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Recent Advances inOrganosilicon Chemistry
Liam Cox
SCI Annual Review Meeting December 2009
2
Contents1. 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
3
Silicon − FundamentalProperties
4
SiliconPosition 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
! !
5
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
SiMe
Me
Mecf
H
CH
H
H
O
SiO
O
O
Si
Si
Si
O
O
O
OO
O
OO
O
6
SiliconThe availability of relatively low energy empty 3d AOs allows Si to attain highercoordination numbers (hypervalent silicon compounds).
Electronegative substituents lower the energy of the 3d AOs, which facilitates theformation of hypervalent silicon compounds.
We will see later how the ability of Si to expand its valence state has ramificationson the mechanisms of many reactions proceeding at Si.
hexafluorosilicate dianion
F
SiF
F
F
F
Si
F
F F
F F
2
2 x F
7
Stabilisation of β-Positive ChargeSilicon 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 theadjacent carbocationic centre.
8
β-Silicon Effect
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 overlapand increased stabilisation.
Siemptyp AO
filled !C-Si MO
E
"E1
"E2
>"E1 "E2
empty p AO
!C-C
!C-Si
empty p AO
C
filled !C-C MO
9
Stabilisation of α-Negative Charge
Carbanions with an α-silicon group are more stable than their carbon analogues:
RSi is more stable than RC
Si exerts a weak +I inductive effect through the σ-framework − but this shoulddestabilise α-negative charge. This effect is over-ridden by a number of factors:
1. Empty 3d AOs allow pπ-dπ bonding.
2. Overlap between the filled σ orbitalof the metal-carbon bond and theunfilled σ*C−Si orbital is energeticallyfavourable. The larger coefficient onthe silicon atom in the σ* MO furtherimproves the orbital overlap.
Si C
empty 3d AO filled sp3 HAO
!M-C
!"Si-CSi
M
(filled orbital)
(unfilled orbital)
M
Si
10
Stabilisation of α-Negative Charge 3. Si is a relatively large atom (van der Waals radius ~2.1 Å) and thereforereadily polarised. Induced dipoles will also stabilise proximal negative charge.
This effect is probably the most important mechanism for stabilising α-negativecharge.
R
Si
11
Bond Strengths and Bond Lengths
1.57565 (in Me3SiF)Si−F
1.66452 (in Me3SiOMe)Si−O
1.85318 (in Me4Si)Si−C
1.48318 (in Me3SiH)Si−H
bond length (Å)bond strength
(kJ mol−1)bond
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.
12
Why Silicon?
13
Attractive Features of OrganosiliconChemistry
Organosilanes display many attractive properties:
• compared with other organometallic reagents they are much moremoisture- 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 ofSilicon
14
Allylsilanes andRelated Nucleophiles
15
Allyltrialkylsilanes
allyltrimethylsilane
cheap and commercially available
not a strong nucleophile;1 thus reaction with aldehydes generally requiresan external Lewis acid.2,3
SiMe3
O
HR
LAO
HR
LAO
R
LA
SiMe3
Nu
OH
R
SiMe3
16
Mechanism
Reaction proceeds through an anti SE2’ reaction pathway.4,5
O
RH
LA
SiMe3
H H
OLA
HR
SiMe3
!
"
open T.S.(range of staggered
reactive conformations needto be considered)
reaction proceedsthrough the γ-carbon
17
Mechanism
O
RH
LA
Si
ORH
LA
Si
HH
H HH
!* LUMO
HOMO
ORH
LA
H HH
Nucarbocation stabilised
by "-Si effectsilyl group remote
from reacting centre
18
Enantioselective Allylation
19
Enantioselective Allylation ofAldehydes
Use a chiral Lewis acid to differentiate the enantiotopic faces of the electrophile:6
O
H
SiMe3
i) 10 mol% active catalyst
CH2Cl2, 0 °C, 4 hOH
90%, 94% e.e
OH
OH(S)-BINOL20 mol% 10 mol% TiF4
MeCN
ii) TBAF, THF
Carreira
20
Enantioselective Allylation of Imines
SiMe3
EtO
O
NCbz
H
NH HN
Ph Ph
10 mol% Cu(OTf)2
3 Å MS, 0 °C, CH2Cl2
Nap Nap
EtO
O
NHCbz
11 mol%
73%, 88% e.e.
Kobayashi:7
Nap = !-naphthyl
EtOP
O
NTroc
H
EtOSiMe3
conditions as above EtOP
O
NH
EtO
Troc
73%, 89% e.e.
21
Stereoselective CrotylationType II allylating agents8 have traditionally not been used widely to effect thestereoselective crotylation of aldehydes: reactions with crotylsilanes are particularlyrare.9
The analogous reaction with crotylstannanes is usually syn-selective.10,11
Effective enantioselective variants have not been developed.9
R H
O SnBu3
(E) : (Z) 90:1
BF3·OEt2, CH2Cl2, !78 °CR
OH
R
OH
R = Ph, syn:anti 98:2 (85%)R = Cy, syn:anti 94:6 (88%)
syn anti
22
AllyltrichlorosilanesUsed on their own, allyltrichlorosilanes are poor allylating agents. However, theirreactivity can be significantly increased when used in the presence of DMF,12 whichacts as a Lewis base activator13 (remember, Si can expand its valence state). Thisobservation opened up the possibility of using chiral Lewis bases to effect theenantioselective allylation of aldehydes using allyltrichlorosilanes.
SiCl3
LBpoor Nu
SiCl3
LB
good Nu
SiCl3OR
H LB
SiCl3OR
H LB
R
OSiCl3
chair T.S.ensures
predictablesyn / antiselectivity
regeneratecatalyst
syn
23
Chiral PhosphoramidesDenmark was the first to exploit chiral Lewis bases as catalysts for the enantio-selective crotylation of aldehydes with allyltrichlorosilanes:14
SiCl3
PhCHO
Ph
OH
68%, 80 : 20 e.r.
syn/anti 2 : 98
conditions as above
SiCl3
PhCHO
N
P
N O
N
1 eq.
CH2Cl2, !78 °C, 6 h Ph
OH
72%, 83 : 17 e.r.
syn/anti 98 : 2
24
Chiral PhosphoramidesCareful analysis of the mechanism of the reaction and consideration of thereactive transition state structures led to the development of improved catalystsbased on a bis-phosphoramide scaffold:15,16
Aliphatic aldehydes are not good substrates for the reaction. Under the reactionconditions, rapid formation of the α-chloro silyl ether occurs. Inclusion of HgCl2 asan additive improves the yield of the allylation; however enantioselectivity iscompromised.15
SiCl3
PhCHO
iPrNEt2, CH2Cl2, !78 °C, 8-10 hPh
OH
82%, 92.8 : 7.2 e.r.
syn:anti 1 : 99
N
P
N
N NP
N
NO O
H
HH
H5
5 mol%
25
Other Chiral Lewis Base Catalysts
N
O O
NH Ph
amine oxides17sulfoxides19
pyridine N-oxides and relatedsystems18
N
OMe
O
O
SOtBu
O
SO tBu
2
S
S
Ph2
P
PPh2
O
O
diphosphine oxides20
Ph N Ph
H O
formamides21
26
Strain-Induced Lewis AcidityWe have seen how the stereoselectivity of an allylation can be improved andpredicted by forcing the reaction to proceed via a closed chair-like T.S. by makingthe Si atom more Lewis acidic. Another way of increasing the Lewis acidity of theSi centre is to include the Si atom in a small ring:22
PhSi
PhCHO
130 °C, 12 h
Ph
OSi
85%
PhSi
PhCHO
160 °C, 24 h
No Reaction
27
Strain-Induced Lewis Acidity
Si 90° (ideal for
two groups occupying
apical and equatorial
positions in a trigonal
bipyramid)
OSi
O
strain released
on coordination
28
Leighton’s Allylsilanes
reagents are crystalline, shelf-stable, and easy to prepare
Leighton has introduced a range of allylsilanes in which the Si atom is containedwithin a five-membered ring. The long Si−N and short C−N bonds ensure thesilacycle is still strained. The electronegative N and Cl substituents further enhancethe Lewis acidity of the Si centre.23, 24
N
Si
N
Cl
Br
Br
RCHO, CH2Cl2,
!10 °C, 20 h
R
OH
95-98% e.e.
