Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr: Convenient Method for the Generation of Subvalent Titanium Alkoxide Reagents and their Reactivity in Pinacol Coupling Reactions

Article abstract of DOI:10.1055/s-2003-43370

The composition of the gaseous products from the reaction of Ti(IV) isopropoxide with ethylmagnesium bromide in diethyl ether evidences the formation of subvalent titanium isopropoxide species in various oxidation states depending on relative amounts of the reactants. Reaction of titanium(IV) isopropoxide with one equivalent of the Grignard reagent gives presumably titanium(III) isopropoxide. The latter is generated as a result of disproportionation of starting Ti(IV) species and titanium(II) isopropoxide-ethene complex which is formed as a result of ethane extrusion from diethyltitanium(IV) isopropoxide. Titanium(III) isopropoxide prepared by this way transforms the aldehydes and the aromatic ketones into the corresponding pinacols in good yields.

Full text of DOI:10.1055/s-2003-43370

LETTER
77
Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr:
Convenient Method for the Generation of Subvalent Titanium Alkoxide
Reagents and their Reactivity in Pinacol Coupling Reactions
A
lkylative Redu
v
ction of
T
ita
g
nium(IV) Is
e
opropoxide
n
with
E
tMgB
i
r
i A. Matiushenkov, Nikolai A. Sokolov, Oleg G. Kulinkovich*
Department of Organic Chemistry, Belarusian State University, Skoriny av. 4, Minsk, 220050, Belarus
Fax +375(17)2264998; E-mail: kulinkovich@bsu.by
Received 2 October 2003
All our attempts to generate titanacyclopropane (3) in the
absence of either carboxylic esters or some other unsatur-
ated substrates, and then to involve it in the carbon-carbon
bond forming reactions with electrophiles met with fail-
Abstract: The composition of the gaseous products from the reac-
tion of Ti(IV) isopropoxide with ethylmagnesium bromide in dieth-
yl ether evidences the formation of subvalent titanium isopropoxide
species in various oxidation states depending on relative amounts of
the reactants. Reaction of titanium(IV) isopropoxide with one ures.
equivalent of the Grignard reagent gives presumably titanium(III)
Our results were in some inconsistency with the data re-
isopropoxide. The latter is generated as a result of disproportion-
ation of starting Ti(IV) species and titanium(II) isopropoxide–
ethene complex which is formed as a result of ethane extrusion from
diethyltitanium(IV) isopropoxide. Titanium(III) isopropoxide
prepared by this way transforms the aldehydes and the aromatic
ketones into the corresponding pinacols in good yields.
cently reported by Eisch and co-workers on the generation
and reactivity of titanium(II) isopropoxide 4.5 The latter
was prepared by alkylative reduction of Ti(i-PrO)4 with
n-butyllithium in THF at –78 °C followed by removal of
the solvent with warming under reduced pressure.The au-
thors clearly demonstrated the ability of this titanium re-
agent 4 to involve olefins and acetylenes in the reactions
where they act as 1,2-dicarbanion equivalents.5a Thus, for
example, redissolving of black solid reagent 4 in THF,
subsequent bubbling of ethylene into the obtained solu-
tion followed by addition of benzonitrile, passing CO2
into the resulting reaction mixture and hydrolysis led to
formation of 3-benzoylpropanoic acid (5) in 30% overall
yield5a (Scheme 2).
Key words: titanium compounds, reduction, Grignard reagents,
carbonyl compounds, pinacol coupling
Some time ago we have found a convenient method for
the cyclopropanation of carboxylic esters by titanium(IV)
isopropoxide (1) catalyzed reaction with ethylmagnesium
bromide.1 Mechanistically, this transformation was ratio-
nalized by assuming the formation of thermally unstable
diethyltitanium compound 2 which rapidly undergoes b-
hydride elimination1,2 to give ethane and titanacyclopro-
pane (3) [titanium(II)-ethylene complex, Scheme 1]. The
latter acts in situ as a 1,2-dicarbanion equivalent in reac-
tion with carboxylic esters producing a 2-fold alkylation
of the alkoxycarbonyl group, leading to cyclopropanols.1,3
It also exhibits the properties of titanium(II) isopro-
poxide-olefin complex by involving an olefin ligand ex-
change reactions with styrene4 and some other
unsaturated compounds.3
Scheme 25a
In this paper we report the data that evidence the genera-
tion of titanium(III) isopropoxide (6) under treatment of
titanium(IV) isopropoxide (1) with one equivalent of
ethylmagnesium bromide. This finding elucidates the
reasons of our failed attempts to generate titanium 1,2-di-
carbanionic equivalents in the absence of the tested sub-
strates and opens a convenient and flexible way for the
preparation of subvalent titanium alkoxide reductants.
Scheme 11,2
When titanium(IV) isopropoxide (1) was treated with a
10-fold excess of ethylmagnesium bromide in diethyl
ether at room temperature, the intensive gas evolution was
only observed during addition of the first 5 equivalents of
SYNLETT 2004, No. 1, pp 0077–0080
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43370; Art ID: G26203ST
© Georg Thieme Verlag Stuttgart · New York

