Lewis-Base
Catalysis
MacMillan Lab. Group Meeting
Anthony Mastracchio
November 5 2008
Lewis Base Catalysis
Presentation Outline
■ Introduction
■ Definitions and basic concepts of Lewis base Catalysis
■ n–π* interactions
● Base catalyzed acylation of alcohols
● Base catalyzed acylation of nucleophiles
■ n–σ* interactions
● Polyhalosilanes
● enoxyenolsilanes
● SiCl4 mediated processes
Relevant and Comprehensive Reviews:
Denmark, S. E.; Beutner, G. L., "Lewis Base Catalysis in Organic Synthesis." Angew. Chem. Int. Ed. 2008, 1560
Gawronski, J.; Wascinska, N.; Gajewry, J. "Recent Progress in Lewis Base Activation and control of Stereoselectivity in the
Additions of Trimethylsilyl Nucleophiles." Chem. Rev. ASAP
Rendler, S.; Oestreich, M. "Hypervalent Silicon as a Reactive in Site Selective Bond-Forming Processes" Synthesis 2005, 11,
1727
Storer, I. MacMillan Group Seminar " Hypervalent Silicon" July 2005
Lewis Base in Organic Synthesis
■ Strongly Lewis basic additive have found important applications as promoters of a variety of diverse
chemical processes.
O
H3C
H3C
OLi
H3C
Ph
CH3
OHCH3
H3C
Ph
Ph
dioxolane
CH3
23 ºC
t1/2 = 80 min
O
CH3
H3CO
O
S
OCH3
H3C
dioxolane
4 equiv HMPA
23 ºC
t1/2 > 1 min
H3C
Ph
CH3
OHCH3
H3C
O
Ph
CH3
10 : 1
> 100 : 1
O
O
O
82% yield
SmI2
SmI2
5.7 equiv HMPA
THF / iPrOH
4h
THF / iPrOH
O
O
1 min
CO2CH3
95% yield
Lewis Base in Organic Synthesis
■ Strongly Lewis basic additive have found important applications as promoters of a variety of diverse
chemical processes.
CHO
OH
Ti(OiPr)4 (1.2 equiv)
OH
Ti(OiPr)4 (1.2 equiv)
Et
Et
23 ºC, 12 h
"good yield"
ZnEt2
NHTf
2 mol %
NHTf
98 % yield
e.r. 99:1
–20 ºC, 1.5 h
■ When compared to the influence of Lewis acids, Lewis bases are seen to effect a much more
diverse array of reactivity patterns.
■ Lewis bases can enhance the chemical reactivity from increasing nucleophilicity or
electrophilicity to modulation of electrochemical properties.
Some Definitions of Lewis Base Catalysis
■ A Lewis base catalyzed reaction is defined as one that is accelerated by the action of an
electron-pair donor (as the catalyst) on an electron-pair acceptor (as the substrate or reagent)
L
D
L
L
Lewis base
D
L
L
X
X
A
X
X
L
A
X
X
reactive intermediate
Lewis acid
● In terms of reactivity, this increase in electron density normally translates to enhanced nucleophilicity
of the acceptor subunit. However, this represent only one possible effect of the binding of a Lewis base.
● A much less appreciated and indeed, even counterintuitive consequence of the binding of a Lewis
base is the ability to enhence the electrophilic character of the acceptor.
Some Definitions of Lewis Base Catalysis
■ Electronic redistribution resulting from Lewis acid–base complexation
L
D
L
L
δ+
Lewis base
L
X
A
δ− δ+
D
L
L
X
δ−
X
A
X
X
X
Lewis acid
increased increased
negative positive
charged charged
● Although the acceptor will possese an increased electron density relative to the parent Lewis acid, it is the distribution
of the electron density among the constituent atoms that must be considered to rationalize
the effect of adduct formation on reactivity
■ To visualize this concept clearly, it is useful to examine the nature of the newly formed dative bond
■ Jensen proposed that all Lewis acid–base interactions could be classified in terms of the identities
of the interacting orbitals
Some Definitions of Lewis Base Catalysis
■ Jensen's orbital analysis of molecular interactions.
Acceptor
Donor
L
L
n*
σ*
π*
n
n–n*
n–σ*
n–π*
σ
σ–n*
σ–σ*
σ–π*
π
π–n*
π–σ*
π–π*
L
■ Although each of these combinations could represent a productive interaction, in practice, only
three of these are significant in terms of catalysis. These are:
1) interactions between nonbonding electron pairs and antibonding orbitals with π character (n–π* interaction)
2) interactions between nonbonding electron pairs and antibonding orbitals with σ character (n–σ* interaction)
3) interactions between nonbonding electron pairs and vacant nonbonding orbitals with n character (n–n* interaction)
Lewis Base Catalysis: n–π* Interactions
■ Generally termed "nucleophilic catalysis", n–π* interactions represents the largest and most
commonly recognized form of Lewis base catalysis.
O
R
O
Nu
R
Nu
O
LB
X
R
X
O
X = LG
X
LB
L
R
LB
O
Nu
O
LB
R
R
Nu
X
Nu
R
X
O
O
Nu
X
X
O
Nu
R
R
LB
X
O
X = LG
LB
R
LB
Nu
■ These processes are the first clearly identified examples of Lewis base catalysis.
■ In both cases the attack by the Lewis base leads to the formation zwitterionic intermediate with
enhanced nucleophilic character at the oxygen atom. If a leaving group is present, this intermediate
collapse to a new ionic species with enhanced electrophilic character.