29
Enantioselective Allylation of Imines
Of particular note in these examples, the choice of nitrogen substituent in the iminedetermines the diastereoselectivity of the reaction.26
Leighton has recently used a related class of chiral γ-substituted allylsilane, readilyprepared from the simple allylsilane by cross metathesis, in enantioselective imineallylation.25
NMe
Si
O
Ph
Ph
Cl
Ph
N
HOH
NHAr
Ph
Ph
Ph
N
H
OH
NHAr
Ph
Ph
68%, 7:1 d.r., 96% e.e. 64%, >20:1 d.r., 96% e.e.
syn-selective anti-selective
30
More Allylsilane Chemistry
31
Substrate-Controlled StereoselectiveAllylations in Ring Synthesis
Intramolecular allylation provides an excellent opportunity for generating rings. Sincecyclisation frequently proceeds through well-defined transition states, levels of stereo-selectivity can be excellent.
Brønsted acids are not commonly used as activators for reactions involvingallylsilanes owing to the propensity for these reagents to undergoprotodesilylation.
This was not a problem in this example however; indeed in this case, the use ofLewis acid activators led to a reduction in diastereoselectivity.27
O
CHOPh
SiMe3
MeSO3H, toluene, !78 °C
Ph OH
88%, d.e. > 95%
32
Allylsilanes in Multicomponent ReactionsLewis- or Brønsted acid-mediated reaction of alcohols or silyl ethers with aldehydesand ketones affords oxacarbenium cations. These reactive electrophiles reactreadily with allylsilanes. Both inter- and intramolecular variants have beenreported.28
OTBDPS
HMe
CHO
OTBDPS TMSO
Et
SiMe3
10 mol% TMSOTf
CH2Cl2, 5 h, ! 78 °C
O Et
TBDPSOH H
81%, d.r. > 95:1
TBDPSO
O
Et
RO H
SiMe3
H
TMSOTf
Felkin-Anh control
Markó28a
33
Allylsilanes in Multicomponent Reactions
In this example, condensation of the TES ether with PhCHO generates oxacarbeniumion I. Further rearrangement to a second oxacarbenium II reveals an allylsilane,which undergoes cyclisation.28b
R
OTES
SiMe3R = C5H11
5 mol% BiBr3
CH2Cl2, rt
PhCHO
OR Ph
70%, single diastereoisomer
O
R
Ph
SiO
R
SiMe3
Ph
oxonia-Cope reveals
a more reactive allylsilane
OR Ph
SiMe3
I II
34
Vinylsilanes are Poor NucleophilesAllylsilanes are far more nucleophilic than vinylsilanes. In an allylsilane, the C−Sibond can align with the developing β-positive charge. In a vinylsilane, the C−Si bondis initially orthogonal to the empty p AO. As a result, the C−Si bond needs to undergoa 60° bond rotation before it can optimally stabilise the β-positive charge. As aconsequence, vinylsilanes are not much more nucleophilic than standard olefins.
Si
E
H
C!Si bond orthogonal
to " bond
H H
E
SiH
HH
H H
E
Si
H
bond
rotation
35
Intramolecular Hosomi Sakurai ReactionUnder Lewis acid-activation, allylsilanes are good nucleophiles for conjugateaddition reactions to α,β-unsaturated carbonyl compounds. Schauss used anintramolecular version of this reaction in a synthesis of the trans decalin scaffoldfound in the clerodane diterpenoid natural products.29,30
H
O
H
BF3
O
PhMe2Si
HH
chair-like T.S. with maximum
number of substituents adopting
pseudoequatorial positions
O OH
SiMe2Ph
O OHH
H
BF3·OEt2
CH2Cl2
!78 to !10 °C
81%, 98% d.e.
36
Reactions of Allylsilanes with otherElectrophiles
Activated alkynes31
R
Si
Ph Ph
1 mol% PPh3AuCl / AgSbF6
rt, CH2Cl2
OH
OSi
Ph Ph
R
71%, (Z):(E) 10:1
AuLn
R
Si
Ph Ph
LnAu SiLnAu
R
Ph Ph
R = C6H13
SiLnAu
R
Ph Ph
OR
HOR
37
Reactions of Allylsilanes withElectrophilic Fluorine Sources
Regio- and stereoselective fluorination strategies
Allylsilanes react with electrophilic halogen sources. Of particular interest is theuse of ‘F+’ electrophiles as a means for generating organofluorines in a controlledmanner.32 As expected, fluorination occurs regiospecifically at the γ-terminus of theallylsilane to provide a cationic intermediate that collapses to provide an allylfluoride (SE2’) product.
SiMe3 "F " SiMe3
F
OBz OBz
desilylation
F
OBz
N
N
Cl
F
2 BF4
Selectfluor is the most commonlyused electrophilic fluorine source.
38
Stereoselective ElectrophilicFluorination of Allylsilanes
Substrate control:33
Auxiliary control:34
OBn
OBn
Selectfluor
SiMe3
OBn
OBnF
OBn
OBnF
82 : 18
82%
Me3Si
Bn
N
O
O
O
Bn
Bn
N
O
O
O
Bn
F
syn : anti = 1 : 2
(diastereoisomers separable)
Selectfluor
39
Enantioselective ElectrophilicFluorination of Allylsilanes
Reagent control: Catalytic enantioselective fluorination of allylsilanes hasrecently also been disclosed:35
N
O
N N
O
N
Ph
Ph
MeO OMe
N
Et
HH
H
N
Et
H
(DHQ)2PYR
Bn10 mol% (DHQ)2PYR
K2CO3, MeCN, !20 °C, 9 h Bn
F
63%, 93% e.e.
F-N(SO2Ph)2 (NFSI)
SiMe3
40
Electrophilic Fluorination of otherOrganosilanes
allenylsilanes36
allenylmethylsilanes37
vinylsilanes38Selectfluor
MeCNC6H13
SiMe3
C6H13
F
(Z):(E) = 4:145%
·
Ph
Me3SiSelectfluor
NaHCO3, acetone
F
Ph
99%
·
PhMe2Si
Bu
H
Cy
Bu
F
CyH
Selectfluor
anti SE2'e.e. > 90% e.e. > 90%
MeCN
47%
41
[3+2] Annulation Approaches
42
Allylsilanes in Annulation ReactionsAllylation of aldehydes is a step-wise process, proceeding via a carbocationicintermediate. Normally, attack of an external nucleophile on the silyl group in thisintermediate is rapid, leading to a homoallylic alcohol product.
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 ofthe easiest ways to redirect the allylation reaction is to replace the methylsubstituents on the silyl group with bulkier groups. In this case, intramoleculartrapping of a carbocationic intermediate provides ring products.
