Hypervalent Silicon in Organic Chemistry	
L

L
L
Si
R

L
L

R

Si

L
L
L

L

Literature Seminar
January 5, 2013
Taisuke Itoh (B4)

L

L

Si

L
L

R
L

Hypervalent Silicion in Organic Chemistry

Introduction
Catalytic Enantioselective Aldol Reaction to Ketones
OSiCl3

+
Ph

OMe

OH

catalyst1 (10 mol%)O

CH2Cl2, -20°C

Me

Me
Ph

O
OMe

96% yield
83% ee

t-Bu

N+
N+
O- -O
OBu
BuO

t-Bu

catalyst1

Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
Enantioselective Passerini-Type ReactionO
Ph+

t-BuNC

SiCl4 (1.5 equiv)
catalyst (5 mol%)i-Pr2EtN (10 mol%)
CH2Cl2, -74°C, 4.5 h;then sat. aq. NaHCO3

H

Me
P
N

N

Me Me
catalyst2

Ph

NHt-BuO
93% yield
93% ee

The first catalytic asymmetric !addition of isocyanides.

Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825.
Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.

O

N

OH

2

Hypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Structure and Property of Hypervalent Silicon
Structure and Property of Hypervalent Silicon

L

L
L
Si
R

L
L

Tetravalent Silicon
Tetrahedral
Weak Lewis Acid
Low Nucleophilicity

R

Si

L
L

L

L

Si

L

R

L

L

L

L

Pentavalent Silicon
Trigonal bipyramidal
Strong Lewis Acid
High Nucleophilicity

Pentavalent Silicon
Octahedral
No Lewis Acidity
Further High Nucleophilicity

L = negatively charged or neutal silaphilic ligands
such as F, Cl, OR and OAr or Lewis bases
R = H or C!+ at silicon!- at ligands L and R
Lewis acidity
nucleophilicity of R

Rendler, S.; Qestreich, M.; Synthesis 2005, 11, 1727.

Hypervalent Silicion in Organic Chemistry

Structure and Property of Hypervalent Silicon
The Moleculer Orbital of Pentavalent Silicon (Trigonal bipyramidal)

d

dp

d

!E > 200kcal/mol
rehybridaze
unreasonable

rehybridazepreasonable

p

sp2

sp2

s
sp2dp

sp2p

Older models for explaining hypervalency invoked d orbitals. However, quantum chemical calculations suggest thatd-orbital participation is negligible due to the large energy difference between the relevant p and d orbitals.
L
R Si LL
L

Pentavalent silicon
Trigonal bipyramidal

How does sp2p moleculer orbital engage in hypervalent bonding?
Magnusson, E. J. Am. Chem. Soc. 1990, 112, 7940.

Hypervalent Silicion in Organic Chemistry

Structure and Property of Hypervalent Silicon
The Moleculer Orbital of Pentavalent Silicon (Trigonal bipyramidal)dThree-center four-electron bondingdAntibonding!E > 200kcal/mol
rehybridaze
3c-4e bondingpp

Non-Bonding

sp2
Bonding
s
sp2p

L

Si

L

• The filled non-bonding molecular orbital has all of the electron density on the ligand atoms.
• Thus, highly electronegative atoms stabilize 3c-4e bonding and hypervalent molecules andelectron density of axial position is higher than that of equatrial position.
• This is why most hypervalent molecules have F, Cl or OR in ligand atoms.
• Consequently, hypervalent molecules get more Lewis acidic.	
Ramsden, C. A. Chem. Soc. Rev. 1994, 23, 111.

Hypervalent Silicion in Organic Chemistry

Structure and Property of Hypervalent Silicon
How do we have access to hypervalent silicon?

Electronegative Ligands
Bent's rule : Atomic p character tends
to concentrate in orbitals that are
directed toward electronegative groups.

L
Si
R

L
L

Tetravalent silicon
Rather strong Lewis acidbecause of electronegative ligands.

L
R

L
L

L
L : Electronegative ligand

Si
L

Pentavalent silicon
Stabilized by electronegative ligands
Strong Lewis acid

Strain Release

Bond angle : eq-ax 90°
Bond angle ~90° : Longer Si-X and
Si-Y bond than C-X and C-Y bond.