Lewis Base Catalysis: n–π* Interactions
■ First study case of Lewis base catalysis: Base promoted acylation of alcohols
O
N
O
NEt3
Cl
H2N
Cl
Ph
R
N
H
Cl
● Studies for the development of more active catalyst showed that donor substituent greatly enhanced the rates
for acylation. These investigations led to the discovery of DMAP (entry 7)
Entry
R
kB [L2mol–2s–1]
pKa (H2O)
σ
1
3-NO2
0.0231
0.81
0.710
8
2
3-Cl
0.0893
2.84
0.373
kB 6
3
H
1.80
5.17
0
4
2-Me
0.0987
5.97
–0.170
5
3-Me
3.8
5.68
–0.069
6
4-Me
3.8
6.02
–0.170
7
4-NMe2
10.0
9.58
–0.830
12
10
4
2
0
-2
-4
-1
-0.5
σ
0
0.5
1
■ Linear relationship were found between reaction rate, Hammett σ values, and pKa values.
■ Both relationships broke down with 2-substituted pyridines despite small change in σ and pKa values.
● This dramatic change in reaction rate between 4- and 2-methylpyridine is inconsistent with simple Brønsted base
catalysis. New "consensus" mechanism involving Lewis base catalysis was formulated
Litvinenko, L.M.; Kirichenko, A.I.; Dokl. Akad. Nauk. SSSR Ser. Chem. 1967, 176, 197
Lewis Base Catalysis: n–π* Interactions
■ Consensus mechanism for pyridine-catalyzed acylations.
R
Ac2O
R'OH
O
NEt3
N
Me
OR'
O
AcOH
Me
R
OR'
N
R
Ac2O
R'
N
O
R
O
AcO
H
Me
N
OAc
I
II
Me
O
R'OH
■ Recent calculations suggest that II is the rate determining structure
■ Support for the formation of the acylpyridinium intermediate has been found by IR and UV spectroscopy as
well as crystallographic studies
■ For maximum conjugation between the pyridine and the acyl group a fully planar conformation must be
obtained. The presence of a flanking 2-substituent creates unfavorable steric interactions and twist the acyl
group out of the plane destabizing the molecule. This explains low reactivity for 2-substituted pyridine.
■ Can catalytic enantioselective processes be developed?
Lewis Base Catalysis: n–π* Interactions
■ Fu's kinetic resolution of secondary alcohols
H3C
N CH3
OH
Ph
OH
Ac2O, Et3N
tBu
tert-amyl alcohol, 0 ºC
catalyst 1 mol %
Ph
N
tBu
H
Fe
Ph
92.2 % ee at 51% conv.
Ph
Ph
Ph
Ph
H3C
N CH3
Me
N
H3C
N CH3
O
O
N
Me H
H
Fe
Ph
Fe
Ph
Ph
Ph
Ph
pro-S
Ph
Ph
Ph
Ph
Ph
pro-R
● The ability of a given complex to exist as a single conformer of this acylated intermediate is directly tied to its
success as a chiral catalyst
■ High levels of selectivity was obtained for the kinetic resolution of alkyl aryl and alkenyl
secondary alcohols
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492.
Lewis Base Catalysis: n–π* Interactions
■ Fu's kinetic resolution of secondary alcohols
H3C
N CH3
OH
Ph
OH
Ac2O, Et3N
tBu
tert-amyl alcohol, 0 ºC
catalyst 1 mol %
Ph
N
tBu
H
Fe
Ph
92.2 % ee at 51% conv.
Ph
Ph
Ph
Ph
tBu
HO
H
Me
H3C
N CH3
N
H3C
N CH3
Me
O
N
O
H
H
Fe
Ph
Fe
Ph
Ph
Ph
Ph
pro-S
Ph
Ph
Ph
Ph
Ph
pro-R
● The ability of a given complex to exist as a single conformer of this acylated intermediate is directly tied to its
success as a chiral catalyst
■ High levels of selectivity was obtained for the kinetic resolution of alkyl aryl and alkenyl
secondary alcohols
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492.
Lewis Base Catalysis: n–π* Interactions
■ Chiral catalysts for the kinetic resolution of alcohols.
OH
OH
catalyst
tBu
Ph
rac
tBu
Ph
conditions
(R)
S
Ph
N
N
N
Ph
4 mol %, CHCl3, 0 ºC
Na2SO4, NiPr2Et, (EtCO)2O
e.r. 99:1 at 51 % conv.
s = 166
NBu2
1 mol %, toluene, –95 ºC
Et3N, (iPrCO)2O
e.r. 95.5:4.5 at 16 % conv.
s = 26
Me
N
N
H
N
BocHN
O
Me
O
Me
N
H
H
N
O
H
N
N
H
O
OtBu
ButO
O
Ph
O
N
iPr
N
H
Me
H
N
O
Me
O
OMe
Me
0.5 mol %, toluene, –65 ºC
NiPr2Et, Ac2O
e.r. >75:25 at 35 % conv.
s > 50
TrtN
Kawabata, T.; Stragies, R.; Fukaya, T.; Fuji, K. Chirality 2003, 15, 71
Birman, V.B.; Jiang, X.; Li, X.; Guo, L.; Uffman, E.W. J. Am. Chem. Soc. 2006, 128, 6536
Miller, S.J.; Acc. Chem. Res. 2004, 37, 601
Lewis Base Catalysis: n–π* Interactions
■ Consensus mechanism for pyridine-catalyzed acylations.
R
Ac2O
R'OH
O
NEt3
N
Me
OR'
O
AcOH
Me
R
OR'
N
R
Ac2O
R'
N
O
R
O
AcO
H
Me
N
OAc
I
II
Me
O
R'OH
■ Can we utilize the nucleophile produced in asymmetric transformation?
