Module 3
Reactions with Organometallic Compounds
Lecture 33
3.8.5 Organotitanium Compounds
Keywords:
Allylation,
Addition,
Nucleophile,
C-C
Bond
Formation,
Ene-Reaction,
Cycloaddition, Oxidation, Lewis Acid
Titanium, an abundant and non-toxic transition metal, has been often used for the modification of
organolithium and organomagnesium compounds. The preparation of individual titanium
reagents is usually carried out by ligand exchange on, e.g. TiCl4, Ti(OiPr)4 or cyclopentadienyltitanium trichloride (Scheme 1). Chloride ligands can be replaced by protonated (LH), silylated
(LSiMe3), stannylated (LSnR3) or metalated (LM, M = Li, MgX) ligands. Volatiles such as HCl
and Me3SiCl can be removed by evaporation. Alkoxide ligands can be exchanged through adduct
formation with alcohols. Many of the titanium compounds are moisture sensitive. The resulting
hydroxo compounds are acidic and form -oxo dimers or trimers. With more water, complete
hydrolysis occurs to give titanium dioxide. This section covers the recent developments on the
use organotitanium compounds in organic synthesis.
L3Ti(OiPr) + ROH
L3Ti
(OiPr)
L3Ti(OR) + iPrOH
O R
H
L3TiCl
L3TiCl + ROH
-HCl
L3TiOR
L3Ti-OTiL3
-HCl
Scheme 1
3.8.5.1 Nucleophilic Addition to Aldehydes
Titanium(IV)-mediated addition of nucleophiles to aldehydes exhibits excellent stereocontrol.
The attacking nucleophile is either ligand of the activating titanium complex or an additional
reagent. The stereoselectivity results from the bias of the titanium center (Scheme 2). For
examples, asymmetric allylation of aldehydes and ‘ene’ reactions mediated by chiral titanium
1
Module 3
Reactions with Organometallic Compounds
complexes provide the corresponding homoallylic alcohols with excellent enantioselectivity
(Scheme 3-4).
TiL4-xNux
O
R
O
TiL4-xNux
H
(x = 0 or 1)
R
internal
nucleophile
O-TiL3
R
Nu
H
O-TiL4
external
nueclophile
activated
aldehyde
R
Nu
Scheme 2
Me
Ti O Ph
Ph
O
O
Ph
Ph O
Cl
Li
R
Ti O
O
Ph H2O/NH4F
O
Ph
Ph
O
Scheme 3
2
OH
R'CHO
Ph
R'
R
95-98% ee
R, R' = alkyl, aryl, allyl
Module 3
Reactions with Organometallic Compounds
Ti(OiPr)4
Y = Li
Cl
O
Ti
O
TiCl4
OY
OY
o
Cl -80 C to rt
53% ee, 31% yield
Y=H
BINOL-Ti*
Active Catalyst
Wet MS 4A or H2O
O
+ H
OiPr
TiCl2(OiPr)
92% ee 2% yield
dry MS 4A
< 0.2% w/w H2O
Wet MS 4A
Ph
Ti
O
Y=H
TiCl2(OiPr)
Wet MS 4A
OiPr
O
OH
CO2nBu
Ph
CH2Cl2, -30 oC
Chem Commun 1997, 281.
CO2nBu
Ti, Pd, Pt, Ni, Cu,
Sc,Co, Cr, Rh
up to 98% ee 97% yield
Scheme 3
Similarly, aldol-type addition of enolates to aldehydes can be accomplished with excellent
selectivity. For examples, the chiral cyclpentadienyltitanium complex derived from CpTiCl3 and
TADDOL has been used for highly enantio- and diastereoselective aldol rections (Scheme 4).
The products are obtained by transmetalating the Li-enolate with the Ti-TADDOL complex.
Ti O Ph
Ph
O
O
Ph
Ph O
Cl
N
Li
O
O
Et2O, -78 oC
O
-78-30 oC
Ti O Ph
RCHO
OH O
o
Ph
-78 C - RT
O
R
OtBu
O
H
O
2
91-96% ee
Ph
Ph O
O
The addition of diketene to aldehydes can be accomplished using chiral titanium(IV) Schiff base
complex to afford -hydroxy--ketoesters with reasonable enantioselectivity (Scheme 5). This
reaction is too most probably proceeding via a Ti-enolate formed in situ from diketone and
3
Module 3
Reactions with Organometallic Compounds
titanium(IV)-Schiff base complex. Catalytic version of this reaction can be carried out using TiBINOL complex. In this case a Mukaiyama-type aldol reaction between aldehydes and ketene
silyl-acetal leads to provide silylated aldols with high optical purity (Scheme 6).