X
Y

Si

L
R

Tetravalent silicon
Strain release Lewis acidity

X
Y

L

Si

L
R

L
Pentavalent silicon
Strain released
Strong Lewis acid

Hypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Hydrosilylation as a Hypervalent Silicon Example
First Lewis Base Catalyzed Hydrosilylation(EtO)3SiH (1 eq.)CsF (1 eq.)

O
Ph

OH

neat, 0°C

Me

Ph

Me

80%
Boyer, J.; Corriu, R. J. P.; Perz, C. Tetrahedron, 1981, 37, 2165.
Probable reaction mechanism
H
EtO

O
Ph

H

EtO Si OEt
H

EtO Si OEt
OEt
F

Tetravalent silicon
Rather strong Lewis acid due
to electronegative atoms

Pentavalent silicon
Stabilized by electronegative atoms
Strong Lewis acid

OEt
OEt

Tetravalent silicon
Weak Lewis acid

Me

F

Cs

F

CsF

Cs

EtO
OEt
Si
EtO
O
H
Ph
Me
Hexavalent sillicon
Good hydride donor

OEt CsEtO Si OEt
O
F
Ph

Me

work-upOH
Ph

MeHypervalent Silicion in Organic Chemistry

Hydrosilylation as a Hypervalent Silicon Example
Chiral Lewis Base Catalyzed Assymetric Hydrosilylation(MeO)3SiH (1.5 eq.)
Catalyst (0.4 mol%)

O
Ph

OH

THF, r.t.

Me

Ph

Me

89%,yield
52% eeN
Li

OLi

Catalyst

Kohra, S.; Hayashida, H.; Tominaga, Y.; Hosomi, A. Tetrahedron Lett, 1988, 29, 89.
Probable reaction mechanism
H
MeO

O

Catalyst

O

Pentavalent silicon
Strong Lewis acid

Li

N
OMe
Si
MeO
O
H
Me
Ph
Hexavalent sillicon
Good hydride donor

Li

N Si OMe
OMe
H

Tetravalent silicon
Strain release Lewis acidity

O
Me

O

N Si OMe
H

OMe
OMe

Tetravalent silicon
Weak Lewis acidPh

StrainreleaseOH
Ph

MeHypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Lewis Base Mediated Allylation via Hypervalent Silicon Intermediates
First hypervalent allylsilane intermediates
OH

TBAF

O

Y3Si

+
Ph

1-4

Entry

Y3Si

1
2
3
4

Me3Si
Me2FSiMeF2Si
F3Si

F3Si

+

Ph

H

5

Allylsilane

Me3Si

OH

5
(%)

6
(%)

ratio of
5:6

23
23
0

17
15
<1
91

58 : 42
61 : 39
0 : 100

Ph
6
Allylic transposition

Allylic trimethylsilane gave two regioisomers.
However, allylic trifluorosilane gave only a single
isomer with allylic transposition. Thus, the reaction of
the allylic trifluorosilane is quite regiospecific.

F+
F-

Me3SiF

F4Si

PhCHO

H
Ph

Pentavalent silicon
Stabilized by fluorines
Strong Lewis acid

SiF4O

6-membered cyclic TS
Hexavalent siliconHigh nucleophilicity

OHPh
single isomer
Sakurai, H. Synlett 1989, 1.

Hypervalent Silicion in Organic Chemistry

Lewis Base Mediated Diastereoselective Allylation
Lewis Base Mediated Addition of Crotylsilanes to Aldehydes

SiF3

+

R

(E)-Crotylsilane

H(Z)-Crotylsilane+

R

THF, r.t.

H

THF, r.t.

68-96% yieldanti/syn = >98/2

R
OH

CsF

O
SiF3

OH

CsF

O

77-96% yieldanti/syn = >2/98

R

R = aryl, alkyl

Kira, M.; Kobayashi, M.; Sakurai, H. Tetrahedron Lett. 1987, 28, 4081.
Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30, 1099.
Lewis acid catalyzed addition of crotylsilanes to aldehyde generally gives syn-products via linear transition state
regardless of starting E/Z isomers. In contrast, Lewis base mediated addition of (E)-Crotylsilanes gave anti-products via 6membered cyclic transition state. Of course, (Z)-Crotylsilanes gave syn-products.
SiF3

F-

SiF4

(E)-Crotylsilane

SiF3(Z)-Crotylsilane

OH

H
O
R

F-

anti-product
OH

H
SiF4

R

O
R

This result strongly suggests that this reaction occurs via 6-membered transition state.