Lewis Base Catalysis: n–π* Interactions
■ Extension to acylation of nucleophiles
O
BnO
N
1 mol % catalyst
O
H3C
O
O
N
O
O
N
R
tert-amyl alcohol
0 ºC
O
BnO
PPY*
BnO
H3C
O
N
O
Ar
Ar
H
N
Fe
Ar
e.r. 95.5 : 4.5
94 % yield
Ph
Ph
Ph
Ph
Ph
PPY*
Ruble, J.C.; Fu, G.C. J. Am. Chem. Soc. 1998, 120, 11532
● This method has been further expanded to furanones, benzofuranones, and oxindoles.
O
Ph
O
Ph
OR
O
O
5 % catalyst
OR
O
CH2Cl2, 35 ºC
O
97 % ee
81 % yield
Hills, I.D.; Fu, G.C. Angew. Chem. Int. Ed. 2003, 42, 3921
Lewis Base Catalysis: n–π* Interactions
■ Fu's C-acylation of silyl ketene acetals
OSiMe3
5 mol % catalyst
OiPr
toluene / CH2Cl2
Ac2O, 23 ºC
Ph
Et
O
N
O
Me
OiPr
Ph
Et
e.r. 92.5 : 7.5
92 % yield
N
Me
H
O
SbF6
Fe
Ph
PPY*
– PPY*
OSiMe3
Ph
O
PPY*
O
Ph
O
O
Ph
Et
Me
Ph
Ph
OiPr
O
Ph
Me
Me
PPY*
– SiMe3
OSiMe3
OiPr
Ph
Et
OiPr
Et
● It is believed that the reaction involves activation of both the anhydride (formation of an
acylpyridinium ion) and the silyl ketene acetal (generation of an enolate). This was concluded
in part because the acylpyridinium SbF6 salt was unreactive towards the silyl ketene acetal.
no reaction
■ Fu's C-acylation of silyl ketene imines
N
Et
C
Ph
NTBS
5 mol % catalyst
ClCH2CH2Cl
(EtCO)2O, 23 ºC
N
O
CN
Et
Ph
Et
e.r. 90.5 : 9.5
85 % yield
H
PPY* =
Fe
Ph
Ph
Ph
Ph
Ph
Lewis Base Catalysis: n–π* Interactions
■ Lewis base catalyzed reactions of ketenes: Wynberg and Staring formal [2+2] cycloadditions
O
C
H2C
1
2
O–
O–
1mol % catalyst
N
– 25 ºC, toluene
R
Cl3CCHO
R
Cl3C
R
H
O
N
R
R
R
O
quinidine >99 % yield / e.r. 99:1
quinine >99% yield / e.r. 12:88
CCl3
O
H
OMe
OMe
OH
OH
N
N
N
N
quinidine
quinine
● The Lewis base catalyst enhances the nucleophilicity at C2 to enable the C–C formation but also enhances the
electrophilicity at C1 to facilitate the final cyclization step.
Wynberg, H.; Staring, A.G.J. J. Am. Chem. Soc. 1982, 104, 166
■ Can the Lewis Base be use to both form the ketene an to perform the asymmetric transformation?
Lewis Base Catalysis: n–π* Interactions
■ Lewis base catalyzed [2+2] cycloadditions with in situ generated ketenes.
I
CO2H
R
R
N
O
5 mol % cat.
Et3N, CH3CN
R
23 ºC
R
Cl
Me
O
O
37-55 % yield
90-92 % ee
OMe
● It was observed that blocking the hydroxyl group with different carbonyl derivatives did
not affect enantioselectivity very much, and thus the following stereochemical rationale
was proposed
● Once the acylammonium enolate is formed, the aldehyde approaches the enolate
from the si face, away from the quinoline
H
H
N
AcO
H
N
O
O
Cortez, G. S.; Tennyson, R.L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945
■ Lewis base catalyzed [2+2] cycloadditions with in situ generated ketenes.
OMe
NTs
O
Ph
Cl
H
CO2Et
5 mol% cat
proton sponge
Ts
toluene, -78 ºC
EtO2C
O
N
Calter, M.A.; Orr, R.K.; Song, W. Org. Lett. 2003, 5, 4745
Ph
65 % yield
d.r. 99:1
e.r. 99:1
OBn
N
N
Lewis Base Catalysis: n–σ* Interactions
■ Lewis acids, such as transitionmetal and electron deficient main-group organometallic reagents, is
representative of a fundamentally different class of catalysis: the n–σ* interaction
enhanced
electrophilic character
Y
L
D
L
Y
L
Lewis base
Si X
Y
D
L
Si
L
Group 14
Lewis acid
δ+
YY
L
Y
−
Xδ
δ+
L
to
X
X
hyperactive
electrophile
enhanced
nucleophilic character
hypervalency
δ−
L − +X
δ δ
D
Si X
L
hyperactive
nucleophile
ionization
■ As in the n–π* Lewis base catalysis, the binding of the Lewis base to the Lewis acid induces a
re-distribution of electron density in the newly formed adduct.
■ In the proposed model of n–σ* interaction, this binding leads to a polarization of the adjacent
bonds, thereby increasing the electron density at the peripheral atoms. Silicon has shown great
success in this type of process.
■ Increase electrophilicity of the Metal center is supported by computational studies.
2
series
SiCl4
SiCl5
SiCl6
Mulliken charge
+0.178
+0.279
+0.539
■ What causes the enhanced electrophilicity of the metal and what makes silicon prone for hypervalency?
Bonding to Silicon - How are 5 or 6 Bonds Accommodated?