R
OLA
SiiPr3RCHO
SiiPr3
LA
Nu
R
OLA
RDS slow
OR
SiiPr3
fast
43
Allylsilanes in Annulation ReactionsAlthough the product outcome is rather substrate-dependent, a tetrahydrofuran productis particularly common.39 This outcome requires rearrangement of the initially formedcationic intermediate:
R
OLA
SiiPr3RCHO
SiiPr3
LA
OR
SiiPr3
R
OLASiiPr3
R
OLA SiiPr3LA
44
Roush’s Synthesis of AsimicinRoush employed the [3+2] annulation of allylsilanes and aldehydes in the synthesis ofthe two tetrahydrofuran rings of asimicin.40
O
O
HO
OH
O
HO
8
9
CHO
O
TBDMSO
9
PhMe2Si
SiMe2Ph
TBDMSO
8
OTBDMS
OTBDPS
asimicin
45
Roush’s Synthesis of Asimicin
The excellent diastereoselectivity of this reaction was attributed to the matchedfacial selectivity associated with using a chiral allylsilane (anti SE2’) and SnCl4-chelated chiral aldehyde reacting through a syn synclinal T.S. as proposed byKeck.41
CHO
O
R2
PhMe2Si
SiMe2Ph
R1O
HH
H
O
H
H
R2
SiMe2PhR1
SnCl4
O
O
PhMe2Si
R1
R2
PhMe2Si
SnCl4, CH2Cl2, 4 Å MS,
0 °C, 3.5 h, 80%
d.r. > 20:1
46
[3+2] Annulation Route to PyrrolidinesA 1,2-silyl shift of the silyl group in the initially formed carbocationic intermediate issometimes unnecessary, as in Somfai’s synthesis of highly functionalisedpyrrolidines where the sulfonamide functions as an internal nucleophile trap:42,43
R
NHTs
H
O
PhMe2Si SiMe2Ph
MeAlCl2, !78 °C, CH2Cl2
NTs
R
SiMe2Ph
SiMe2PhHO
d.e. > 98:2
R
TsHN
OLA
SiMe2Ph
SiMe2Ph
KBr, AcOOH
stereospecific oxidation
of Si!C bondsNTs
R
OH
OHHO
Tamao-Fleming44
47
Synthesis of Allylsilanes
48
Cross Metathesis ApproachCross-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-metathesisprocesses. Particularly good results are obtained with Type II olefins:45a
If the cross-metathesis product is required from an allylsilane and an alkene ofsimilar reactivity, the best yields of product are obtained by employing theallylsilane in excess:45c
Me3Si
4 eq.
CH2Cl2, 4 h, !
(E) : (Z) 92 : 8
ref 45c
Ph
OH
1 eq.
Ph
OH
SiMe3
5 mol%
Grubbs II
86%
Me3Si EtO
O
1 eq. 3 eq.
Ru
OCl
Cl
iPr
NMesMesN
Me3SiOEt
O
5 mol%
CH2Cl2, rt
40%
(E) : (Z) 30:1
ref 45a
49
A Silylsilylation Approach
Use of a temporary silyl ether connection47 enables an intramolecular bis-silylation of the proximal olefin. In the second step, syn-specific Peterson48 of anintermediate oxesiletane unveils the allylsilane product.49
Ph2Si
O
SiMe2Ph
C6H13
NC2 mol%
Pd(acac)2
xylene, !
8 mol%
i)
ii) nBuLi, THF,
then KOtBu, 50 °C
H
SiMe2Ph
90%, 99.1% e.e.
C6H13
99.7% e.e.
50
Mechanism
Si
Ph
Ph2Si
O
SiMe2Ph
R
Pd
Me
Ph
R
O Si
H
Pd(0) oxidative addition into Si!Si bond
syn-silasilylation of olefin
Si
Ph
Me
Ph
R
O Si
H H
HO SiPh2
R
Si
Ph2Si O
SiPh2O
Si
R
Si
R
O SiPh2
R
Si
OPh2Si
R
Si
strain-induced
Lewis acidity drives
dimerisation
chair-like T.S., Me pseudoeq.
minimises 1,3-diaxial int'ns
51
Mechanism
Ph2Si O
SiPh2O
Si
R
Si
R
syn-specific ring
contraction
SiMe2Ph
H
R
O
Ph2SiO
Ph2
SiSi
R
nBuLi, KOtBu
NuSiMe2Ph
H
R
O
Ph2SiO
SiPh2Nu
syn-specific
Peterson
O SiR3
R'
52
Allenyl, Propargyl and Vinylsilanes
53
AllenylsilanesSince the C−Si bond can align with the nucleophilic π-bond, allenylsilanes react in ananti SE2’ fashion similar to allylsilanes.51 Chiral allenylsilanes can also be preparedenantioselectively, often by SN2’ displacement of a propargyl mesylate by a silylnucleophile, or in this example,52 by a Johnson orthoester Claisen rearrangement.
OH
SiMe2Ph
MeC(OMe)3
cat. EtCO2H
xylenes, !·
HSiMe2Ph
CO2Me
81%, 98% e.e.99% e.e.
CHO
Br
TMSO
BF3·OEt2, MeCN, "20 °C
Br
OCO2Me
78%, >20:1 d.r.
·
Me
H
O
Ar
H
SiMe2Ph
proposed reactive
conformation
CO2Me
54
Propargylsilanes
Propargylsilanes also react in an SE2’ fashion although anti selectivity is not as highas is observed with allyl- and allenylsilanes.51 Reaction with aldehydes, and relatedelectrophiles, proceeds under Lewis- or Brønsted acid activation to afford allenylalcohol products.
ref 27
O
Ph
SiMe3
O
MeSO3H, CH2Cl2, !78 °C O
Ph OH
·
single diastereoisomer
55
VinylsilanesWe have already explained why vinylsilanes are far less nucleophilic than allyl-,allenyl- and propargylsilanes. Nevertheless this class of organosilane still reacts withelectrophiles with predictable regioselectivity. Panek used a stereodefined vinylsilaneas a masked vinyl iodide in his synthesis of discodermolide. The trisubstituted vinyliodide was unmasked upon treatment with NIS. This iododesilylation proceeded withcomplete retention of configuration.53
MeO
O OO
PMP
OMOM
OTBS
SiMe3
MeO
O OO
PMP
OMOM
OTBS
I
NIS
MeCN, 95%
(+)-discodermolide
O
OH
O
HOH
OH
OH O NH2
O
56
Enantioselective Vinylation of AldehydesShibasaki used vinyltrimethoxysilane as a starting reagent in an enantioselectivevinylation of aldehydes in the presence of CuF2 and a chiral bis-phosphine.54
RCHO
Si(OMe)3
i) CuF2·2H2O, DTBM-SEGPHOS,
DMF, 40 °C
ii) TBAF
OH
R
O
O
P
P
OMe
tBu
tBu
tBu
OMe
tBu
2
2
DTBM-SEGPHOS
84-99% e.e.
57
Enantioselective Vinylation of Aldehydes
The likely nucleophile in this reaction is a vinylcopper reagent, which is generatedin situ by transmetallation of a fluoride-activated vinylsilane intermediate.
The formation of the hypervalent silyl species is important as transmetallation fromstandard organosilanes to other vinyl metal species is less efficient.
Evans has since reported an enantioselective vinylation of aldehydes that proceedsin the presence of a chiral scandium catalyst directly from a vinylsilanenucleophile.55
Si(OMe)3
CuF2
Si(OMe)3
F
transmetallation
activation
CuLn
58
Organosilanes in Cross-Coupling Reactions
59
DisconnectionPd-catalysed cross-coupling strategies require an ‘electrophilic’ coupling partner,usually an organohalide or pseudohalide (sulfonate, phosphate, diazonium spetc) and a ‘nucleophilic’ coupling partner. Commonly used organometallicreagents include B, Sn, Zn, Cu, Mg, Zr and Si species.
R
S
OTfR
M
SX M
Pd catalystPd catalyst
Reactions which employ organosilanes in this type of cross-coupling are commonlyreferred to as Hiyama couplings.1
60
Hiyama CouplingOwing to the low polarisation of the C−Si bond, organosilanes are relatively unreactivenucleophilic coupling partners for Pd(0)-catalysed cross-coupling reactions.
