn F

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 Cross- Coupling 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 Pd catalyst

R OTf M X S M

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 C−Si 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.

II ArPd X R3SiX + Nu Nu SiR3 SiR3 Pd Ar Nu Ar

The substituents on the silyl group are also important. Silanes containing electron- withdrawing groups tend to be most useful: Me2FSi−, MeF2Si− (but not F3Si−) are 2 good, as are alkoxysilanes (Me2(RO)Si− and Me(RO)2Si− better than (RO)3Si−). 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 OH [Pd(dba)2] R1 Si 2 eq. base, r.t., DME R2

61 Denmark Modifications

t A range of bases can be employed including: NaO Bu, 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 base- mediated 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 MX Ar R OH B R O M R O Si Si Si Pd Ln

intramolecular Si O transmetallation n reductive R elimination R Ar 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 > i t Pr2SiOH > Si(OEt3) >> Bu2SiOH

For TMSOK-activated cross-couplings, the order of reactivity is:

Ph2SiOH > (CF3CH2CH2)MeSiOH > MeSi(OEt)2 > Me2SiOH > Si(OEt3) ~ Me2Si(OEt) >> i Pr2SiOH

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 R1 2 eq. TMSOK SiMe OH 2.5 mol% [Pd(dba) ] RMe Si 2 2 2 RMe2Si dioxane, rt R2 I THF, rt R = 2-thienyl or benzyl 2 eq. TBAF

2.5 mol% [Pd(dba)2]

Lopez has recently applied this cross-coupling strategy to a highly stereoselective synthesis R2 of retinoids.6

64 Biaryl Synthesis

Hiyama couplings have been used to prepare biaryls, including, after optimisation, particularly challenging 2-aryl heterocycles:7

I CF3

5 mol% [Pd2(dba)3·CHCl3] MeO MeO OH t 2 eq. NaO Bu, 0.25 eq. Cu(OAc)2 Si CF3 N toluene, 3 h, 4 h, 82% N Boc Boc

Cl OMe

O Na 2.5 mol% [(allyl)PdCl]2 OMe Si THF, 60 °C, 8 h 5 mol% O O 77% PCy2 MeO OMe

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 7 inclusion of a copper salt all need to be considered. 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] N 1.5 eq. Ag2O THF, 60 °C, 76%

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% NiCl2·glyme 15 mol% ephedrine Br PhSiF3 Ph 12 mol% LiHMDS, 8 mol% H2O 3.8 eq. CsF, DMA, 60 °C 88%

O O conditions as above N PhSiF3 N Cl O Ph O

86%

67 Hiyama Couplings in Pd-Catalysed Sequences Prestat and Poli used a Pd-catalysed intramolecular allylic alkylation − Hiyama cross- coupling sequence in their synthesis of a series of picropodophyllin analogues:10

Ar Ar 1 mol% Pd(OAc)2 Si Si 2 mol% dppe MeO2C MeO2C O O DMF, 60 °C, 1.5 h, 59% Ar = 2-thienyl O O O O MeO2C O 2.4 eq. TBAF O

2.5 mol% Pd2(dba)3 O THF, rt, 69% O I O O O

O O

HCO2H, THF, 0 °C O HO quant. MeO2C MeO2C

O O O O 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 9 mol% ionic gel Pd cat. Si Ph EtO Si Ph 1.4 eq. PS-TBAF Si 1.3 eq. dioxane, 60 °C, 2 h

filter through Celite Hiyama with more reactive alkoxysilane 3 eq. Ac O Narasaka with 2 remaining vinylsilane 5 mol% [RhCl(CO)2]2 90 °C, 24 h

83%

69 Direct Arylation of Cyclic Enamides In contrast to standard Hiyama couplings, which employ halide coupling partners, this example uses C−H 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 13 cycle. NHAc

Ag(0) O

Pd(OAc)2 Ag(I) HOAc

Pd(0)

NHAc HN O Ar Pd L OAc O HN O O Pd L Ar O ArSi(OMe)3F activated arylsilane facilitates transmetallation AcOSi(OMe)3 + F 70 Brook (and related) Chemistry

71 Brook Rearrangement

Si−F and Si−O bonds are notably stronger than Si−H and Si−C 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 so- called Brook rearrangement:1

SiMe OH O 3 1,2-Brook O B R SiMe R SiMe 3 3 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 Cu SiPh O 3 1,2-Brook O CuOtBu SiPh3 DMF SiPh3 Cu

The generated alkenyl copper species is ripe for further elaboration:

Cl Ph SiO OSiPh3 OSiPh3 3 PhI, [Pd(PPh3)4] R R R 61% Cu 71% Ph

R = Me R = PhCH2CH2

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 O i) tBuLi

SitBuMe ii) PhCHO, Et2O SitBuMe S 2 S 2 !78 °C to !20 °C

EtCHO 1,4-Brook THF, DMPU !20 °C to 0 °C

Ph Ph t OSi BuMe2 t OSi BuMe2 Et S S H Et OH 50% O 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 β-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 Ph SnMe3 Ph SnMe3 nBuLi OH THF Li O SitBuPh Me3Sn O !78 °C 2 Si Ph Si Ph Selectfluor Ph tBu Ph tBu 1,4-retro Brook Ph F Ph F OH

SitBuPh t 2 SitBuPh Si BuPh2 2

F Ph

10 mol% TBAF 75 Ph Ph 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

O S t n t O SiMe2 Bu O BuLi, KO Bu S S THF, !78 °C S S S S THF, !78 °C R1 M R1 S OMe O S S t SiMe2 Bu R1 1,4-Brook

Si* Si* 1,4-Brook t SiMe2 Bu O O THF O S S S S S S S S S S S 1 !78 °C 1 R1 R R S d.r. 1.3 : 1 O SiMe O OSiMe3 3 THF, !78 °C to 0 °C Me3Si H Br Si*

O O OH S S S S TBAF S S S S O R1 37% (2 steps) OSiMe3 OMe OH 76 ref 8d 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

HO Ph ref 9c SiMe3 SiMe3F TBAF PhCHO S H S H S H S S S

note: overall retention of configuration cf: H H H Ph n S H BuLi S Li PhCHO S S THF, !78 °C S S OH

77 Fluoride-Mediated Carbanion Generation

Trifluoromethylation:

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

CF3 F Me Me3Si CF3 Si Me "CF3 " Me F

E 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

CF3 Me3SiCF3 Bn CF3CO2H, KHF2 N H MeCN, rt, 3 h Ph O Bn O 73% N Ph O O Bn Me3SiCF3 , TBAF N Ph THF, 4 °C, 18 h F3C O

OH 70% 79 Trifluoromethylation of Imines

The authors proposed the reaction was mediated by HF, generated in situ from KHF2 - and the Brønsted 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 H R2 H R2 N HF N N

1 1 1 R H R H R CF3

CF3 Me Si Me Me F H F

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 R R R R2C R dimerisation C Si Si Si Si R R R R R silene silylene 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 π bonds:

R R R R Si Si R Si R

silacyclopropane silacyclopropene

Insertion reactions into σ bonds (e.g. O−H, Si−H, Si−O) 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

t t tBu tBu t Bu Bu h! Bu dimerisation Si Si Si Si tBu Me3Si SiMe3 tBu tBu

t t Bu AgX Ag Bu Si Si tBu X 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 Si O 5 mol% AgOTf Bu OMe 20 mol% ZnBr2, HCO2Me Bu

87%, d.r. 76:24

t tBu Bu OMe tBu tBu Si O Si O Bu H Bu OMe H strain-induced regioselective insertion Lewis acidity into C=O group 85 Application to 1,2,4-Triol Synthesis5,6

OH OH Pr Bu OTIPS Ph

t Bu OH 10 mol% Bu 82% (2 steps) i) LiAlH (d.r. >99:1) Ag PO Si 4 3 4 tBu ii) TBAF tButBu Si tBu tBu O O Si Ph Pr Bu OTIPS Bu O 89% d.r. 92:6:2 PrCHO, CuI regioselective C=O insertion tBu tBu tBu PhCHO t Si O Bu Si O 25 mol% Sc(OTf)3 O 2 mol% CSA Pr 1,3-Brook Pr Bu Bu 2:1 PhMe:CH2Cl2 Ph OTIPS OTIPS !78 °C to 22 °C 86% Mukaiyama aldol 86 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 4π-electrocyclisation to provide the strained product.

t Bu tBu Si tBu tBu Si Ph NBn 1 mol% AgOTf Ph NBn 80%

" t " Ag Bu Si TfO tBu 4!-electrocyclic tBu Si Ph N tBu Bn

87 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 Si−N bond.7 tBu t iPr Bu tBu tBu PhCHO Si Si 1 mol% AgOTf N O iPr NBn Bn >95% (by NMR) d.r. 91:9 Ph