Valence Shell Electron Pair Repulsion Theory (VSEPR)
■ Theory to account for molecular bond geometries
■ Predicted hybrid orbitals for 2–6 coordinate compounds
linear
sp
trigonal planar
sp2
tetrahedral
sp3
■ Tetrahedral coordination – sp3 rehybridization
octahedral
sp3d2
trigonal bipyramid
sp3d
■ Trigonal bipyramidal – sp3d rehybridization?
d
p
dp
hybridize
sp3
hybridize
p
s
sp2
s
H
H
H
C
H
H
H
sp3
tetrahedral
M H
H
H
sp2dp
trigonal bipyramid
Gillespie, R. J. Chem. Soc. Rev., 1992, 21, 59.
Storer, I. MacMillan Group Seminar: Hypervalent Silicon, 2005.
The Role of d–Orbitals in Main-Group Compounds
pentavalent compounds
■ How do 3s, 3p and 3d orbitals really hybridize to permit pentavalency?
d
d
dp
>200 kcal/mol
p
hybridize
hybridize
p
sp2
sp2
s
sp2p
sp2dp
■ The d-orbitals must be close enough in energy to the s and p orbitals to mix favourably
■ The 3sp2dp hybridization would come at a massive energetic cost of >200 kcal/mol rendering this unlikely
to ever occur – sp2p hybridization is likely to occur preferentially
■ 3d orbitals are still involved to a limited extent
■ The d-orbitals have been essential for complete computation of all main group compounds
■ Their role appears to be confined to that of polarization of the p-orbitals – d-orbital occupation of <0.3e
+
p
=
0.0–0.3 d
'polarized p-orbital'
Storer, I. MacMillan Group Seminar: Hypervalent Silicon, 2005.
Hypervalent Main Group Complexes
The Existence of 3c–4e Bonds
■ How do 3s, 3p and 3d orbitals really hybridize to permit pentavalency?
d
5-coordinate
p
sp2
p
hybridize
p
sp2
sp2
sp2
3 x sp2
1 x 3c–4e with p
s
sp2p
■ The 3c–4e bond – MO consideration
■ Mixing of the filled σ orbital of the acceptor with the filled
n orbital of the donor generates a pair of hybrid orbitals
■ The HOMO of this hybrid orbital (Ψ2) contains a node
at the central atom and localizes the electron density at
the peripheral atoms
■ This explains the enhances electrophilicity of the metal
center while increasing the nucleophilicity of the ligands.
This also explains why virtually all hypervalent
compounds bond with electronegative F, Cl and O.
antibonding Ψ3
LUMO
nonbonding Ψ2
HOMO
bonding Ψ1
Cl
Si
Cl
Chemical Reactivity of Hypervalent Silicon
■ Hybridization scheme and orbital picture of silicon complexes
4-coordinate
L
5-coordinate
L
+L
Si L
R
L
poor Lewis acid
poor R nucleophile
6-coordinate
R
L
+L
Si L
L
L
R
L
good Lewis acid
good R nucleophile
Si
L
L
L
not Lewis acidic
v good R nucleophile
sp
sp3
p
sp2
sp3
sp3
sp2
p
p
sp2
sp3
sp
p
p
sp3
sp2
sp2
 Increasing δ+ at silicon
 Increasing δ– at ligands L and R
 6-coordinate species not Lewis acidic because it has no room for binding
■ Electron density at Si decreases with increased coordination, causing the electropositive character
(Lewis acidity) of the Silicon centre to be increased.
Lewis Base Catalysis: n–σ* Interactions
■ Corriu first introduced fluoride ions to promote formation of hypervalent silicate in the mid-1970s.
However, it was the introduction of soluble fluoride sources that later captivated the chemical community
■ First example of the use of homogeneous fluoride ions in C–C bond formation by H. Sakurai
SiMe3
OH
OSiMe3
5 mol % TBAF
acid workup
O
THF, 4 h
H
86 % yield
O
■ The process involves the formation of an alkoxide
TBA
R
■ In the critical turnover step, the alkoxide must be to release fluorides and regenerate the catalyst.
■ In view of the strenght of the Si–F bond (135 kcalmol-1), many have disputed the role of TMSF as the active
silylating agent
■ Most generally accepted pathway was first suggested by Kuwajima
Hosomi, A.; Shirahata, A.; Sakurai, H. Tett. Lett. 1978, 19, 3043
Lewis Base Catalysis: n–σ* Interactions
■ Fluoride ion initiated versus catalyzed processes
OSiMe3
SiMe3
R2CHO
SiMe3
R2
TBAF
R2CHO
R2CHO
OSiMe3
O
fluoride
catalysis
R2
TBAF
TBA
auto
catalysis
R2
FSiMe3
O
Me3
Si
R2
SiMe3
● This kind of autocatalytic behavior is supported by the observation of an induction period in the reaction-rate profile.
Thus, a slower initial phase of the reaction is promoted by fluoride ions while the faster, later phase is promoted by
some other in situ generated anion.