As a result, reaction is usually performed in the presence of an activator, typically afluoride source (TBAF, TASF etc).
In the presence of an activator, reaction proceeds more readily owing to the in situformation of a pentacoordinate siliconate species, which undergoes more rapidtransmetallation.
SiR3
Nu
SiR3
Nu
ArPdIIX
Pd
Ar
R3SiX + 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−) aregood, as are alkoxysilanes (Me2(RO)Si− and Me(RO)2Si− better than (RO)3Si−).2
61
Recent DevelopmentsAlkoxysilanes and silanols are particularly attractive coupling partners for Hiyamacouplings. Reactions proceed efficiently in the presence of a fluoride source.1,3
Hiyama couplings under fluoride-free conditions are also possible. Denmark hasmade significant contributions to this field,1,4 showing that organosilanols undergoPd-catalysed cross-coupling in the presence of a base.1,4
SiOHR1
I
2 eq. base, r.t., DME
[Pd(dba)2]R1
R2
R2
62
Denmark ModificationsA range of bases can be employed including: NaOtBu, NaH and Cs2CO3. KOSiMe3 is aparticularly 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 apentavalent siliconate species, rather transmetallation proceeds in a direct, intra-molecular fashion on an intermediate tetracoordinate PdII species:
SiOHR
SiO MR
ArPdIIX MX
SiOR
PdLn
Ar
PdLn
Ar
R
reductive
elimination
intramolecular
transmetallationSi O
n
ArR
B
63
Effect of Silicon Substituents
Denmark has studied the effect of silicon substituents on the efficiency of Hiyamacross-coupling reactions.2
For fluoride-activated cross-couplings, the order of reactivity is:
(CF3CH2CH2)MeSiOH > Me2SiOEt > Me2SiOH > Ph2SiOH > Et2SiOH > MeSi(OEt)2 >iPr2SiOH > Si(OEt3) >> tBu2SiOH
For TMSOK-activated cross-couplings, the order of reactivity is:
Ph2SiOH > (CF3CH2CH2)MeSiOH > MeSi(OEt)2 > Me2SiOH > Si(OEt3) ~ Me2Si(OEt) >>iPr2SiOH
Fluoride-activated cross-couplings tend to be faster and less sensitive to structuraland electronic features of the substrates than base-mediated couplings.
64
ApplicationsThe different activity of organosilanes can be exploited in sequential Hiyama couplingreactions:5
Lopez has recently applied this cross-couplingstrategy to a highly stereoselective synthesis of retinoids.6
SiMe2OHRMe2Si
I
2 eq. TMSOK
2.5 mol% [Pd(dba)2]
dioxane, rt
RMe2Si
I
2 eq. TBAF
THF, rtR = 2-thienyl or benzyl
R1
R1
R2
R1
R2
2.5 mol% [Pd(dba)2]
65
Biaryl SynthesisHiyama couplings have been used to prepare biaryls, including, after optimisation,particularly challenging 2-aryl heterocycles:7
These couplings require careful optimisation of the reaction conditions. Choice ofprotecting group on the indole nitrogen, pre-forming the sodium silanolate prior toreaction, judicious choice of Pd catalyst and ligand, and in some cases theinclusion of a copper salt all need to be considered.7
NBoc
MeO
Si
OH
I CF3
5 mol% [Pd2(dba)3·CHCl3]
2 eq. NaOtBu, 0.25 eq. Cu(OAc)2
toluene, 3 h, 4 h, 82% NBoc
MeO
CF3
O
Si
O Na
Cl OMe
O
OMeTHF, 60 °C, 8 h
2.5 mol% [(allyl)PdCl]2
MeO OMe
PCy2
5 mol%77%
66
All-Carbon Substituted Organosilanesfor Hiyama Couplings
Although silanols, fluorosilanes and alkoxysilanes are the most commonly employedcross-coupling agents for Hiyama couplings, a range of latent silane couplingpartners, which generate the reactive coupling agent in situ can also be used. Theseinclude, 2-pyridyl-, 2-thienyl, benzyl and allylsilanes:8
Yoshida has previously shown that 2-pyridylsilanes are useful alkenyl, alkynyl andbenzyl transfer agents; however in this example, in the presence of a Ag(I) salt, theallyldimethylsilyl group functions as a 2-pyridyl transfer agent.8a
N Si 5 mol% [Pd(PPh3)4]
1.5 eq. Ag2O
THF, 60 °C, 76%
I
1.5 eq.
N
67
Ni-Catalysed Hiyama ReactionsFu recently reported a Ni-catalysed variant of the Hiyama coupling between 2° alkylhalides and aryltrifluorosilanes.9 The inclusion of norephedrine as a ligand wasimportant for obtaining good yields of product.
Br
10 mol% NiCl2·glyme
15 mol% ephedrine
12 mol% LiHMDS, 8 mol% H2O
3.8 eq. CsF, DMA, 60 °C
PhSiF3 Ph
88%
Cl
N
O
O
PhSiF3
Ph
N
O
O
conditions as above
86%
68
Hiyama Couplings in Pd-CatalysedSequences
Prestat and Poli used a Pd-catalysed intramolecular allylic alkylation − Hiyama cross-coupling sequence in their synthesis of a series of picropodophyllin analogues:10
O
MeO2C
O
Si
Ar
O
O
MeO2C
1 mol% Pd(OAc)2
2 mol% dppe
DMF, 60 °C, 1.5 h, 59%
OO
MeO2C
Si
Ar
I
O
O
O
O
2.4 eq. TBAF
2.5 mol% Pd2(dba)3
THF, rt, 69%
OO
MeO2C
O
O
O
O
OO
OO
MeO2C
HO
HCO2H, THF, 0 °C
quant.
Ar = 2-thienyl
69
One-Pot Hiyama / Narasaka CouplingMioskowski exploited the different reactivity of differentially substituted vinylsilanesin a synthesis of stereodefined enones:11,12
SiSiEtO
Ph
1.0 eq. PhI
9 mol% ionic gel Pd cat.
1.4 eq. PS-TBAF
dioxane, 60 °C, 2 h1.3 eq.
SiPh
filter through Celite
O
3 eq. Ac2O
5 mol% [RhCl(CO)2]2
90 °C, 24 h
83%
Hiyama with more
reactive alkoxysilane
Narasaka with
remaining vinylsilane
70
Direct Arylation of Cyclic EnamidesIn contrast to standard Hiyama couplings, which employ halide coupling partners, thisexample uses C−H activation to generate the vinyl-Pd transmetallation precursor. TheAgF additive is proposed to play a dual role, activating the alkoxysilane towardstransmetallation, and as an oxidant in regenerating Pd(II) at the end of the catalyticcycle.13
O
NHAc
O
HN O
Pd
Pd(OAc)2
HOAc
OAc
L
O
HN O
Pd
Ar
L
ArSi(OMe)3F
AcOSi(OMe)3 + F
Pd(0)
Ag(I)
Ag(0)
O
NHAc
Ar
activated arylsilane
facilitates transmetallation
71
Brook (and related)Chemistry
72
Brook RearrangementSi−F and Si−O bonds are notably stronger than Si−H and Si−C bonds. This differencein bond strength can be a strong driving force for chemical reactions, and has beenparticularly widely exploited to generate carbanions from alkoxides through the so-called Brook rearrangement:1
R
OH
SiMe3
B
R
O
SiMe3
O
R
SiMe3
1,2-Brook
1,2-retro-Brook
The rearrangement is reversible. The position of the equilibrium depends on a numberof factors including: i) solvent polarity, ii) anion-stabilising ability of the carbonsubstituents, 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 whereinvestigated, been shown to proceed via intramolecular silyl group transfer.