R
syn-productHypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Allylation via Hypervalent Silicon Intermediates
Reactivity and Chemoselectivity of Allysilanes
SiF4

O F
Si
O
F

O O
Si
O O

F3C
F3C

O
Si
O

Lewis acidity

high

low

steric hindarance

small

large

reactivity

high

low

no reaction

selectivity

low

high

no reaction

discriminate linear
from !-branchedalkanals

CF3
CF3

only react with aromatic
aldehydes under reflux in THF
Kira, M.; Sato, K.; Sakurai, H. J. Am. Chem. Soc. 1988, 110, 4599.
Kira, M.; Sato, K.; Sakurai, H. J. Am. Chem. Soc. 1990, 112, 257.

Does "-position of hypervalent allylic silanes really possess high reactivity?
X

X
Si X

X

X X
Si X

X-

low

X
Nu

# - $ conjugation effect

X X
Si X
Nu

high

13C-NMR chemical shift of the "-carbon showed a higher field shift as silicon's electron-donating ability incresed.

Grishin, Y. K.; Sergeyev, N. M.; Ustynyuk, Y. A. Org. Magn. Reson. 1972, 4, 377.

Hypervalent Silicion in Organic Chemistry

Neutral Lewis Base Mediated Allylsilylation
Dramatic Solvent Effect on Allylsilyation of Aldehydes
OH

O
SiCl3

+

solventPhPh

H

solvent

temp. (°C)

time (h)yield (%)

CH2Cl2
CH3CN
benzene
Et2O
THF
DMF
HMPA
CH2Cl2-HMPA (2:1)

r.t.
r.t.
r.t.
r.t.
r.t.
0
0
0

24
24
24
24
24
2
3
18

trace
trace
trace
trace
trace
90
28
97

The allylation of aldehydes using allyltrichlorosilanes
proceeded smoothly in DMF or HMPA as a solvent
without any additives!
Does this allylation reaction in DMF proceeds via theneutral hypervalent silicon intermediate as shown
below?

Me2N
Me2N
O

H

H

SiCl3
DMF coordinated to silicon atom??

H

O

RCHO

SiCl3

OH
R

O
R
Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453.
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620.

Hypervalent Silicion in Organic Chemistry

Neutral Lewis Base Catalyzed Allylsilylation
Diastereoselective Allylation of Aldehydes using Crotyltrichlorosilanes in DMF
OH

O
SiCl3

+

Ph

H

DMF, 0°C

89% yield
anti/syn = 97/3

Ph

E/Z = 97/3
OH

O
SiCl3

+

Ph

H

DMF, 0°C

82% yield
anti/syn = >1/99

Ph

E/Z = >1/99
These high diastereoselectivities can be explained by 6-membered cyclic transition state.
29Si-NMR Chemical Shifts of (Z)-Crotyltrichlorosilane in Several Solvents

solvent
CDCl3
CD3CN
C6D6
THF-d8
DMF-d7
HMPA

chemical shift (ppm)
+8.0
+8.6
+7.9
+8.5
-170
-22

This 29Si-NMR spectra of (Z)-crotyltrichlorosilane indicated that DMF or
HMPA coordinated to the silicon atom of (Z)-crotyltrichlorosilane toform the corresponding penta- or hexavalent silicate.
Me2N
O
SiCl3

Me2N NMe2
H

O

P NMe
2

SiCl3

Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453.
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620.