Lewis Base Catalysis: n–σ* Interactions
■ Fluoride ion initiated versus catalyzed processes
OSiMe3
SiMe3
R2
R2CHO
SiMe3
TBAF
R2CHO
R2CHO
OSiMe3
O
fluoride
catalysis
R2
TBA
auto
catalysis
R2
O
Me3
Si
R2
TBAF
FSiMe3
SiMe3
■ Hou has shown that the ammonium alkoxides generated are active catalysts for subsequent allylations
O
nBu4N
THF, 1 day
Ph
SiMe3
no reaction
Et3SiF
O
PhCHO
Ph
nBu4N
OH
THF
76 % Yield
Ph
Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, L. -X. J. Org. Chem. 1999, 64, 4233
Lewis Base Catalysis: n–σ* Interactions
Polyhalosilanes
■ Nucleophilicity of allylic silanes on the Mayr scale
BCl4
H
H
CH2Cl2
SiMenCl3-n
Ph
MeO
MeO
■ In light of the analysis by Mayr et al., allyltrifluorosilane and
allyltrichlorosilane should be completely unreactive towards
aldehydes. This provides adramatic illustration of the power of
Lewis base activation
SiMe3
k = 1.87 x 102L mol-1s-1
SiMe2Cl
k = 2.76 x 10-1L mol-1s-1
SiCl3
no reaction
■ Fluoride ion catalyzed allylations with fluorosilanes
OH
H3C
SiF3
PhCHO
CsF
THF, 0 ºC
CH3
Me
OH
H3C
SiF3
PhCHO
CsF
THF, 0 ºC
H
F
F
Si
O
F
F
H Ph
CH3
■ The strict correlation of the silane geometry with the product configuration (E -->anti, Z -->syn) indicates the
reaction proceeds through a cyclic chair like transition structure, with dual activation of both nucleophile and electrophile
Kira, M.; Kobayashi, M.; Sakurai, H. Tett. Lett. 1987, 28,4081
Lewis Base Catalysis: n–σ* Interactions
Polyhalosilanes
■ Lewis basic solvent can promote aldehyde allylation (Kobayashi and Nishio)
Solvent
OH
O
R1
R2
H
solvent, 0 ˚C
SiCl3
CH2Cl2
Et2O
benzene
THF
DMF
CH2Cl2 +
1 equiv DMF
R1
R2 R3
R3
Yield
trace
trace
trace
trace
90%
68%
 Important discovery: Neutral Lewis bases such as DMF can activate trichlorosilanes!!
■ Strict correlation of the silane geometry with the product configuration also obtained
O
Ph
H
H
O
DMF
SiCl3
Me
H
Me
N
SiCl3 Me
Me
OH
Ph
O
H Ph
H
Me
97:3 E:Z
 High diastereoselectivity indicative of a rigid closed transition state
 Dual activation of both electrophile and nucleophile via a 6-membered closed TS.
Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453-3456.
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620-6628.
Solvent
Si NMR
CDCl3
CD3CN
C6D6
THF-d8
DMF-d7
HMPA
+8.0
+8.6
+7.9
+8.5
–170
–22
Lewis Base Catalysis: n–σ* Interactions
Polyhalosilanes
■ Denmark
Me2N
O
P
OH
H
SiCl3
O
Me2N
Lewis Base
NMe2
Hexamethyl phosphoramide
HMPA
1 equiv. HMPA, CDCl3
86 % yield
■ Can chiral HMPA derivatives be developed to catalyze the enantioselective variant?
Me
Ph
N
Ph
N
O
P
Ph
N
Me
Me
O
N
P
NMe2
Me
N
Ph
NMe2
Me
O
H
P
N
N
N
O
P
Me
N
N
Pr
Pr
6h, –78 ºC, CH2Cl2
1 equiv
e.r. 66.5:33.5
6h, –78 ºC, CH2Cl2
1 equiv
e.r. 70.5:29.5
6h, –78 ºC, CH2Cl2
0.1 equiv
40% yield
e.r. 76.5:23.5
168h, –78 ºC, THF
0.1 equiv
67 % yield
e.r. 92.5:7.5
■ Weak loading dependence was observed in which lower loadings led to lower selectivities.
Denmark, S.E.; Su, X.; Nishigaishi, Y.; Coe, D.M.; Wong, K.-T.; Winter, S. B. D.; Choi, J.-Y, J. Org. Chem. 1999, 64, 1958
Lewis Base Catalysis: n–σ* Interactions
■ Loading dependence on the enantioselectivity
Me
SiCl3
Ar
N
OH
O
23 ˚C, 1M
O
P
Ar
H
N
N
Me
60
% ee product
50
40
30
20
10
0
0
20
40
60
80
100
% ee catalyst
■ These results represented the first suggestion that they were two distinct pathways involving the
chiral phosphoramide with different levels of enantioselectivity
■ Subsequent kinetic studies showed a non-integral order dependence of 1.77. This is due to
competing mechanisms involving 1 or 2 prosphoramides on silicon
Lewis Base Catalysis: n–σ* Interactions
Polyhalosilanes
■ Divergent mechanistic pathways in reactions of allyltrichlorosilane
OH
H
Cl
P(NR2)3
Si O
O
O
Ph
Cl
Cl
Ph
low selectivity
H
SiCl3
OH
H
Cl
Si Cl
O
Ph
O
P(NR2)3
O
P(NR2)3
high selectivity
■ It is believed that that the monophosphoramide complex would be less enantioselective than a
diphosphoramide pathway due to the diminished influence of the singular chiral promoter in the former
 In the transition state with only one phosphoramide, there is no experimental support for either a hexacoordinate
octahedral neutral transition structure or a cationic, trigonal bipyramindal transition structure
■ Would a bidentate phosphoramide avoid the problem of mono-coordination on allylations?
Denmark, S.E.; Fu, J.; Coe, D.M.; Su, X.; Pratt, N.M.; Griedel, B.D. J. Org. Chem. 2006, 71, 1513
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021
Lewis Base Catalysis: n–σ* Interactions
Dimeric phosphoramide
■ Dimeric phosphoramide catalyzed allylations.
OH
O
SiCl3
Ph
Me
N
O
P
N
CH2Cl2, –78 ºC
H
Me
N
catalyst
N
Me
O
P
Me
N
N
Me
Me
1 equiv.