73
Novel Silyl Enol Ether SynthesisTreatment of acyl silanes with a copper alkoxide affords the corresponding copperenolate, which undergoes a 1,2-Brook rearrangement to afford the correspondingalkenylcopper species with high stereoselectivity. The use of DMF as solvent and acopper rather than alkali metal alkoxide is important to ensure smooth 1,2-silylmigration.2,3
The generated alkenyl copper species is ripe for further elaboration:
regioselective synthesis from ketoneusing standard deprotonation chemistry
would be difficult
R
OSiPh3
Cu
Cl
R
Ph3SiO
61%
PhI, [Pd(PPh3)4]
R
OSiPh3
Ph
R = Me
71%
R = PhCH2CH2
O
SiPh3
CuOtBu
DMF
O
SiPh3
Cu
O
Cu
SiPh3
1,2-Brook
74
One-Pot Synthesis of 2,3-DisubstitutedThiophenes
In this example from Xian, the inclusion of DMPU as a co-solvent was important toensure a smooth 1,4-Brook rearrangement:4,5
SSitBuMe2
Br
i) tBuLi
ii) PhCHO, Et2O
!78 °C to !20 °CS
SitBuMe2
Ph
O
EtCHO
THF, DMPU
!20 °C to 0 °C
S
Ph
OSitBuMe2
S
Ph
OSitBuMe2
OH
Et
1,4-Brook
50%
O
EtH
75
Retro Brook RearrangementsWhen used in its reverse sense, the retro-Brook rearrangement provides a useful methodfor preparing organosilanes. Cox used a 1,4-retro-Brook rearrangement to generatestereodefined tetrasubstituted β-halovinylsilanes, which serve as masked alkynes foroligoyne assembly. Intramolecular silyl group transfer allowed the incorporation ofbulky silyl groups, which would be difficult to introduce by standard intermoleculartrapping methods.6,7
Li
SnMe3
O
Si
tBu
Ph
Ph
Ph
Me3Sn
SnMe3
O
Si
tBu
Ph
Ph
Ph
nBuLi
THF
!78 °CSitBuPh2
SnMe3Ph
OH
1,4-retro Brook
Selectfluor
SitBuPh2
FPh
OH
SitBuPh2
F
F
SitBuPh2
Ph
Ph
Ph Ph
10 mol% TBAF
76
Anion Relay ChemistryOrganosilanes and Brook-type rearrangements have been employed to great effectin multicomponent synthesis. Recent work from Smith is particularly noteworthy:8
ref 8d
OMe
O
O
S
SnBuLi, KOtBu
THF, !78 °C
SiMe2tBu
O SS
R1
S S
R1 M
THF, !78 °C S S
R1
O SiMe2tBu
S
S
1,4-Brook
S S
R1
O
S
S
SiMe2tBu
O
HMe3Si
S S
R1
OSS
O SiMe3
Si*
!78 °C
THFS S
R1
OSS
OSiMe3
Si*
Br
THF, !78 °C
to 0 °C
S S
R1
OSS
OSiMe3
Si*
1,4-Brook
TBAF S SOH
SS
OHOMe
O
O
d.r. 1.3 : 1
37% (2 steps)
77
Fluoride Activation of Latent CarbanionsOther carbanionic nucleophiles can be unmasked from organosilanes, often providingan alternative to using a strong base on the corresponding protonated precursor.9Silylated 1,3-dithianes provide a nice illustration:8,9
S
S H
SiMe3
TBAF
S
S H
SiMe3F
PhCHO
S
S H
PhHO
note: overall retention
of configuration
cf:
ref 9c
nBuLi
THF, !78 °CS
S H
H
S
S Li
H
PhCHO
S
S
H
Ph
OH
78
Fluoride-Mediated Carbanion Generation
Trifluoromethylation:
The formation of a thermodynamically stable Si−F bond allows a range of organo-silanes to be used as latent carbanions. For example, the Ruppert-Prakash reagentMe3SiCF3 is a useful source of the CF3
− anion.10
Me3Si CF3
FCF3
Si Me
FMe
Me
"CF3 "
E
E CF3
79
Trifluoromethylation of IminesWhilst 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 Me3SiCF3in the presence of a fluoride source such as TBAF. Tartakovsky recently showed thattrifluoromethylation of simple imines proceeds under acidic conditions under optimisedconditions.11
O
O
Ph
NBn
O
O
Ph
NH
Bn
CF3
O
OH
F3C
NBn
Ph
CF3CO2H, KHF2
Me3SiCF3
MeCN, rt, 3 h
Me3SiCF3 , TBAF
THF, 4 °C, 18 h
73%
70%
80
Trifluoromethylation of IminesThe authors proposed the reaction was mediated by HF, generated in situ from KHF2and the Brønsted acid additive. CF3
- anion transfer proceeds via a hypervalent silylspecies, rather than the free CF3
- anion, which would be quenched under the acidicreaction conditions.
R1
N
H
H R2
R1
N
H
R2
HF
CF3
Si
FH
F
MeMe
Me
R1
N
CF3
H R2
81
Low-Coordinate SiliconCompounds
82
Silylenes, Silenes and Related SpeciesSince Silicon lies immediately below Carbon in the Periodic Table, much effort hasfocused on preparing the Silicon analogues of carbenes, olefins and relatedunsaturated species.1
Si
R
R
silylene
dimerisationSi Si
R
R R
R
disilene
R2C
C Si
R
R R
R
silene
Silenes, disilenes and silylenes and related low-coordinate Silicon species tend tobe highly reactive; however this instability can be tempered by using sterically verybulky substituents and donor groups. Metal coordination offers another importantstabilisation strategy.
83
Silylenes
Silylenes are the Silicon analogues of carbenes. They invariably possess singletground states and as a consequence of the vacant orbital on the Silicon, are highlyelectrophilic in character.
In analogy with singlet carbenes, the chemistry of silylenes is typified by additionto π bonds:
Insertion reactions into σ bonds (e.g. O−H, Si−H, Si−O) are also common. In thesecases, reaction often proceeds via a nucleophilic addition-rearrangementmechanism.
Si
R
RSi Si
R RR R
silacyclopropane silacyclopropene
84
Silylene PreparationSilylenes have commonly been accessed by thermolysis- or photolysis-inducedfragmentation or rearrangement processes. They dimerise readily to thecorresponding disilene; however in the presence of a suitable trapping agent, suchas cyclohexene, the silylene can react to afford the correspondingsilacyclopropane. With bulky tert-butyl substituents on the silicon, this speciesexhibits sufficient stability for its application as a silylene transfer agent undermetal catalysis.2
Si
tButBu
Me3Si SiMe3
h!Si
tBu
tBu dimerisationSi Si
tBu
tBu tBu
tBu
Si
tBu
tBu
AgX
X
AgSi
tBu
tBu
silver silylenoid
85
Metal-Catalysed Silylene TransferIn the presence of metal salts, commonly Ag(I) salts, silacyclopropanes react to afforda metal silylenoid species, (cf. metal carbenoids formed from diazo compounds andRh or Cu species). The resulting silver silylenoid displays a rich chemistry that hasbeen investigated in significant detail by Woerpel.2-4
Si
tBu
tBu
Bu5 mol% AgOTf
20 mol% ZnBr2, HCO2Me
Bu
Si
tButBu
O
OMe
H Bu
Si
tButBu
O
OMe
H
Bu
OSi
tBu
tBu
OMe
87%, d.r. 76:24
regioselective insertion into C=O group
strain-inducedLewis acidity
ref 3
86
Si
tBu
tBu
10 mol%
Ag3PO4
Bu OTIPS
Bu OTIPS
Si
tBu tBu
Bu
OSi
OTIPS
Pr
tButBu 25 mol% Sc(OTf)3
2 mol% CSA
2:1 PhMe:CH2Cl2
!78 °C to 22 °C
OSi
O
tButBu
Ph
Bu O
Pr
PhCHO
d.r. 92:6:2
89%
Ph
OH
Bu
OH
Pr
OH
i) LiAlH4 (d.r. >99:1)
ii) TBAF
82%
(2 steps)
OSi
OTIPS
Pr
Bu
O
Ph
86%
tButBu
PrCHO, CuI
Application to 1,2,4-Triol Synthesis5,6
regioselective C=O insertion
Mukaiyama aldol
1,3-Brook
87
Metal-Catalysed Silylene Transfer to IminesSilylene transfer to imines is also possible.7 The mechanism of silaaziridine formationlikely proceeds via nucleophilic addition of the imine nitrogen to the electrophilicsilylenoid to provide an ylide which undergoes a 4π-electrocyclisation to provide thestrained product.