In contrast, reaction with tert-butylisocyanide (a softer E+) proceeds via insertion into the more covalent Si−C bond.7

tBu tBu tBuN t Bu Si tBu Si tBuNC, 23 °C N iPr NBn >95% (by NMR) iPr Bn 88 Silaaziridines

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

t Bu i) Ph H NHBn tBu Si [Pd(PPh3)4], 50 - 80 °C iPr iPr NBn ii) KOtBu, TBAF Ph Pd(0) step ii protodesilylation 72% oxidative tBu addition tBu tBu Pd Si tBu Si Bn N step i N iPr Bn

tBu tBu Ph iPr Ph H Si Bn 90% N regioselective alkyne insertion i reductive Ph Pd Pr Pd(0) elimination 89 Silenes

Silenes are also reactive species. Traditionally, they have been generated by thermolysis processes:1

O OSiMe3 180 °C R Si(SiMe ) R Si(SiMe ) 3 3 Brook 3 2

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

SiMe3 SiMe3 Ph Ph SiMe SiMe3 BuLi, Si 3 Si(SiMe )Ph Si 10 mol% LiBr Peterson 3

R OH R O R 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 α,β-unsaturated carbonyls.

Si(SiMe ) Ph BuLi 3 2 Si(SiMe )Ph 10 mol% LiBr 3 Ph OH Ph H

Diels-Alder ref 9

allylsilane Tamao-Fleming chemistry Si Ph oxidation ref 10 ref 11 SiMe3

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 1 2 bistrifluoromethanesulfonamides (R3SiNTf2), developed by Ghosez and Mikami, are proving particularly useful.

In light of their very high reactivity, R3SiNTf2 Lewis acids are most conveniently prepared in situ from the corresponding Brønsted acid and an allylsilane or related species:

HNTf2

SiR 3 R3Si NTf2

(g)

93 Application3

OTMS 1.4 eq. t O OAc Bu O OAc 5 mol% HNTf2 N N O CH2Cl2, 15 min, 0 °C Bn OAc Bn 90% tBu > 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 4 Sawamura. 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 OTMS 1 mol% LA OH O toluene, !78 °C Ph Ph Ph 1 h Ph

Et3Si(toluene) B(C6F5)4 97%

TMSNTf2 12% TMSOTf 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 SiCl SiCl (LB) Cl 4 SiCl4(LB) 3

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

N O 10 mol% OSiCl O 3 Ph Ph SiCl , iPr NEt, CH Cl Ph Ph 4 2 2 2 !78 °C, 48 h Cl

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 O The Lewis acid is readily prepared from pseudoe- Ph Si phedrine and PhSiCl3 as an inconsequential 2:1 Cl mixture of diastereoisomers. N Me Me

NHBz N

R H

H N Reaction with the acyl hydrazone generates an activated N Ph intermediate in which the faces of the electrophile are Ph Si O sterically differentiated. O Ph NMe H Me Cl 97 Synthetic Application

d.r. ~ 2:1 O Ph O Ph Ph NHBz 1.5 eq. Si Cl N N HN N Me Me Ph OtBu Ph OtBu H toluene, 23 °C, 24 h 2 84%, d.r. 96 : 4, 90% e.e. 2 i) AcCl ii) TMSOTf,

SiMe3 iii) SmI [3 + 2] cycloaddition of acyl hydrazones with tert- 2 butyl vinyl ether proceeds with excellent enantioselectivity and diastereoselectivity to NHAc NHBz provide an aminal product that is primed for Ph further reaction.6 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

d.r. ~ 2:1 p-CF -C H O 3 6 4 Ph O O tBu NH 1.3 eq. Si Ar(O)CHN N N Cl NH O Me Me Ph Ph OMe Me OTMS 2 Me PhCF3 , 23 °C, 30 min 89%, 90% e.e. OMe

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 R1 R2 1 2 3 R R R SiOTf Si F source R OH R O R3 R OH base, B

B·HCl or B·HOTf

101 Formation of Silyl Ethers

New methods for forming silyl ethers that avoid the formation of HX·amine 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. O OH O S Et3SiO O OSiEt3 OEt OEt 20 °C, CH2Cl2, < 5 min quant (1H-NMR)

O 1.5 eq. S t t OH OSi BuMe2 OSi BuMe2 Ph Ph 20 °C, 7 h, CH2Cl2 quench excess reagent quant (1H-NMR) with MeOH to generate volatiles side-products