73% yield; 51% ee
N
N
0.1 equiv
54% yield; 72% ee
N
O
P
N
N
Me
(CH2)n
n
equiv
4
5
6
0.05
0.05
0.05
O
N
P
Me
O
P
P
N
Me Me
Me Me
N
N
O
N
0.05 equiv
56% yield; 56% ee
yield
ee
54% 18%
85% 87%
58% 67%
■ Advantages of dimeric phosphoramides
● Disfavors the less selective one-phosphoramide pathway
● Help overcoming the entropic disadvantage for the formation of the structure containing two Lewis bases.
Lewis Base Catalysis: n–σ* Interactions
Addition to hydrazones
■ Allylation and crotylation of benzoylhydrazones - Kobayashi
RE
SiCl3
N
RZ
R1
NHBz
H
HN
catalyst
CH2Cl2, –78 ºC
NHBz
Me
O
O
S
P(4-Tol)2
P(4-Tol)2
O
R1
RE
RZ
A
R1
RE
RZ
Catalyst
(equiv)
Yield [%]
d.r.
(syn/anti)
ee [%]
80
A (3.0)
60
< 1:99
91
H
A (3.0)
58
> 99:1
89
H
H
B (2.0)
91
–
98
EtO2C
H
Me
B (2.0)
92
98:2
99
EtO2C
Me
H
B (2.0)
96
< 1:99
96
H
A (3.0)
73
iPr
H
H
A (3.0)
PhCH2CH2
H
Me
PhCH2CH2
Me
EtO2C
Cl
Si
93
H
*L
R
–
–
PhCH2CH2
B
98
N
Me
H
N
H
Z-Crotyltrichlorosilane
HN
■ The E-geometry of hydrazone put the R group at an axial direction; consequently,
syn- and anti- homoallylic hydrazines are stereospecifically obtained from (E)- and (Z)crotyltrichlorosilanes, respectively
O
Cl
NHBz
R1
Me
anti-Adducts
Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 9493
Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew. Chem. Int. Ed. 2004, 43, 6491
Lewis Base Catalysis: n–σ* Interactions
Propargylation and Allenylation
■ Lewis base catalyzed allenylation and propargylation - Kobayashi
HSiCl3
CuCl, iPr2EtN
Et2O
OH
OH
SiCl3
SiCl3
Cl
PhCHO
Ph
Ph
C
C
CH2
CH2
99:1
> 1:99
92 % yield
OH
OH
SiCl3
SiCl3
HSiCl3
[Ni(acac)2], iPr2EtN
Et2O
PhCHO
Ph
Ph
C
C
CH2
CH2
> 99:1
92 % yield
1:99
■ Assumed transition state:
H
H
C
SiClxDMFy
R
O
SiClxDMFy
R
O
Schneider, U.; Sugiura, M.; Kobayashi, S. Tetrahedron. 2006, 62, 496
Schneider, U.; Sugiura, M.; Kobayashi, S. Adv. Synth. Catal. 2006, 348, 323
Lewis Base Catalysis: n–σ* Interactions
Enoxytrichlorosilane
■ Phosphoramide-catalyzed asymmetric aldol reactions of trichlorosilyl enol ethers
R
OSiCl3
O
O
Ph
Ph
OH
N
O
P
CH2Cl2
R
Ph
H
N
N
R
Catalyst
Temp [ºC]
d.r.
% ee
none
0
98:2
–
R = Me
–78
< 1:99
93
R = Ph
–78
99:1
53
■ In analogy to catalyzed reactions with allylic trichlorosilanes a rate enhancement is observed using a Lewis base.
This support the formation of a cationic hypervalent siliconium ion as reactive intermediate.
■ Dramatic difference between the observed diastereoselectivities indicates that the two catalysts must participate in
different manners
Denmark, S. E.; Su, X.; Nishigaishi, Y. J. Am. Chem. Soc. 1998, 120, 12990
Lewis Base Catalysis: n–σ* Interactions
Enoxytrichlorosilane
■ Pathway to anti aldol - double coordination
Me
Ph
OSiCl3
O
Ph
Me
R1
R2N
NR2Cl
N
N
R2N
P
R2N
E-enolsilane
+
NR2
R2N
P
O
H
N
O
R1
O
Si O
O
Cl
O
OH
Cl–
R1
2
RR
R3
H
Hexacoordinate Si proposed
(Octahedral)
Good Enantioselectivity
anti aldol
(92% ee)
■ Pathway to syn aldol – mono coordination
Ph
Ph
OSiCl3
Ph
R1
N
Ph
N
Cl
H
O
P
O
H
N
R
O
O
Si
+
Cl
O
R2N
O
NR2
OH
Cl–
R1
NR2
E-enolsilane
Pentacoordinate Si proposed
(Trigonal bipyramidal)
Poor Enantioselectivity
■ Ligand binding forces Cl– dissociation. Experimental evidence:
 Bu4NCl retards the reaction rate - common ion effect
 Bu4NOTf and Bu4NI accelerate the rate by increasing ionic strength
Denmark J. Am. Chem. Soc. 1998, 120, 12990.
syn aldol
(50% ee)
Lewis Base Catalysis: n–σ* Interactions
Enoxytrichlorosilane
■ Dimeric phosphoramide catalyzed asymmetric aldol reactions between aldehydes
OH
OSiCl3
C5H9
H
+
O
Cl
5 mol % cat.