Ph NBn
Si
tBu
tBu
1 mol% AgOTf Ph NBn
Si
tButBu
80%
Si
tBu
tBu
Ag
TfO
" "
Ph NSi
tBu
tBu
Bn
4!-electrocyclic
88
SilaaziridinesSilaaziridines are sensitive to air and moisture; they can be isolated (with care) bydistillation. More commonly, they are used directly in further transformations.
They undergo ring-expansion reactions with aldehydes to afford the correspondingN,O-acetal resulting from insertion into the more ionic Si−N bond.7
In contrast, reaction with tert-butylisocyanide (a softer E+) proceeds via insertioninto the more covalent Si−C bond.7
iPr NBn
Si
tButBu
BnN O
Si
iPr
tBu
tBu
Ph
PhCHO
1 mol% AgOTf
>95% (by NMR) d.r. 91:9
iPr NBn
Si
tButBu
tBuNC, 23 °C
>95% (by NMR)N
Si
tBuNtBu
tBu
BniPr
89
SilaaziridinesAlkynes undergo regioselective insertion into the Si−C bond under Pd-catalysis toprovide an azasilacyclopentene ring-expanded product. Subsequent protodesilyl-ation affords an allylic amine product.7
iPr NBn
Si
tButBu
[Pd(PPh3)4], 50 - 80 °C
Ph Hi)
ii) KOtBu, TBAFPh
iPr
NHBn
Pd
N
Si
tBu
tBu
BniPr
Pd(0)
Pd
NSi
tBu tBu
Ph iPr
Bn
N
Si
Ph
tBu tBu
Bn
iPr
Ph H
Pd(0)
90%
step i
step ii
72%oxidative
addition
regioselective
alkyne insertion reductive
elimination
protodesilylation
90
SilenesSilenes are also reactive species. Traditionally, they have been generated bythermolysis processes:1
More recently, anionic approaches have allowed silenes to be generated under muchmilder conditions:1,8
R
Si(SiMe3)Ph
H
BuLi,
10 mol% LiBr
R
Si
O
PhSiMe3
SiMe3
R
Si
OH
PhSiMe3
SiMe3Peterson
R
O
Si(SiMe3)3
180 °C
R
OSiMe3
Si(SiMe3)2Brook
91
SilenesSilenes are reactive species. For example, they react in a [2+2] cycloadditionfashion with carbonyl compounds, imines, alkenes and alkynes, whilst [4+2]cycloaddition pathways are (usually) observed with dienes and α,β-unsaturatedcarbonyls.
cycloadduct ripe for elaboration
Ph
Si(SiMe3)2Ph
OH
Si Ph
SiMe3
BuLi
10 mol% LiBr
Ph
Si(SiMe3)Ph
H
Diels-Alder
d.r. 74:20:6
allylsilane
chemistry
45%
Tamao-Fleming
oxidation
ref 10
ref 9
ref 11
92
Silicon Lewis Acids
93
Strong Lewis AcidsTMSOTf, and to a lesser extent TMSCl, are synthetically Lewis acids. Recent variantsthat exhibit increased Lewis acidity have been introduced. Of these, trialkylsilylbistrifluoromethanesulfonamides (R3SiNTf2), developed by Ghosez1 and Mikami,2 areproving particularly useful.
In light of their very high reactivity, R3SiNTf2 Lewis acids are most convenientlyprepared in situ from the corresponding Brønsted acid and an allylsilane or relatedspecies:
SiR3
HNTf2
(g)
R3Si NTf2
94
Application3
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 adiastereoselective fashion by the silyl enol ether.
Reaction is 108 times faster than the TIPSOTf-catalysed process.
N
O
Bn OAc
OActBu
OTMS
5 mol% HNTf2
1.4 eq.
CH2Cl2, 15 min, 0 °CN
O
Bn
OAc
O
tBu90%
> 95 : 5
95
Even Stronger Lewis AcidsThe effect of the counteranion on the strength of silyl Lewis acids was studied bySawamura.4 Silyl borates of the form R3Si(L)BAr4, which contain a very weaklycoordinating counteranion, were shown to be even more powerful Lewis acids thansilyl bistrifluoromethanesulfonamides.
O
Ph
OTMS
Ph
Et3Si(toluene) B(C6F5)4
OH O
PhPh
1 mol% LA
toluene, !78 °C
1 h
97%
TMSNTf2
TMSOTf
12%
0%
Et3SiH Ph3CB(C6F5)4Et3Si(toluene) B(C6F5)4
toluene
Ph3CH
Preparation:
96
Lewis Base Activation of SiCl4Whilst SiCl4 is a very weak Lewis acid, we have already seen how Lewis baseadditives can generate much more reactive Lewis acidic species:
SiCl4
LB
SiCl4(LB) SiCl3(LB) Cl
In a nice illustration of this strategy, Takenaka recently used helical chiral pyridineN-oxide Lewis bases with SiCl4 in an efficient desymmetrisation of meso epoxides:5
N
O
O
Ph Ph
10 mol%
SiCl4 , iPr2NEt, CH2Cl2
!78 °C, 48 h
PhPh
OSiCl3
Cl
77%, 93% e.e.
97
Strain-Induced Lewis AcidityWe have already seen how Leighton has used strain-induced Lewis acidity inenantioselective allylation reactions with allylsilanes. Using a similar concept, he hasintroduced a new class of Silicon Lewis acids for enantioselective synthesis using acylhydrazones:6
The Lewis acid is readily prepared from pseudoe-phedrine and PhSiCl3 as an inconsequential 2:1mixture of diastereoisomers.
Reaction with the acyl hydrazone generates an activatedintermediate in which the faces of the electrophile aresterically differentiated.
NMe
Si
OPh
Me
Ph
Cl
d.r. ~ 2:1
N
HR
NHBz
N
Si
NMe
O
PhO
N
R
H
Ph
MeH
Cl
Ph
98
NMe
Si
OPh
Me
Ph
Cl
d.r. ~ 2:1
H
N
Ph
NHBz
OtBu
NHN
Ph OtBu
Ph
O
1.5 eq.
toluene, 23 °C, 24 h
84%, d.r. 96 : 4, 90% e.e.2 2
i) AcCl
ii) TMSOTf,
SiMe3
iii) SmI2
NHAc
Ph
NHBz
2
56% (3 steps)
> 20 : 1
Synthetic Application
[3 + 2] cycloaddition of acyl hydrazones with tert-butyl vinyl ether proceeds with excellentenantioselectivity and diastereoselectivity toprovide an aminal product that is primed forfurther reaction.6
99
A More Active Leighton LALeighton has recently shown that replacing the Ph substituent in his 1st gen LA withan alkoxy group provides a more straightforward method for catalyst tuning.Moreover the more electron-withdrawing alkoxy group generates a more reactiveactivator, which allowed its application in an enantioselective Mannich reactioninvolving aliphatic ketone-derived acyl hydrazones.7,8
NMe
Si
OPh
Me
O
Cl
d.r. ~ 2:1
Me
N
Ph
NH
2
p-CF3-C6H4 O
tBu
NH O
OMeMe
Ar(O)CHN
Ph
1.3 eq.