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

t C8H17 C8H17 2 mol% CuO Bu Et SiO HO 3 99 2 mol% DTBM-xantphos : OH OSiEt3 Et3SiH, 22 °C, 19 h, toluene 1 95% C8H17 C8H17

t PAr2 PAr2 Bu O DTBM-xantphos = Ar = OMe

tBu

Under the optimised conditions, a range of silanes can be employed, although poor i results are observed with very hindered silanes such as Pr3SiH. 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 SiPPh O 2 2 O 5 mol% [(dppp)Rh(cod)]ClO4 5 mol% dppp, Et3N

1,4-dioxane!H2O 10:1 60 °C, 2 d PPh2 77%

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 O 6 mol% phosphoramidite ligand OH

2 eq. Et3SiOK, CH2Cl2, rt Ph O OtBu Ph ii) TBAF 88%, 97% e.e.

O Ph ligand = P N O Ph

t i BuMe2SiOK and Pr3SiOK could also be used if the the desired product is a alcohol that is protected as a more robust silyl ether.

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 Jørgensen, have been used particularly widely, for example in this recent example of a direct enantioselective α-benzoylation of aldehydes.6

t OSi BuMe2 N Ph H Ph 20 mol% O 1.5 eq. BzOOBz THF, rt, 20 h OH H then NaBH4 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. OPMB TBAF, THF O Ph O µw, 90 °C O HO OR 74%

OPMB OH O Ph O Ph O O O DDQ O O OR O OR CH2Cl2-H2O 80% R = adamantyl

F F t t OSi BuPh2 OSi BuPh2 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.

56% conversion N 5 mol% CuCl N d.r. = 86:14 N 10 mol% PAr3 5 mol% NaOtBu toluene, 25 °C Ph OH Ph O Si Ph OH t 96% e.e. Bu 1.0 eq. 84% e.e. H Si tBu DIBALH 0.6 eq.

H Si tBu Ph OH 78%, 71% e.e. 98%, 96% 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 H N MeN N H N O tBu OH OH 20 mol% HO OH TESO OH TESCl, DIPEA THF, !78 °C, 48 h tBu H 85%, > 98% e.e. Me H N N MeN H H t O Bu N H H H O Et O O Cl Si R Et 109 Et 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 tBu i) tBuLi, PhH, rt P Br P Si Ph ii) Cl H Si H Ph tBu Cl O N P = polystyrene resin O N Cl tBu P Si Ph Cl

R OH

i) solid-supported t chemistry Bu R' OH P Si Ph ii) TASF, rt, < 1 h O 110 R 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

form silyl R R R R tether FG1 FG2 FG1 FG2 X Y Si

reaction

R R R R remove tether

X' Y' Si

112 Silyl Ether Connection in Intramolecular Allylation2

SiMe3 Et Et Et Et Si Si O TMSOTf, 2,6-DTBMP O 21:1

O CH2Cl2, !78 °C O OTMS O >95:5

H2O2, KF, KHCO3, 1. silyl ether links allylsilane to aldehyde THF-MeOH

2. highly stereoselective intramolecular allylation OH OH

3. subsequent stereospecific (retention of configuration) oxidative cleavage of silyl tether O OH provides a stereodefined 1,2,4-triol

113 Tandem Silylformylation-Crotylation- Oxidation Route to Polyketides4 ref 4a

Si O H O Si O Rh(acac)2(CO)2

iPr CO, PhH, 60 °C iPr H intramolecular silylformylation intramolecular crotylation

H2O2, KF, OH O OH THF-MeOH O Si O 40 °C iPr iPr C!Si oxidation and diastereoselective 62% protonation 15 : 1 (major: all minor diastereoisomers) 114 Diastereoselective Oxidative Coupling of Bis-Silyl Enol Ethers5

CAN, NaHCO O O O 3 Si MeCN, !10 °C R R O

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

d / l meso

R O ! Si " R O increase increase decrease destabilise T.S. size of R size of ! size of " leading to meso

116 Silyl-Tethered Tandem Ring-Closing Metathesis6

HO O O EtO2C Roush TBSO H H

O OTBS ref 7 O H OAc H H TBSO HO

(!)-cochleamycin A

117 Formation of Metathesis Precursor

OEt Si Si EtO OH O

S R1 S 10 mol% NaH, hexane 2 81% R R1

PivO

HO 10 mol% NaH, Note the use of silyl R2 hexane 8 acetylides as an alternative Si 68% to silyl chlorides or silyl O O triflates for silyletherification R1