Hypervalent Silicion in Organic Chemistry

Chiral Lewis Base Mediated Asymmetric Allylation of Aldehydes
Allylation of Benzaldehyde using Allyltrichlorosilane and 1 equiv of Additives

SiCl3

+

Ph

OH

additive (1 eq.)OHsolvent, r.t.

additive

solvent

t1/2 (min)conversion(%)

isolatedyield (%)

DMF
HMPA
HMPA
HMPA

C6D6
C6D6
CDCl3
CD3CN

18
-

83 (70 h)
63 (4 min)63 (4 min)

77
85
86

Ph

Kobayashi has shown that DMF is an efficient promoter as solvent. However, Denmark found that 1 equiv of DMF in benzene
is relatively less effective than that of HMPA, which promoted complete conversion within minutes.
Chiral Phosphoramide Mediated Asymmetric Allylation of Aromatic Aldehydes using Allyltrichlorosilanes

SiCl3

+

Ar

OH

catalyst (1 eq.)O
H

CH2Cl2-78°C, 6 hAr
67-81% yield
21-65% ee

Only aromatic aldehyde underwent allylation in good yields, but electron-donatingand electron-withdrawing substituents dramatically reduced enantioselectivity.

Me
N O
P
N N
Me
catalyst

Denmark, S. E.; Coe, D. A.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161.

Hypervalent Silicion in Organic Chemistry

Chiral Lewis Base Catalyzed Asymmetric Allylation of Aldehydes
Denmark also tried catalytic amount of chiral phosphoramide

SiCl3

+

Ph

catalyst(equiv)time (h)yield (%)

ee (%)

1.0
0.5
0.25
0.1

6
24
24
24

81
78
74
40

60
57
59
53

P
N

Ph

CH2Cl2-78°C, time

H

O

N

OH

catalystON

catalyst

With as little as 25 mol% of catalyst, the yield is only sightly reduced
and the enantioselectivity essentially the same.

Denmark, S. E.; Coe, D. A.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161.
Chiral Formamide Catalyzed Asymmetric Allylation of Aliphatic Aldehyde

R1

SiCl3
R1 = Me, H

+

R

OH

catalyst 20-40 mol%
HMPA 100-200 mol%O
Haliphatic aldehydes

EtCN, -78°C

R
R1
51-94% yield
68-98% ee

Ph

N

Ph

H
O
catalyst(DMF analogue)

HMPA can promote a diisociation of the chiral formamide from silicon atom in the product by ligand exchange toregenerate the chiral formamide. Only aliphatic aldehydes gave good to high enantioselectivity. Aromatic aldehyde also
gave good yield but low enantioselectivity was observed.
Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 1998, 39, 2767.
Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 1999, 55, 977.

Hypervalent Silicion in Organic Chemistry

Chiral Bidentate Lewis Base Catalyzed Asymmetric Allylation of Aldehydes
Chiral N-Dioxide Catalyzed Asymmetric Allylation of Aromatic Aldehyde

SiCl3

catalyst (10 mol%)i-Pr2EtN (5 equiv)

O
+

Ar

H

OH

CH2Cl2-78°C, 6 hNPh
68-91% yield
71-91% ee

N
O O

catalyst

Bidentate Lewis base enhanced the enantioselectiviy. This is probably because the allylation mediated by the bidentate Ndioxide catalyst proceeds via rigid 6-membered cyclic chairlike transition state as shown below, where one of a pair of Noxide moieties occupies an axial position. DIPEA can promote a diisociation of the chiral catalyst from silicon atom in the
product.
Cl
Cl
O

Ar
H

Si

Cl O

O

N

N

axial position
making this structure regid?
Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120, 6419.

Hypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Aldol Reaction via Hypervalent Silicon Intermediates
Denmark thought if Lewis base catalyzed allylation strategies could apply to aldol reaction.

OSiCl3

O
+

OCH3

t-Bu

solvent

additive

toluene-d8
CD2Cl2
THF-d8
CD2Cl2

none
none
none
HMPA 0.1 eq.

OHadditive
solvent, -80°C

Htime (h)
120
120
120
<3

conversion (%)
18
50
69
100

O

t-Bu

OCH3

Surprisingly, trichlorosilyl ketene acetal reacted
spontaneously with a number of aldehydes at -80°C.
Only pivalaldehyde reacted slowly enough to be followed
spectroscopically.
On pivalaldehyde, the accelation was observed with acatalytic amount of HMPA.