OTMS
OMe
PhCF3 , 23 °C,
30 min 89%, 90% e.e.
100
Silyl Protecting Groups
101
Silyl Ethers as Alcohol ProtectingGroups
Silyl ethers are important alcohol protecting groups. They are particularly usefulbecause they can be cleaved with a fluoride source, which leaves other protectinggroups intact. Moreover, the size of the substituents on the silyl group can be used tomodulate their stability.
Silyl ethers are usually formed by treating the alcohol with a silyl chloride or triflate. Abase is invariably included to scavenge the acid by-product.
R OH
R1R2R3SiCl or
R1R2R3SiOTf
R OSi
R3
R1 R2
F source
R OHbase, B
B·HCl or B·HOTf
102
Formation of Silyl EthersNew methods for forming silyl ethers that avoid the formation of HX·amine saltshave been developed. For example, Vogel has introduced silyl methallylsulfinatesas silylating agents for alcohols, phenols and carboxylic acids.1 The reactionproceeds under mild and non-basic reaction conditions. Volatile by-products (SO2and isobutene) facilitate work-up:
OH
OEt
O SOSiEt3
O
20 °C, CH2Cl2, < 5 min
Et3SiO
OEt
O
quant (1H-NMR)
PhOH
SOSitBuMe2
O
20 °C, 7 h, CH2Cl2
1.1 eq.
1.5 eq.
PhOSitBuMe2
quant (1H-NMR)quench excess reagent
with MeOH to generate
volatiles side-products
103
Formation of Silyl EthersThe dehydrogenative coupling of a silane with an alcohol is an attractive method forsilyletherification since the only by-product is H2. Ito and Sawamura have developedone of the best reagent systems for effecting this type of silyletherification.2a
O
PAr2 PAr2
Ar = OMe
tBu
tBu
DTBM-xantphos =
Under the optimised conditions, a range of silanes can be employed, although poorresults are observed with very hindered silanes such as iPr3SiH. Excellent levels ofselectivity are observed in the selective silylation of 1° over 2° alcohols. A related Au(I)-xantphos catalyst system has also been developed.2b
HOC8H17
C8H17
OH
2 mol% CuOtBu
2 mol% DTBM-xantphos
Et3SiH, 22 °C, 19 h, toluene
Et3SiOC8H17
C8H17
OSiEt3
99
1
:
95%
104
Modifying Reactivity by SilylationSilylation can be used to modify the reactivity of a range of reagents:
In this example from Oestreich, the silyl phosphine functions as a maskedphosphinide in a Rh(I)-catalysed phosphination of cyclic enones.4
OtBuMe2SiPPh2
1,4-dioxane!H2O 10:1
60 °C, 2 d
5 mol% [(dppp)Rh(cod)]ClO4
5 mol% dppp, Et3N
O
PPh2
77%
105
Modifying Reactivity by SilylationCarreira has introduced silanolates as hydroxide equivalents in an Ir-catalysedenantioselective synthesis of allylic alcohols:5
Ph O OtBu
O
2 eq. Et3SiOK, CH2Cl2, rt
3 mol% [Ir(cod)Cl]2
6 mol% phosphoramidite ligand
i)
ii) TBAF
Ph
OH
88%, 97% e.e.
tBuMe2SiOK and iPr3SiOK could also be used if the the desired product is a alcoholthat is protected as a more robust silyl ether.
O
O
P N
Ph
Phligand =
106
Modifying Activity by SilylationProline derivatives have emerged as powerful organocatalysts for mediating a rangeof transformations. Diarylprolinol silyl ethers, introduced by Hayashi and Jørgensen,have been used particularly widely, for example in this recent example of a directenantioselective α-benzoylation of aldehydes.6
H
O
OH
OBz
NH
OSitBuMe2
Ph
Ph
20 mol%
1.5 eq. BzOOBz
THF, rt, 20 h
then NaBH4
77%, 92% ee
The silyl protecting group in this class of organocatalyst generates a sterically bulkysubstituent off the pyrrolidine and is important for achieving high levels of asymmetricinduction.
107
New Silyl Protecting GroupsCrich has introduced the 3-fluoro-4-silyloxy-benzyl ether protecting group. The groupis readily introduced and can be removed by treatment with TBAF in THF undermicrowave irradiation.7
The electron-withdrawing fluoro substituent imparts enhanced stability to acid andthe oxidative reaction conditions used to remove PMB protecting groups, whichallows these two types of benzyl ethers to be used as orthogonal alcohol protectinggroups.
O
OPMB
OO
OR
OPh
F
OSitBuPh2
O
OPMB
HOO
OR
OPhTBAF, THF
µw, 90 °C
DDQ
CH2Cl2-H2O
O
OH
OO
OR
OPh
F
OSitBuPh2
R = adamantyl
80%
74%
108
Chiral Silylating Agents in KineticResolutions
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 thesilyl ether by treatment with DIBALH.
N
OHPh
5 mol% CuCl
10 mol% PAr3
5 mol% NaOtBu
toluene, 25 °C
Si
tBu
H
N
OPhSi
tBu
0.6 eq.
N
OHPh
1.0 eq.96% e.e.
DIBALH
N
OHPh
HSi
tBu
98%, 96% e.e.78%, 71% e.e.
56% conversion
d.r. = 86:14
84% e.e.
109
Catalytic Enantioselective Silylation ofTriols
Imidazole is commonly used as a nucleophilic catalyst (as well as an acid scavenger)in silylation reactions involving silyl chlorides. Hoveyda and Snapper havedeveloped 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
N
MeN N
tBu
N
OtBu
H
H
MeH
SiCl
Et
EtEt
OO
O
H HH
R
H
HO OH
OHN
MeN NH
tBu
HN
O tBu
20 mol%
TESO OH
OH
TESCl, DIPEA
THF, !78 °C, 48 h
85%, > 98% e.e.
110
Silyl Linkers for Solid-Supported SynthesisSilyl groups have been used as traceless linkers for solid-supported synthesis.14
Tan showed that a tert-butyldiarylsilyl linker exhibited increased stability to acidsthan previously used diisopropylsilyl-based linkers.14a
BrP
P = polystyrene resin
i) tBuLi, PhH, rt
ii) ClSi
H
Ph tBu
SiP
tBu
H
Ph
SiP
tBu
Cl
Ph
SiP
tBu
O
Ph
i) solid-supported
chemistry
ii) TASF, rt, < 1 hR' OH
R OH
N
NO
O
Cl
Cl
R
111
Temporary SiliconConnection
112
Silyl TethersSilyl groups have been used widely to tether two reacting species. Subsequent reactioncan then occur in an intramolecular fashion and therefore benefit from all theadvantages associated with intramolecular processes. Cleavage of the tether postreaction provides a product of an overall net intermolecular process.1
FG1
X
R
FG2
Y
R
R R
FG1
R
FG2
Rform silyl
tether
reaction
X'
R
Y'
Rremove
tether
Si
Si
113
Silyl Ether Connection in IntramolecularAllylation2
1. silyl ether links allylsilane to aldehyde
2. highly stereoselective intramolecularallylation
3. subsequent stereospecific (retention ofconfiguration) oxidative cleavage of silyl tetherprovides a stereodefined 1,2,4-triol
O
O
O
Si
SiMe3
Et Et
TMSOTf, 2,6-DTBMP
CH2Cl2, !78 °C
OSi
Et Et
OTMS
O
H2O2, KF, KHCO3,
THF-MeOH
OH OH
OHO
>95:5
21:1
114
Tandem Silylformylation-Crotylation-Oxidation Route to Polyketides4
ref 4a
iPr
OSi
HRh(acac)2(CO)2
CO, PhH, 60 °C
O
iPr
Si
H
O
O
iPr
Si O
intramolecular
silylformylation
intramolecular
crotylation
OH
iPr
O OH
H2O2, KF,
THF-MeOH
40 °C
C!Si oxidation and
diastereoselective
protonation
15 : 1 (major: all minor diastereoisomers)
62%
115
Diastereoselective Oxidative Couplingof Bis-Silyl Enol Ethers5
OSi
O
R R
O
O
d/l : meso
R = Me 29% 2.4 : 1
R = iPr 57% 10 : 1
CAN, NaHCO3
MeCN, !10 °C
isolated yield of
d/l diastereoisomer
The R substituents in the silyl tether were important in governing the yieldand diastereoselectivity of the reaction.