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

R2 O Si Grubbs II Si O O O

1 R R1

TBAF

Double RCM generates an intermediate R2 bicyclic siloxane. Subsequent fluoride- induced protodesilylation provides the HO stereodefined (E,Z)-1,3-diene. (Z) H HO (E) R1

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 F

N N N N HO Si O N N Si N N N Si N flusilazole N F antifungal agent ($$$)

Pc4 (photodynamic agent for application in cancer treatment) F

Si Ph OH OPh

Si silafluofen N EtO insecticide ($$$)

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 R2 2 2 O R HO OH R H2O O H3N N N H protease H R1 O R1 O R1 O peptide chain 2 HO OH R Si

R1 O

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 Angiotensin- Converting Enzyme (ACE)

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

O HO OH H H Ph N N Ph N Si N

O Bn O CO2H O Bn 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

Ph Ph Ph H TfOH H Ph N Si N Ph N H Si N

t t O Bn O CO2 Bu O Bn O CO2 Bu

! 2 PhH

Ph O F F NH OH H 4 CO H Ph N Si N Si 2 HF HN (aq) O N O Bn O CO2H Bn

NaOH

HO OH H Ph N Si N

O Bn 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 config’n: 1s2, 2s2, 2p6, 3s2, 3p2 pos’n in Periodic Table: Period 3, therefore capable of expanding its valence state stereoelectronics: C−Si bond is good at stabilising β-positive charge bond strengths: Si−O and Si−F bonds are significantly stronger than Si−C and Si−H bonds.

126 References

127 References General References and introductory section

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.

2. 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.

3. 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.

4. (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.

5. 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. Soc., 2002, 124, 12928-12929; (c) A. Bottoni et al., J. Am. Chem. Soc., 1997, 119, 12131-12135. 128 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.

7. H. Kiyohara et al., Angew. Chem. Int. Ed., 2006, 45, 1615-1617.

8. For the classification of allyl metals: (a) R. W. Hoffmann, Angew. Chem. Int. Ed. Engl., 1982, 21, 555-566; (b) ref 4c.

9. (a) K. Ishihara et al., J. Am. Chem. Soc., 1993, 115, 11490-11495; (b) S. Aoki et al., Tetrahedron, 1993, 49, 1783-1792.

10. G. E. Keck et al., J. Org. Chem., 1994, 59, 7889-7896.

11. For a review on stereoselective allylation: Y. Yamamoto, Acc. Chem. Res., 1987, 20, 243-249.

12. S. Kobayashi et al., J. Org. Chem., 1994, 59, 6620-6628.

13. Lewis base activation of silyl nucleophiles has been recently reviewed, see: J. Gawronski et al., Chem. Rev., 2008, 108, 5227-5252.

14. S. E. Denmark et al., J. Org. Chem., 2006, 71, 1513-1522.

15. S. E. Denmark et al., J. Org. Chem., 2006, 71, 1523-1536.

16. For reviews on chiral Lewis base-catalysed allylations: S. E. Denmark et al., Chem. Commun., 2003, 167- 170. 129 References

Allylation and related nucleophiles (contd)

17. (a) J. F. Traverse et al., Org. Lett., 2005, 7, 3151-3154; (b) V. Simonini et al., Synlett, 2008, 1061-1065..

18. (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.

19. (a) P. Wang et al., Org. Biomol. Chem., 2009, 7, 3741-3747; (b) A. Massa et al., Tetrahedron: Asymmetry, 2009, 20, 202-204.

20. (a) V. Simonini et al., Adv. Synth. Catal., 2008, 350, 561-564; (b) S. Kotani et al., Tetrahedron, 2007, 63, 3122-3132.

21. K. Iseki et al., Tetrahedron, 1999, 55, 977-988.

22. K. Matsumoto et al., J. Org. Chem., 1994, 59, 7152-7155.

23. (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.

24. 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.

25. J. D. Huber et al., Angew. Chem. Int. Ed., 2008, 47, 3037-3039.

26. J. D. Huber et al., J. Am. Chem. Soc., 2007, 129, 14552-14553.

27. P. J. Jervis et al., Org. Lett., 2006, 8, 4649-4652. 130 References

Allylation and related nucleophiles (contd)

28. (a) J. Posp ísil 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.

29. S. A. Rodgen et al., Angew. Chem. Int. Ed., 2006, 45, 4929-4932.

30. B. D. Stevens et al., J. Org. Chem., 2005, 70, 4375-4379.

31. S. Park et al., J. Am. Chem. Soc., 2006, 128, 10664-10665.

32. 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.