Denmark also tried chiral phosphoramide.
OSiCl3
OCH3

O
+
R

OH

catalyst (10 mol%)H

R = Ph, t-Bu

CH2Cl2, -78°C

R

Ph

O

O

N
P

OCH3

R = Ph : 38% ee
R = t-Bu : 40% ee

Ph

N

N

catalyst

Poor enantioselectivity was observed probably because of the intervention of the uncatalyzed pathway.
Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 1996, 118, 7404.

Hypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Asymmetric Aldol Reaction
Chiral Phosphoramide Catalyzed Asymmetric Aldol Reaction of Trichlorosilyl Ketone Enolates
OSiCl3OO

catalyst (10 mol%)

+
R

Ph

OH

H

CH2Cl2, -78°C, 2 h

94-98% yield
syn/anti = <1/61
88-97% ee (anti)R

R = aryl, cinnamyl
The corresponding uncatalyzed reaction at 0°C gave high syn selectivity (syn/anti = >5.7/1).

O

N
P

Ph

N

N

catalyst

Trichlorosilyl ketone enolates were also highly reactive but much less reactive than trichlorosilyl ketene enolates. Thus, chiral
phosphoramide catalyzed aldol reaction proceeded with high selectivity. Surprisingly, uncatalyzed aldol reaction of Eenolate gave syn adduct while Lewis base catalyzed reaction gave anti adduct .
This is because pentavalent siliconate transition structures were shown computationally to prefer boat-like arrangements
while hexavalent siliconate to prefer chair-like arrangements.
Cl

H
R

P(NR2)3

O
O

O

Cl

Si
Cl

Cl

H

syn

Si

O
O

Cl

anti

Cl

R
Pentavalent silicon intermediate
Boat-like transtion state

Hexavalent silicon intermediate
Chair-like transtion state
Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333.
Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. J. Org. Chem. 1998, 63, 918.

Hypervalent Silicion in Organic Chemistry

Mechanistic Duality in the Lewis Base Catalyzed Aldol Reaction
Dramatic Switch in Diastereoselectivity with Phosphoramide Structures
OSiCl3

O
O
+
Ph

Ph
Ph

H

Me
N O
P
N N

OH

O

catalyst 10 mol%

Ph
Ph

Ph

CH2Cl2, -78°C

MePh

catalyst (1)catalyst (2)+Phanti adduct

Ph
N O
P
N N

OH

syn adductcatalyst

yield (%)

anti/syn

ee

(1)
(2)

95
94

60/1
1/97

92 (anti)
51 (syn)

Lewis base catalyzed aldol reaction proceeds via different
transition states due to phosphoramide structures??

Denmark's Observation on the Influence of the Catalyst Concentration on Selectivity
OSiCl3O
O

OH

catalyst (1)

+

Ph
Ph

H

CH2Cl2, -75°C

catalyst (1)anti/syn

10 mol%2 mol%
0.5 mol%

>50/1
28/1
5/1

anti adduct
The syn/anti selectivity dramatically decreased with decreased loading of catalyst (1).
Lewis base catalyzed aldol reaction proceeds via different competitive transition states due to catalyst concentration??
Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998, 120, 12990.
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.

Hypervalent Silicion in Organic Chemistry

Mechanistic Duality in the Lewis Base Catalyzed Aldol Reaction
Denmark's Observation on Non-linear Effect of Chiral Phosphoramide Catalyzed Aldol ReactionO

OSiCl3OO

catalyst 10 mol%

+
Ph

OH

H

Ph

CH2Cl2, -78°C

Ph
Ph

Me
N O
P
N N
Me
catalyst (1)

Ph
Ph

Ph
N O
P
N N
Ph
catalyst (2)+Phsyn adduct% ee of productanti adductOH

A positive non-linear effect was only measured using catalyst (1)and no asymmetric amplification was seen using catalyst (2).
Those results strongly suggest that relatively less bulkyl
phosphoramide catalyzed aldol reaction proceeds via a transition stateincluding more than one phosphoramide molecule.

% ee of catalyst (1)or (2)

Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998, 120, 12990.
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.