Unsymmetrical bis-silyl enol ethers can also be used.
116
Origins of Diastereoselectivity
O
OSi
R
R
O
OSi
R
R
d / l meso
O
O
Si
R
R
! "
increase
size of R
increase
size of !decrease
size of "destabilise T.S.
leading to meso
117
Silyl-Tethered Tandem Ring-ClosingMetathesis6
HO
OTBS
TBSO
O
EtO2CTBSO
O
O
O
OAcH
H
H
H
H
HO
Roush
(!)-cochleamycin A
ref 7
118
Formation of Metathesis Precursor
Note the use of silyl acetylides8 as an alternative to silyl chlorides or silyl triflates for silyletherification
S
S
OEt
EtO OH
R1
O
R1
SiSi
10 mol% NaH,
hexane
81%
PivO
HO
10 mol% NaH,
hexane
R2
O
R1
Si
O
R2
68%
119
Double RCM - ProtodesilylationSynthesis of (E,Z)-1,3-Diene
O
R1
Si
O
R2
Grubbs II
OSi
O
R2
R1
TBAF
HO
HO
R2
R1
H
(E)
(Z)
61% over two steps
Double RCM generates an intermediatebicyclic siloxane. Subsequent fluoride-induced protodesilylation provides thestereodefined (E,Z)-1,3-diene.
120
Biological Applications ofOrganosilanes
121
Bioactive OrganosilanesIn spite of the similarity of Silicon and Carbon, silicon-containing organic compoundsare relatively rare in biological chemistry research programmes. However, bioactiveorganosilanes are known and in some cases have been commercialised:
Si
Ph OH
N
muscarinic receptor agonist
NN
N
Si
F
Fflusilazole
antifungal agent
($$$)
Si
EtO
F
OPh
silafluofen
insecticide
($$$)
Si
N
N
N
N
N
N
N NHO O
Si N
Pc4 (photodynamic agent for
application in cancer treatment)
122
Silanediols as Protease InhibitorsProteases are enzymes that catalyse the hydrolysis of a peptide bond. Aspartic acidproteases and metalloproteases both catalyse the addition of a water molecule to theamide carbonyl group. Molecules that mimic the hydrated form of the hydrolysingamide bond have therefore been used as inhibitors of these two classes of enzymes.
Silanediols have recently come to the fore as potentially useful isosteres of thetetrahedral intermediate in this type of hydrolysis reaction. Providing theirpropensity to oligomerise to siloxanes can be controlled (e.g. by steric blocking),they are potentially very attractive stable hydrate replacements since they are neutralat physiological pH.1,2
NH
O
R1 O
R2
H2O
proteaseNH
R1 O
R2HO OH
H3N
O
R1 O
R2
O
peptide chain
Si
R1 O
R2HO OH
123
Silanediol Inhibitors of Angiotensin-Converting Enzyme (ACE)
Sieburth prepared the silanediol analogue of a known ACE inhibitor.1b
HNPh
O Bn
O
N
O CO2H
HNPh
O
Si
Bn
N
O CO2H
HO OH
known ACE inhibitor
IC50 1.0 nM IC50 3.8 nM
Significantly, the inhibitory activity of the silanediol analogue compared favourablywith the keto lead.
The synthesis of the silanediol is noteworthy.
124
Silanediol Synthesis
HNPh
O
Si
Bn
N
O CO2H
HO OH
HNPh
O
Si
Bn
N
O CO2tBu
Ph PhTfOH H
NPh
O
Si
Bn
N
O CO2tBu
Ph
H
! 2 PhH
HNSi
O
O
Ph
Bn
N
CO2HNH4OH
HF(aq)
HNPh
O
Si
Bn
N
O CO2H
F F
NaOH
125
Some Conclusions
126
The chemistry of organosilicon compounds is rich and diverse and findsapplication 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 valencestate
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 andSi−H bonds.
127
References
128
ReferencesGeneral References and introductory section
For a useful introduction to organosilicon chemistry: Organic Synthesis: The Roles of Boron and Silicon (OxfordChemistry Primers series), S. E. Thomas, 1991.
1: J. B. Lambert et al., Acc. Chem. Res. 1999, 32, 183-190.
Allylation and related nucleophiles
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3. Note that additives, such as fluoride, which activate the allylsilane, have occasionally been used. In thesecases, 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 activatesilyl 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.
129
ReferencesAllylation and related nucleophiles (contd)
6. D. R. Gauthier Jr. et al., Angew. Chem. Int. Ed. Engl., 1996, 35, 2363-2365. Note the enantioselectiveallylation 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.
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ReferencesAllylation and related nucleophiles (contd)
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19. (a) P. Wang et al., Org. Biomol. Chem., 2009, 7, 3741-3747; (b) A. Massa et al., Tetrahedron: Asymmetry,2009, 20, 202-204.
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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.
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27. P. J. Jervis et al., Org. Lett., 2006, 8, 4649-4652.
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ReferencesAllylation and related nucleophiles (contd)
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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 recentapplication: 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.
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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.
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ReferencesAllylation 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.
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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. Romeroet 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, partx, 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 OrganicSynthesis; 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.
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ReferencesAllylation 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 ofvinylsilanes: 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 etal., 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 powerfulillustration of Panek’s chiral allylsilane reagents in stereoselective synthesis. Note judicious choice ofsolvent 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 oforganosilanes to organocopper reagents: J. R. Herron et al., J. Am. Chem. Soc., 2008, 130, 16486-16487.
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134
ReferencesOrganosilanes 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. Denmarket 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. Hosoiet 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.
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135
ReferencesOrganosilanes 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;
(c) Hiyama coupling in oligoarene synthesis: Y. Nakao et al., J. Am. Chem. Soc., 2007, 129, 11694-11695.
136
ReferencesBrook 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.
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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.
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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.
11 J. D. Sellars et al., Org. Biomol. Chem., 2006, 4, 3223-3224.
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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.
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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.
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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.
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ReferencesUse 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 OrganicSynthesis; 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. Robertsonet 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.
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ReferencesBiological 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 recentexamples 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, 5235-52485 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.
144
ReferencesSilyl 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.
145
ReferencesSilyl Enol Ethers contd
10. Silyl enol ethers in Claisen Rearrangements: D. Craig et al., Chem. Commun., 2007, 1077-1079.
146
ReferencesSilanes 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 applicationin 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.
147
ReferencesSilanes 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 etal., 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 etal., 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 etal., Org. Biomol. Chem., 2004, 2, 2558-2562; (f) B.-M. Fan et al., Angew. Chem. Int. Ed.,2007, 46, 1275-1277.
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ReferencesMiscellaneous
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.
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8. Pd-cat. intramolecular coupling of 2-[(2-pyrrolyl)silyl]aryl triflates through 1,2-silicon migration: K. Mochidaet al., J. Am. Chem. Soc., 2009, 131, 8350-8351.
9. Synthesis of tetraorganosilanes by Ag-catalysed transmetallation between chlorosilanes and Grignardreagents: 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 arylhalides: 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. LEpstein 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.