33. S. Purser et al., Chem. Eur. J., 2006, 12, 9176-9185.

34. M. Tredwell et al., Org. Lett., 2005, 7, 1267-1270.

35. T. Ishimaru et al., Angew. Chem. Int. Ed. Engl., 2008, 47, 4157-4161 and references therein.

36. (a) L. Carroll et al., Org. Biomol. Chem., 2008, 6, 1731-1733; (b) L. Carroll et al., Chem. Commun., 2006, 4113-4115.

37. M. C. Pacheco et al., Org. Lett., 2005, 7, 1267-1270.

38. B. Greedy et al., Chem. Commun., 2001, 233-234.

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.

40. J. M. Tinsley et al., J. Am. Chem. Soc., 2005, 127, 10818-10819.

41. G. E. Keck et al., J. Am. Chem. Soc., 1995, 117, 6210-6223.

42. M. Dressel et al., Chem. Eur. J., 2008, 14, 3072-3077.

43. Isocyanates have also been used to trap β-carbocations resulting in heterocyclic ring products: A. Romero et al., Org. Lett., 2006, 8, 2127-2130.

44. For reviews on the oxidation of C−Si bonds: (a) I. Fleming, Chemtracts: Org. Chem., 1996, 9, 1-64; (b) G. R. Jones et al., Tetrahedron, 1995, 52, 7599-7662.

45. (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.

46. A. K. Chatterjee et al., J. Am. Chem. Soc., 2003, 125, 11360-11370.

47. 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.

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. McNulty et al., Chem. Commun., 2008, 1244-1245.

49. (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.

50. 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.

51. 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.

52. (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.

53. A. Arefelov et al., J. Am. Chem. Soc., 2005, 127, 5596-5603. This paper also provides a powerful illustration of Panek’s 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.

54. 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.

55. D. A. Evans et al., J. Am. Chem. Soc., 2006, 128, 11034-11035. 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.

2 S. E. Denmark et al., J. Org. Chem., 2006, 71, 8500-8509.

3 S. E. Denmark et al., J. Am. Chem. Soc., 2004, 126, 4865-4874.

4 S. E. Denmark et al., J. Am. Chem. Soc., 2004, 126, 4876-4882.

5 S. E. Denmark et al., J. Am. Chem. Soc., 2005, 127, 8004-8005.

6 J. Montenegro et al., Org. Lett., 2009, 11, 141-144.

7 (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.

8 (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, 5821- 5822; (g) Y. Nakao et al., J. Am. Chem. Soc., 2005, 127, 6952-6953.

9 N. A. Strotman et al., Angew. Chem. Int. Ed., 2007, 46, 3556-3558.

10 M. Vitale et al., J. Org. Chem., 2008, 73, 5795-5805.

134 References

Organosilanes in metal-catalysed cross-coupling chemistry (contd)

11. C. Thiot et al., Eur. J. Org. Chem., 2009, 3219-3227.

12. 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.

13. H. Zhou et al., Angew. Chem. Int. Ed., 2009, 48, 5355-5357.

14. 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;

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.

2 A. Tsubouchi et al., J. Am. Chem. Soc., 2006, 128, 14268-14269.

3 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.

4 N. O. Devarie-Baez et al., Org. Lett., 2007, 9, 4655-4658.

5 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, 3363- 3366.

6 (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.

7 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.

8 (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.

136 References

Brook Chemistry (contd)

9. (a) A. Degl’Innocenti 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.

10. For a review on the use of this reagent: R. P. Singh et al., Tetrahedron, 2000, 56, 7613-7632.

11. V. V. Levin et al., Eur. J. Org. Chem., 2008, 5226-5230.

137 References Low coordination silicon compounds

1 For a recent overview: H. Ottosson et al., Chem. Eur. J., 2006, 12, 1576-1585.

2 (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, 9993- 10002.

3 (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.

4 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.

5 T. B. Clark et al., Org. Lett., 2006, 8, 4109-4112.

6 For other examples of silylene transfer to alkynes: (a) W. S. Palmer et al., Organometallics, 2001, 20, 3691- 3697; (b) T. B. Clark et al., J. Am. Chem. Soc., 2004, 126, 9520-9521.

7 Z. Nevárez et al., Org. Lett., 2007, 9, 3773-3776.

8 (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.

9 (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.