Hypervalent Silicion in Organic Chemistry

Mechanistic Duality in the Lewis Base Catalyzed Aldol Reaction
Proposed Pathway to the Two Diastereomers
NR2

OSiCl3

O

H

+
Ph

H
Ph
Ph

Me
N O
P
N N
Me

relatively less bulky

O

H
Ph
Ph

relatively more bulky

Ph
N O
P
N N
Ph

OH
Ph

anti adduct92% eenon-linear effect

Cl
O

Si
O

+
Ph

Cl

Ph
Hexavalent silicon intermediate
Cationic chair-like transition state

Ph
O

O

Cl

Si

O

H
OSiCl3

NR2
P NR2
NR2
O

R2N P
R2N
O

O

Cl

NR2
P NR
2
NR2

O

OH
Ph

syn adduct
50% eePentavalent silicon intermediate
Cationic boat-like transition state

no asymmetric amplification

This mechanism explains the different diastereoselectivity by phosphoramide structures and concentrasion, non-linear effect byrelatively less bulky phosphoramide, and low enantioselectivity of syn adduct.
Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998, 120, 12990.
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.

Hypervalent Silicion in Organic Chemistry

Mechanistic Duality in the Lewis Base Catalyzed Allylsilylation
Denmark thought the same mechanistic duality in allysilylation as aldol reaction.

SiCl3

catalyst (1 equiv)

O
+

Ph

H

-78°C, 6 h

60% eePhMecatalyst% ee of productA positive non-linear effect was measured on allylation
reaction, too. This result suggests the presence of two
molecules of catalyst in the stereochemicallydetermining transition structure.

Denmark also determined the overall rate expression.
According to that, the reaction is overall second order,and first order in allylsilane and benzaldehyde.
A In/In plot of the second-order rate constants(ln(k)) versus the catalyst concentration(In[catalyst]) gave a straight line with a slope of 1.77.
This result also suggests the presence of more than
one molecules of catalyst in the stereochemicallydetermining transition structure.

PhPh

positive non-linear effect

The rate expressionv = k[allylsilane][benzaldehyde]
A plot of k versus [catalyst]2 give a straight line.

OH

Me
N O
P
N N

% ee of catalyst

Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021.

Hypervalent Silicion in Organic Chemistry

Mechanistic Duality in the Lewis Base Catalyzed Allylsilylation
Proposed Two Transition Structures in the Lewis Base Catalyzed Allylsilylation
NR2

Cl

H
Ph

O

Si
O
Cl

NR2

H

P NR
2
NR2

NR2
P NR2
NR2
O

R2N P
R2N
O

Ph

O

Si

Cl

Cl
Pentavalent silicon intermediate
Cationic boat-like transition state

Hexavalent silicon intermediate
Cationic chair-like transition statehigh selective pathway
less selective pathway
A competing less selective pathway would reduce the enantioselectivity of this phosphoramide catalyzed reaction??
Thus, Denmark tried a bidentate chiral phosphoramide catalyst.
R1

SiCl3
R2
R1 = H, Me
R2 = H, Me+

i-Pr2EtN, CH2Cl2-78°C, 8-10 h
R = aryl, cinnamyl, furyl
ROH

catalyst (5 mol%)

O
H

R
R1 R2
67-92% yield
80-96% ee
99/1 dr

H
H

O

N

O

P
N

N
P

N

5N

Me

Me

N

H
H

catalyst

Denmark's well thought-out bidentate chiral phosphoramide strategy sccessfully gave high enantioselectivity!
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.

Hypervalent Silicion in Organic Chemistry

Synthetically Useful Application of Denmark's Bisphosphoramide Catalyst
Asymmetric Construction of Quaternary Centers
Me

SiCl3

catalyst1 (10 mol%)
Bu4N+ I-

O

+
Ph

Ph

CH2Cl2, -78°C

H

N

O
N

R

OH

OCH3

Ph

H

Ph Me
92% yield
99/1 dr, 94% ee

H

O

N

O

P
N

N
P

N

5N

Me

Me

N

H
H

catalyst1

R = phenyl
R = cyclohexyl

Ph Me

Serotonin Antagonist LY426965
The first application of catalytic, enantioselective allylation to generate quaternary carbon centers!!
Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951.
Asymmetric Crossed Aldol Reaction of Aldehydes
OSiCl3n-C5H11+Ph

H

CHCl3/CH2Cl2=4:1-78°C, 6 h;then MeOH

Cl3
Si
O
O
The First Asymmetric
Crossed Aldol Reactonof Aldehydes!!