CHCl3/ CH2Cl2
O
Ph
H
Cl
Si
Ph
Cl
OH
C5H9
N
+
N
OMe
Ph
OMe
92 % yield ; syn/anti 99:1; 90% ee
(E) enolsilane
92 % yield ; syn/anti 3:97; 82% ee
O
O
P
P
N
Me Me
5N
N
N
Me Me
bisphosphoramide catalyst
C5H9
(Z) enolsilane
Me
Me
OMe
MeOH
O
H
C5H9
OMe
■ In situ formation of an inactive chlorohydrin prevents oligomerization
■ The aldehyde is bound trans to one of the of the
phosphoramides at the less sterically encumbered
position
■ The exposure of the Re face of the aldehyde is
determined by two factors: Interaction with the Nmethyl group and one of the naphtyl group
Denmark, S. E.; Ghosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759
Lewis Base Catalysis: n–σ* Interactions
Limitations with trichlorosilanes
■ Trichlorosilanes are difficult to prepare and handle
1) LDA, –78 ˚C
2) Bu3SnCl
O
Me
OMe
1) SiCl4 (6 equiv)
2) distill 20 ˚C
O
Bu3Sn
OMe
60%
OSiCl3
OMe
65%
Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 1996, 118, 7404-7405.
OTMS
R
O
Hg(OAc)2 (1 mol%)
XHg
SiCl4, CH2Cl2
OSiCl3
~60%
R
R
R = iPr, nBu, iBu, tBu, TBSOCH2, Ph, CH2CH
Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Org. Chem. 1998, 63, 9517-9523.
■ Possible solution to this problem?
R2N
R2N
O
R2N
P
NR2
SiCl4
NR2
Lewis Base Poor Lewis acid
+
NR2
P
O
Cl
Cl–
O Si
Cl
R2N P
Cl
R2N NR
2
Qu: Is this a useful Lewis Acid?
Lewis Base Catalysis: n–σ* Interactions
SiCl4 mediated reactions
■ SiCl4 mediated / phosphoramide-catalyzed allylatiions with stannanes
SnBu3
+
O
R
H
5 mol % cat.
SiCl4
(NR2)3P
(NR2)3P
CH2Cl2, –78 ºC
6h
Cl
O
O Si Cl
Cl
Cl
O
OH
R
R
OH
OH
OH
■ Good yields and enantioselectivities
obtained, but only aromatic and olefinic
aldehydes were reactive
91 % yield
94 % ee
91 % yield
66 % ee
Me
Me
N
N
O
O
P
P
N
Me Me
5N
N
N
Me Me
bisphosphoramide catalyst
Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199
no reaction
Lewis Base Catalysis: n–σ* Interactions
SiCl4 mediated reactions
■ Catalytic cycle for SiCl4-mediated / phosphoramide-catalyzed reactions
■ The lack of reaction with aliphatic aldehydes is explained through the unproductive equilibrium between the
hexacoordinated cationic intermediate and the unreactive chlorohydrin.
■ Open transition state leads to the opposite sense of diastereoselection when compared to trichlorosilyl enol ethers,
making this method complementary to the existing one. This allows access to both diastereomers starting from the
same synthetic precursor.
Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199
Lewis Base Catalysis: n–σ* Interactions
SiCl4 mediated reactions
OTBS
N
+
R
N
5 mol % cat.
SiCl4
O
OMe
Me
Me
■ Silyl ketene acetal
H
OH
CH2Cl2, –78 ºC
6h
OH
R
P
5N
N
O
OMe
OMe
OMe
97 % yield
93 % ee
95 % yield
94 % ee
72 % yield
81 % ee
■ Propionate-derived silyl ketene acetal
OTBS
5 mol % cat.
SiCl4
O
+
OMe
R
H
CH2Cl2, –78 ºC
6h
Me
OH
OH
OMe
Me
OH
O
97 % yield
d.r. 99:1 ; 93 % ee
OH
O
O
OMe
OMe
OMe
Me
O
R
Me
98 % yield
d.r. >99:1 ; 94 % ee
N
bisphosphoramide catalyst
OH
O
N
Me Me
Me Me
OMe
OH
O
O
O
O
P
Me
71 % yield
d.r. 91:9 ; 81 % ee
Denmark, S. E.; Wynn, T.; Beutner, G.L. J. Am. Chem. Soc. 2002, 124, 13405
Lewis Base Catalysis: n–σ* Interactions
SiCl4 mediated reactions
R3
OTBS
+
OR2
R
H
CH2Cl2, –78 ºC
R4
R3
O
R1
P
P
N
OH
O
O
N
1 mol % cat.
SiCl4
O
Me
Me
■ Addition of vinylogous enol ether
5N
N
N
N
Me Me
Me Me
bisphosphoramide catalyst
OR2
R4
OH
H3C
O
OH
O
CH3
OH
O
OEt
OtBu
O
89 % yield
γ/α >99:1 ; 98 % ee
O
CH3
92 % yield
γ/α >99:1 ; 74 % ee
92 % yield
d.r. 99:1 ; 89 % ee
Denmark, S. E.; Beutner, G.L. J. Am. Chem. Soc. 2003, 125, 7800
■ Addition of N-O-ketene acetals
OTBS
R3
5 mol % cat.
SiCl4
O
+
N
R
R2
H
CH2Cl2, –78 ºC
6h
O
OH
OH
O
C5H11
N
OH
O
R
N
R2
O
OH
O
O
N
N
O
O
O
80 % yield
γ/α >99:1 ; 98 % ee
R3
79 % yield
γ/α >99:1 ; 87 % ee
71 % yield
γ/α >99:1 ;94 % ee
Denmark, S. E.; Beutner, G.L.; Wynn, T.; Eastgate, M.D . J. Am. Chem. Soc. 2005, 127, 3774
Lewis Base Catalysis: n–σ* Interactions
SiCl4 mediated reactions
■ Addition of isocyanide
C
N
tBu
1 mol % cat.