O
N
OH
O
Ti(OiPr)4
+ 2 iPrOH
N
RT
OH
O
Ti O
O O
(*L)n
O
Ti
O
O
CH2Cl2, -20 oC
O
RCHO
H+
OH O
O
R
O
67-84% ee
Scheme 5
OSiMe3
O
t-Bu +
S
R
H
Me3SiO
O
5 mol% Ti-BINOL
R
Et2O, -20 to 0 oC
Cl
O
S-t-Bu
Ti
O
Cl
81-96% ee
Ti-BINOL
Scheme 6
The addition of alkyl nucleophile to aldehydes can be accomplished with high optical purity. For
an example, the chiral cyclpentadienyltitanium fluoride complex catalyzes the addition of
methyltitanium triisopropoxide to benzaldehdye with excellent enantioselectivity (Scheme 7).
4
Module 3
Reactions with Organometallic Compounds
Ti O Ph
Ph
O
O
Ph
Ph O
OH
O
F
H
2.0 % Ti-catalyst
Me
+ MeTi(OiPr)3
CH2Cl2
-78 oC
95% ee
Ti-Catalyst
Scheme 7
OH
CHO Ti*Ln
* CN
TMSCN/H+
Ti*Ln
CHO
TMSCN/H+
OH
N
O
O
N
Ti
O
O
* CN
Ti*Ln
Scheme 8
The synthesis of cyanohydrins can be achieved with high optical purity using chiral titaniumpolymer complex (Scheme 8). In these reactions, the catalyst catalyzes the reactions under
homogeneous conditions, however, after completion, the catalyst can be precipitated from the
reaction mixture and collected for recyclability without loss of activity and selectivity using
MeOH. This catalytic system has the advantages of both homogeneous as well as heterogeneous
processes.
3.8.5.2 Cycloadditions
Chiral titanium(IV) complexes have been found to be excellent Lewis acid catalysts for
cycloaddition reactions. For example, chiral titanium(IV) complex prepared from TADDOL and
TiCl2(OiPr)2 catalyzes Diels-Alder reactions of dienes with oxazolidinone derivatives of several
-unsaturated carboxylic acids with excellent optical purity (Scheme 9). These systems could
also be used for [2+2]-cycloadditions between unsaturated N-acyl-oxazolidinones and electron-
5
Module 3
Reactions with Organometallic Compounds
rich alkenes. For example, fumaryol derivative reacts with alkynyl sulfide to give cyclobutene
derivative with excellent yield and enantioselectivity (Scheme 10).
O
+ Me
Me
O
N
O
cat. TiLn*
H O
H
-15 oC
O
endo : exo 92 : 8
JACS, 1989, 111, 5340.
N
Ph Ph
H
O
O
O
Ph
91% ee
Me
O
O
H
TiCl2
Ph Ph
cat. TiLn*
O
O B
O
+
O
N
OAc
O
N
O
cat. TiLn*
o
0 C
toluene
OAc O
O
N
O
O
95% ee
Scheme 9
O
O
MeO
O
N
MeO
TiLn*
O +
S-Me
O
toluene
0 oC
O
O
N
SMe
98% ee
Ph
O
Me
O
O
Ph Ph
H
O
O
H
TiCl2
Ph Ph
TiLn*
Scheme 10
3.8.5.3 Asymmetric Epoxidation
Sharpless epoxidation of allylic alcohols is one of the important processes in asymmetric
catalysis. It provides an effective route for the transformation of prochiral allylic alcohols are to
epoxy alcohols in the presence of Ti(Oi-Pr)4, t-BuOOH and (R,R) or (S,S)-diethyltartarate
(Scheme 11).
6
Module 3
Reactions with Organometallic Compounds
Ti(O-iPr)4, t-BuOOH
OH
O
OH
L-(+)-DET
85% yield, 94% ee
Scheme 11
The reaction proceeds through a dimeric complex having two titanium centers (Scheme 12). The
allylic hydroxyl group coordinates with the metal thereby allowing the transfer of oxygen atom
from one face only.