10 (a) N. J. Hughes et al., Org. Biomol. Chem., 2007, 5, 2841-2848; (b) J. D. Sellars et al., Tetrahedron, 2009, 65, 5588-5595. 138 11 J. D. Sellars et al., Org. Biomol. Chem., 2006, 4, 3223-3224. References

Silicon Lewis acids

1 B. Mathieu et al., Tetrahedron Lett., 1997, 38, 5497-5500.

2 A. Ishii et al., Synlett, 1997, 1145-1146.

3 R. B. Othman et al., Org. Lett., 2005, 7, 5335-5337.

4 K. Hara et al., Org. Lett., 2005, 7, 5621-5623.

5 N. Takenaka et al., Angew. Chem. Int. Ed., 2008, 47, 9708-9710.

6 S. Shirakawa et al., J. Am. Chem. Soc., 2005, 127, 9974-9975.

7 G. T. Notte et al., J. Am. Chem. Soc., 2008, 130, 6676-6677.

8 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 X. Huang et al., Chem. Commun., 2005, 1297-1299.

2 (a) H. Ito et al., Org. Lett., 2005, 7, 1869-1871; (b) H. Ito et al., Org. Lett., 2005, 7, 3001-3004.

3 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.

4 V. T. Trepohl et al., Chem. Commun., 2007, 3300-3302.

5 I. Lyothier et al., Angew. Chem. Int. Ed., 2006, 45, 6204-6207.

6 H. Gotoh et al., Chem. Commun., 2009, 3083-3085 and references therein.

7 D. Crich et al., J. Org. Chem., 2009, 74, 2486-2493.

8 For the development of very bulky silyl protecting groups for stabilising oligoynes: W. A. Chalifoux et al., Eur. J. Org. Chem., 2007, 1001-1006.

9 (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.

10 Y. Zhao et al., Nature, 2006, 443, 67-70.

11 Z. You et al., Angew. Chem. Int. Ed., 2009, 48, 547-550.

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.

13 For the use of chiral silyl ethers in diastereoselective synthesis: M. Campagna et al., Org. Lett., 2007, 9, 3793-3796.

14 (a) C. M. DiBlasi et al., Org. Lett., 2005, 7, 1777-1780; (b) A. Ohkubo et al., J. Org. Chem., 2009, 74, 2817- 2823; (c) T. Lavergne et al., Eur. J. Org. Chem., 2009, 2190-2194.

15 For an application of fluorous silyl ether protecting groups in natural product synthesis: Y. Fukui et al., Org. Lett., 2006, 8, 301-304.

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.

2 J. Beignet et al., J. Org. Chem., 2008, 73, 5462-5475.

3 For another recent example where a temporary Silicon connection was used with allylsilanes: J. Robertson et al., Org. Biomol. Chem., 2008, 6, 2628-2635.

4 (a) J. T. Spletstoser et al., Org. Lett., 2008, 10, 5593-5596; see also: (b) S. J. O’Malley 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.

5 C. T. Avetta, Jr., et al., Org. Lett., 2008, 10, 5621-5624.

6 S. Mukherjee et al., Org. Lett., 2009, 11, 2916-2919.

7 T. A. Dineen et al., Org. Lett., 2004, 6, 2043-2046.

8 J. B. Grimm et al., J. Org. Chem., 2004, 69, 8967-8970.

9 For other recent examples where temporary Silicon connections have been usefully employed in synthesis: (a) C. Rodríguez-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. 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.

2 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 S. E. Denmark et al., J. Am. Chem. Soc., 2007, 129, 14684-14865. 2 S. E. Denmark et al., J. Am. Chem. Soc., 2006, 128, 1038-1039. 3 S. E. Denmark et al., J. Am. Chem. Soc., 2005, 127, 3774-3789. 4 S. E. Denmark et al., J. Org. Soc., 2005, 70, 5235-5248 5 S. E. Denmark et al., J. Org. Soc., 2005, 70, 10823-10840. 6 S. E. Denmark et al., J. Org. Soc., 2005, 70, 10393-10399. 7 M. Hatano et al., Org. Lett., 2007, 9, 4527-4530.

2 Enantioselective synthesis of quaternary stereogenic centres:

1 K. Mikami et al., J. Am. Chem. Soc., 2007, 129, 12950-12951. 2 A. H. Mermerian et al., J. Am. Chem. Soc., 2005, 127, 5604-5607. 3 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 T. Poisson et al., Angew. Chem. Int. Ed., 2007, 46, 7090-7093. 2 A. Yanagisawa et al., Angew. Chem. Int. Ed., 2005, 44, 1546-1548.