OH

catalyst2 (5 mol%)

O

Ph

H
n-C5H11

Ph

OMe

Me

n-C5H1192% yield
99/1 dr, 90% ee

N

Ph

Cl2
Si
O
O

OMe

O
P

N

N

Me Me
Cl

2

catalyst2

n-C5H11
Denmark, S. E.; Gosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759.

Hypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Propargylation and Allenylation of Aldehydes
The Addition of Allenyl- and Propargyltrichlorosilanes to Aldehydes
HSiCl3
CuCl, i-Pr2EtN
Et2O

OH

SiCl3

SiCl3
+

•

RCHO

R

DMF

HSiCl3Ni(acac)2, i-Pr2EtN
Et2O

SiCl3
+

> 99 : 1
55-92% yield

R = Aryl, Alkyl

SiCl3
•

OH
RCHO

R

DMF

R

+

> 1 : 99
56-90% yield

Proposed transition states
H

H•

SiClxDFMy
OOH•> 1 : 99

R

R

+

•

Cl
> 99 : 1

OH

SiClxDFMy
R

O

Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392.
Schneider, U.; Sugiura, M.; Kobayashi, S. Tetrahedron 2006, 62, 496.

Hypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Asymmetric Propargylation of Aldehydes
Asymmetric Propargyltrichlorosilanes to Aldehydes with Allenyltrichlorosilane
SiCl3•

catalyst (10 mol%)i-Pr2EtN

O

+
Ar

H

Proposed Stereochemical Models

CH2Cl2

OH

Py

N
O

Ar
55-98% yield
74-96% ee
catalyst

The Si face addition is favored due to the
expected !-stacking between the boundaldehyde and the helicene framework.
In contrast, the 11, 12- benzo unit is very
close to the aldehyde bound in the Re
face addition mode.

Chen, J.; Captain, B.; Takenaka, N.
Org. Lett. 2011, 13, 1654.

Hypervalent Silicion in Organic Chemistry

Lewis Base Catalyzed Other C-C Bond-Forming Reactions via Hypervalent Silicon
Chiral Amino Acid Salt Catalyzed Asymmetric Cyanosilylation to KetonesO+Phcatalyst (30 mol%)
TMSCN
IPA, THF, -45°C

MePh

Me Si MeMeCat
Pentavalent silicon
Strong Lewis acid

COONa

Me

96% yield
94% ee

Cat
Me
Me
Si
Me
O
CN

CN

NH2

TMSO CNMe
Ph
Hexavalent silliconHigh nucleophilicity

catalyst

Liu, X.; Oin, B.; Zhou, X.; He, B.; Feng, X.
J. Am. Chem. Soc. 2005, 127, 12224.

Lewis Base Catalyzed Alkynylsilylation to Ketones
O

EtO
EtO Si
EtO

R1 +

R1

R2

KOEt (10 mol%)
R3OEt
Si OEt
OEt
LB

Pentavalent silicon
Strong Lewis acid

THF, 0°C

R3OH

R1, R2, R3 = Aryl, Alkyl

R2

54-93% yield
R1

R1
R2

OEt
OEt
Si
O
OEt
LB

R3
Hexavalent silliconHigh nucleophilicity

Lettan, R. B., II; Scheidt, K. A. Org. Lett. 2005, 7, 3227.

Hypervalent Silicon in Organic Chemistry	

Contents	
• Structure and Property of Hypervalent Silicon• Hydrosililation as a Hypervalent Silicon Example• Lewis Base Catalyzed Allylsilylation• Denmark’s Contribution to Lewis Base Catalyzed
Aldol Reaction and Allylsilylation• Other Examples of Hypervalent Silicon
Nucleophilicity• Hypervalent Silicon as a Chiral Lewis Acid	Hypervalent Silicion in Organic Chemistry

Hypervalent Silicon as a Chiral Lewis Acid
Asymmetric Propargylation of Aldehydes
SnBu3

O
+
Ph

H

•

Me
SiCl4 (1.1 equiv)
catalyst (5 mol%)
CH2Cl2, -78°C, 8 h

O

N

OH

P
N

Ph

N

Me Me

81% yield
97% eeAllyltributyltin also gave the homoallylic alcohol with high yield and enantioselectivity.