SiCl4
O
+
R
H
CH2Cl2, –78 ºC
OSiCl3
N
R
tBu
MeOH / NaHCO3
or
NaHCO3
OH
OH
OMe
R
Cl
or
O
R
Quench
Yield [%]
ee [%]
Ph
NaHCO3
96
> 98
Ph
(E)-PhCH=CH
MeOH
NaHCO3
97
>98
N
81
96
N
(E)-PhCH=CH
MeOH
71
96
PhCH2CH2
NaHCO3
92
64
PhCH2CH2
MeOH
88
64
NHtBu
R
O
Me
Me
O
O
P
P
N
Me Me
5N
N
N
Me Me
bisphosphoramide catalyst
■ Under standard reaction conditions developed for the SiCl4-mediated reactions, of enoxysilanes, an isocyanide can
add to aromatic, olefinic, and aliphatic aldehydes in high yields and enantioselectivities
■ After hydrolysis either the amide or the ester product can be obtained selectively
■ After formation of the carbon–carbon bond, a nitrilium ion is generated. This highly electrophilic species can serve
as a competitive trap for the ionized chloride ion, thereby forming a chloroimine and disfavoring the formation of
inactive chlorohydrins
Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825
Lewis Base Catalysis: n–σ* Interactions
Reduction of carbonyls and imines
■ Hydrosilation – Corriu (1981)
HSi(OEt)3 (1.0 equiv.)
CsF (1.0 equiv.)
O
Ph
Me
OH
Ph
neat, 0 ˚C
80%
Me
■ Probable mechanism
O
H
Lewis base
Si OEt
EtO
OEt
activation
H
Ph
EtO Si OEt
OEt
F
Me
Cs
5-coordinate
good L.A.
F
F
EtO
EtO
Si
H
Me
OEt
OEt
Cs
O
Ph
EtO Si OEt
O
F
Me
Cs
work-up
Ph
6-coordinate
good H– donor
Boyer, J.; Corriu, R. J. P.; Perz, R.; Reye, C. Tetrahedron, 1981, 37, 2165.
Corriu, R. J. P.; Perz, R.; Reye, C. Tetrahedron, 1983, 39, 999.
OH
Ph
Me
Lewis Base Catalysis: n–σ* Interactions
Reduction of carbonyls and imines
■ Hosomi (1988)
HSi(OMe)3 (1.5 equiv.)
cat. (0.4 mol%)
O
Ph
Me
OH
Ph
THF, RT
Me
89%
52% ee
N
Li
OLi
catalyst
Kohra, S; Hayashida, H.; Tominaga, Y.; Hosomi, A. Tetrahedron Lett., 1988, 29, 89.
 Hosomi discovered that lithium alkoxides can act as reversible binding Lewis bases
 Development of highly catalytic processes (0.4 mol%)
 Problem: Product alkoxide can also act as a Lewis base catalyst –
alternative low ee reaction
■ Iwasaki (1999)
HSiCl3 (1.5 equiv.)
cat. (10 mol%)
O
Ph
Me
CH2Cl2, 0 ˚C
Iwasaka et al. Tett. Lett., 1999, 40, 7507.
OH
Ph
Me
87%
29% ee
NH
N
H
O
catalyst
Lewis Base Catalysis: n–σ* Interactions
Reduction of carbonyls and imines
■ Reduction of ketones with trimethylsiloxane
HSi(OMe)3
catalyst
O
Ar
OH
Me
Ph
Me
 Problem: Product alkoxide can also act as a Lewis base catalyst – alternative low ee reaction
O
OLi
OLi
Ph
OLi
OH
NHLi
NLi
4 mol %
Ar = Ph
62 % yield
77 % ee
10 mol %
Ar = Ph
80 % yield
61 % ee
NHLi
4 mol %
Ar = 4-anisyl
89 % yield
70 % ee
Schiffers, R.; Kagan, H. B. Synett., 1997, 1175.
Lewis Base Catalysis: n–σ* Interactions
Reduction of carbonyls and imines
■ Reduction of imines with trichlorosilane
Me
SO2(4-tBuC6H4)
N
Ar
Ph
Me
Cl3SiH
HN
Ph
N
activator
Ar
Me
H
N
H
N
O
O
N
O
Ph
H
Ac
O
O
H
N
Ph
O
Ph
Me
NH
Me
H3C
H3C
■ My proposed TS:
H
10 mol %
Ar = 4-NO2C6H4
99 % yield
90 % ee (S)
10 mol %
Ar = 4-NO2C6H4
99 % yield
90 %
CH3
O
H
N
Me
O
Ac
10 mol %
Ar = 4-anisyl
95 % yield
93 % ee
O
Me
Ph
hydrogen bonding
or size, or docking?
Cl
Si N
O
Cl
H
arene-arene
arene-arene
interactions
interactions
with substrate with catalyst
Me
sense of
asymmetric
induction
H
Me
chiral
relay
R
N
N
O
Ar
N
O
H
(S)-major
coordination
of Si
R1
R2
Me
size
Malkov, A.V.; Stoncius, S.; MacDougall, K.N.; Mariani, A.; McGeoch, G.D.; Kocovski, P. Tetrahedron, 2006, 62, 264.
Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett, 2006, 8, 999.
Wang, Z.; Cheng, P.; Wei, S.; Wu, P.; Sun, J. Org. Lett, 2006, 8, 3045.
Conclusion
■ Lewis base catalysis has seen tremendous growth over the past 10 years due in part to the efforts
of Scott. E. Denmark
■ Considering the different ways in which electron-pair donors can enhance chemical reactivity
through various mechanis, the opportunities for invention are important.
■ Problem: It is difficult to accurately assess the precise nature, coordination and conformation of
the active catalyst and transition state orientation.