4. Enantioselective synthesis of quaternary stereogenic centres:

1 K. Mikami et al., J. Am. Chem. Soc., 2007, 129, 12950-12951. 2 A. H. Mermerian et al., J. Am. Chem. Soc., 2005, 127, 5604-5607. 3 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, 4556- 4557.

6. Silyl enol ethers as the ene component of enyne cyclisations: B. K. Corkey et al., J. Am. Chem. Soc., 2007, 129, 2764-2765.

7. Alkylation of silyl enol ethers: E. Bélanger et al., J. Am. Chem. Soc., 2007, 129, 1034-1035.

8. Silyl enol ethers and related species in conjugate addition reactions:

1 T. E. Reynolds et al., Org. Lett., 2008, 10, 2449-2452. 2 N. Takenaka et al., J. Am. Chem. Soc., 2007, 129, 742-743.

9. Applications of (tristrimethylsilyl)silyl enol ethers:

1 M. B. Boxer et al., J. Am. Chem. Soc., 2007, 129, 2762-2763. 2 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 Silver-catalysed hydrosilylation of aldehydes: B. M. Wile et al., Chem. Commun., 2006, 4104- 4106. 2 Enantioselective hydrosilylation of ketones: (a) L. Zhou et al., Chem. Commun., 2007, 2977- 2979; (b) N. S. Shaikh et al., Angew. Chem. Int. Ed., 2008, 47, 2497-2501. 3 Hydrosilylation of ketones: (a) S. Díes-González 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). 4 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. César et al., Chem. Eur. J., 2005, 11, 2862-2873.

2 Amide reduction:

1 Practical synthesis of 2° and 3° amines: S. Hanada et al., J. Org. Chem., 2007, 72, 7551- 7559. 2 Chemoselective amide reduction in the presence of ketones and esters: H. Sasakuma et al., Chem. Commun., 2007, 4916-4918.

3 Dehydration of amides to nitriles:

1 S. Zhou et al., Chem. Commun., 2009, 4883-4885. 2 S. Zhou et al., Org. Lett., 2009, 11, 2461-2464. 146 References

Silanes as reducing agents (contd)

4. Reductive amination: O.-Y. Lee et al., J. Org. Chem., 2008, 73, 8829-8837.

5. 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.

6. Reduction of alkyl halides: J. Yang et al., J. Am. Chem. Soc., 2007, 129, 12656-12657.

7. Cleavage of alkyl ethers: J. Yang et al., J. Am. Chem. Soc., 2008, 130, 17509-17518.

8. Reduction of propargylic alcohols: Y. Nishibayashi et al., Angew. Chem. Int. Ed., 2006, 45, 4835-4839.

9. 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. 2. 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. Aricó et al., Org. Biomol. Chem., 2004, 2, 2558-2562; (f) B.-M. Fan et al., Angew. Chem. Int. Ed., 2007, 46, 1275-1277.

147 References

Miscellaneous

1. For recent applications of (Me3Si)3SiH in radical chemistry:

1 L. A. Gandon et al., J. Org. Chem., 2006, 71, 5198-5207. 2 A. Postigo et al., Org. Lett., 2007, 9, 5159-5162. 3 C. Chatgilialoglu, Chem. Eur. J., 2008, 14, 2310-2320.

2. Silylmetallation:

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

4. Rh-cat enantioselective 1,4-addition of silylboronic esters: C. Walter et al., Angew. Chem. Int. Ed., 2006, 45, 5675-5677.

5. Rh-cat. arylation of tertiary silanes: Y. Yamanoi et al., J. Org. Chem., 2008, 73, 6671-6678.

6. Rh-cat. coupling of 2-silylphenylboronic acids with alkynes for benzosilole synthesis: M. Tobisu et al., J. Am. Chem. Soc., 2009, 131, 7506-7507.

7. Si-based benzylic 1,4-rearrangement / cyclisation reaction: B. M. Trost et al., Org. Lett., 2009, 11, 511-513. 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.

9. Synthesis of tetraorganosilanes by Ag-catalysed transmetallation between chlorosilanes and Grignard reagents: K. Murakami et al., Angew. Chem. Int. Ed., 2008, 47, 5833-5835.

10. 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.

11. 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.

12. Accelerated electrocyclic ring-opening of benzocyclobutenes under the influence of a β-silicon atom: Y. Matsuya et al., J. Am. Chem. Soc., 2006, 128, 412-413.

13. Enantioselective synthesis of silanols: K. Igawa et al., J. Am. Chem. Soc., 2008, 130, 16132-16133.

149