2

catalyst

Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.
Asymmetric Addition of Silyl Ketene Acetals to Aldehydes
OTBS

O
Ph

+
H

Ot-Bu
Me

SiCl4 (1.1 equiv)
catalyst (1 mol%)OH
Ph

CH2Cl2, -78°C, 3 h

O
Ot-Bu

Addition of silyl ketene acetals
proceeded via acyclic transition
state to give anti products.

Me
E/Z = 95/5 : 93% yield, 99% ee, 99/1 dr
E/Z = 12/88 : 73% yield, 99% ee, 99/1 drDenmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405.
Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774.

SiCl4(R2N)3P=O(R2N)3POO(R2N)3P

Si
Cl

Cl
Cl

Cl
in situ generated
chiral Lewis acid

Hypervalent Silicion in Organic Chemistry

Hypervalent Silicon as a Chiral Lewis Acid
Asymmetric Addition of Silyl Enol Ethers of Aldehydes
SiCl4 (1.5 equiv)
OTMS
O
catalyst (5 mol%)+i-Pr2EtN (10 mol%)
n-Bu
Ph
H
CH2Cl2, -72°C, 3 h

Me
OH

O

O

N

Ph

P

n-Bu

N

99% yield
99% ee

N

Me Me

2

catalyst
Denmark, S. E.; Heemstra, Jr., J. R.; Org. Lett. 2003, 5, 2303.
Asymmetric Vinylogous Aldol Reaction
OTBS

O
Ph

+
H

Me
!

"

Ot-Bu

SiCl4 (1.1 equiv)
catalyst (1 mol%)

OH

O

Ph
Ot-Bu
92% yield, !/" = 99/1
>99/1 dr, 89% ee
Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800.
Denmark, S. E.; Heemstra, Jr., J. R. J. Am. Chem. Soc. 2006, 128, 1038.
CH2Cl2, -78°C, 3 h

Enantioselective Passerini-Type Reaction
O
Ph

+
H

t-BuNC

SiCl4 (1.5 equiv)
catalyst (5 mol%)i-Pr2EtN (10 mol%)
CH2Cl2, -74°C, 4.5 h;then sat. aq. NaHCO3

OH
Ph

NHt-BuThe first catalytic asymmetric "addition of isocyanides.

O
93% yield
93% eeDenmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825.
Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.

Hypervalent Silicion in Organic Chemistry

Hypervalent Silicon as a Chiral Lewis Acid
Enantioselective Ring Opening of Epoxides
SiCl4 (1.2 equiv)
catalyst1 (5 mol%)

O
Ph

Ph

O

CH2Cl2, -85°C, 24 h

Ph
Cl-

LB

Ph

HO

N
Ar

Cl

Fe

Ar

88% yield
94% eeAr = 3, 5-(CH3)2C6H3
Ar

catalyst1

Ar
Ar

LB
Cl
Si
Cl
Cl
O
Ph

Ph

Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353.

Strained Silacycle-Catalyzed Asymmetric Diels-Alder Cycloaddition

+

Me

CHO

catalyst2 (20 mol%)
CH2Cl2, -78°C, 8 h

CHOMe
78% yield
94% eeStrain release Lewis acidity!!
Ring strain exsists including silicon.

Ts
N

Cl
Si

N

catalyst2
Kubota, K.; Hamblett, C. L.; Wang, X.; Leighton, J. L. Tetrahedron 2006, 62, 11397.

Hypervalent Silicon in Organic Chemistry	

Summary	• Hypervalent silicon is crucial intermediate in Lewisbase catalyzed allylsilylation and aldol reaction.
Using chiral Lewis bases, these reactions could givehigh diastereo- and enantioselectivity.
• Hypervalent silicon is also used as chiral Lewis acidcatalyst in aldol reaction, ring opening of epoxides,
Diels-Alder cycloaddition and so on.