OEt
O
EtO
Ti(Oi-Pr)4 + DET
i-PrO
O
i-Pr
O
O
O
E Ti
Oi-Pr + 4 i-PrOH
O
O-iPr
Ti
O E
t-BuOOH
Me
O
O
EtO
O
i-PrO
Ti
O
i-Pr
O E
E Ti
O
O
OH
E
O
+ 2 i-PrOH
O
Me
t-Bu
E = CO2Et
Scheme 12
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Module 3
Reactions with Organometallic Compounds
OH
R1
O
"O" transfer mediated
by (S,S)-DET
R3
OH
OH
R2
R1
R2
CO2Et
EtO2C
D-(-)-DET
R3
OH
R1
O
"O" transfer mediated
by (R,R)-DET
OH
R3
EtO2C
OH
CO2Et
OH
R2
L-(+)-DET
Scheme 13
The absolute configuration of the epoxy alcohol can be predicted by the following mneumonic
model in which the hydroxymethylene group is positioned at the lower right. The epoxidation
takes place from the upper face of the allyl alcohol when (+)-(R,R)-DET is used and vice versa
(Scheme 13).
These reaction conditions, Ti(Oi-Pr)4, t-BuOOH and (R,R) or (S,S)-diethyltartarate, could also be
used for asymmetric oxidation of aryl alkyl sulfides (Scheme 14).
S
Me
Me
O
S
Ti(O-iPr)4, t-BuOOH
L-(+)-DET/H2O
Me
Me
89% ee
Scheme 14
3.8.5.4 Olefination
Tebbe’s reagent, (η5-C5H5)2TiCH2ClAlMe2, allows even less reactive carbonyl compounds to be
transformed to the corresponding methylene compounds in the presence of pyridine. The reagent
is prepared by the reaction of titanocene dichloride with trimethyl aluminium in toluene (Scheme
15).
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Module 3
Reactions with Organometallic Compounds
Ti
Cl
Me
Ti
Al2Me6
+
Cl
Al
Cl
Me
Scheme 15
In the presence of pyridine the reagent transforms into a Schrock carbene and reacts with the
carbonyl group in a [2+2] cyclization which then undergoes ring opening metathesis to form the
alkene (Scheme 16).
Me
Ti
Ti
+
Al
pyridine
Cl
Me
O
O
Me
OEt
Ti
Me
OEt
Scheme 16
Alternatively the same objective can be accomplished using Petasis reagent. It is synthesized by
treating titanocene chloride with methyl lithium (Scheme 17). It shows reactivity similar to
Tebbe’s reagent. Petasis reagents can methyleneate ketones, aldehydes and esters on thermolysis
at 60 °C.
Ti
Cl
+
MeLi
Ti
Cl
Me
Me
Scheme 17
McMurry reaction is used to synthesize alkenes from dicarbonyl compounds (Scheme 18). This
reaction first generates an intermediate 1,2-diol which is then dehydrated on the surface of
titanium to form alkene. However, the reaction is not stereospecific since the two the carbonoxygen bonds do not break simultaneously. In case of cyclic 1,2-diols, a titanocycle has to be
formed for this reaction to occur. Thus, trans diols are inert under these conditions.
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Module 3
Reactions with Organometallic Compounds
2 Me
CHO
C7H15
OMe
K, TiCl3
DME, reflux
Me
K2CO3, H2O
Zn(Cu), TiCl3
DME, reflux
Me
7:3 trans:cis
Me
C7H15
O
Scheme 18
This methodology may be extended to ketoesters, where cyclic enol ether is formed which on
hydrolysis forms the corresponding cycloalkanone (Scheme 19).
O
O
Me
OMe
8
Me
LiAlH4, TiCl3
DME, reflux
Scheme 19
Problems:
Complete the following reactions with mechanism.
CHO
1.
Cat. Ti
Me
+
OMe
O
2.
Cat. Ti
H
+ Et2Zn
O
Cat. Ti
+
3.
OAc
O
NO2
4.
O
5.
Cat. Ti
+ Et2Zn
Cat. Ti
H
Me
OMe H+/H O
2
TMSCN
10
O
Module 3
Reactions with Organometallic Compounds
Text Book
M. B. Smith, Organic Synthesis, McGraw Hill, Singapore, 2004.
11