78
E. A. Matiushenkov et al.
LETTER
the Grignard reagent (Table 1, entry 1–5). Ethane and
ethene were the main components of the gaseous products
from the reaction together with the formation of about
10% of the C4 hydrocarbons. In total a little bit less than 4
equivalents of gaseous hydrocarbons were evolved, which
indicated nearly complete alkylative reduction5a of Ti(IV)
isopropoxide into the Ti(0) species. After addition of the
first equivalent of Grignard reagent to titanium(IV) iso-
propoxide (1), ethylene formation decreased drastically
(Table 1, entry 2–6). This result evidences the total con-
sumption of titanium(IV) isopropoxide (1) and its alkyla-
tive reduction to titanium(III) isopropoxide (6)6
(Scheme 3). The reactivity of the latter towards ethylmag-
nesium bromide could be lower, in comparison with tita-
nium(IV) isopropoxide (1), due to the formation of its
homogenous binuclear complexes or mixed complexes
with magnesium salts.7 The observed distinct viscosity in-
crease of a solution of 1 in diethyl ether after treatment
with one equivalent of ethylmagnesium bromide was in
agreement with this supposition.
Scheme 3
hydrobenzoins 8 as the main products (Scheme 4). In
these experiments the reagent 6 was preliminary prepared
in 1.5–2 fold excess toward the carbonyl substrate9 and
used immediately to reduce the complications caused by
its instability. When benzaldehyde was treated with 6 in
diethyl ether the pinacol coupling product was formed
in good yield and low dl-/meso-stereoselectivity after hy-
drolytic workup of the heterogeneous reaction mixture
(entry 1). Small amounts of benzylic alcohol and 1-phe-
nylpropanol were detected as byproducts. The reaction
proceeded more smoothly and in homogeneous con-
ditions when tetrahydrofuran was used as the solvent
(entry 2). Formation of 1-phenylpropanol was not ob-
served in this case, which indicates the total decomposi-
tion of organometallic impurities after a short reflux of 6
in THF. Aromatic aldehydes bearing acceptor halogen
substituents (entries 3, 4) or donor dimethylamino group
(entry 5) also gave the corresponding pinacols in good
yields and low stereoselectivity. A similar result was
obtained with hexanal, however larger amounts of the
corresponding primary alcohol 9 were formed (entry 6).
Table 1 Yields and Ratios of the Gaseous Products Formed in the
Reaction of Ethylmagnesium Bromide with Titanium(IV) Isopro-
poxide in Diethyl Ether
Entry EtMgBr Time
(equiv)a (min)b
Gaseous productsc
C2+C4 hydrocarbons Ethylene Ethane
(equiv)
0.64
0.86
0.74
0.61
0.54
0.18
(%)
48
15
1
(%)
51
77
87
88
85
84
1
2
3
4
5
6
1
9
15
18
20
33
60
2
3
4
<1
4
5
6–10
8
a Added to a solution of 1 (0.02 mol) in Et2O (15 mL) at r.t.
Scheme 4
b Time for the complete gas evolution after addition of EtMgBr.
c Gaseous product ratio was determined by GC.
Hydrogenation of the carbonyl group in dibutylketone and
aldol self-condensation of cyclohexanone were dominant
processes when these compounds were treated with re-
agent 6 (entries 7, 8). Aromatic ketones showed similar
reactivity as aldehydes and the pinacol coupling products
were formed in high yields (entries 9–11). It is interesting
to compare these results with published data on the inter-
action of benzophenone with titanium(II) isopropoxide
reagent 4.5a The latter was prepared by reductive alkyla-
tion of Ti(i-PrO)4 with two equivalents of n-butyllithium,
and reduced benzophenone to benzhydrol in 95% yield.
The authors suppose that the reduction proceeded via epi-
metallation of the carbonyl group to afford the corre-
sponding oxatitanacyclopropane intermediate, which was
further transformed into benzhydrol upon hydrolytic
work-up. We found, in contrast, that pinacol coupling
remained the dominant reaction pathway even when
two equivalents of ethylmagnesium bromide were used
for the alkylative reduction of titanium(IV) isopropoxide.
Taking into account the considerable amount of ethene in
the gaseous products at this step of the alkylative reduc-
tion (Table 1, entry 1), we believe that 6 is formed by
ethene displacement in titanacyclopropane (3) with titani-
um isopropoxide (1) (Scheme 3). Further alkylative re-
duction of titanium(III) isopropoxide (6) with excess of
ethylmagnesium bromide proceeds possibly via homolyt-
ic cleavage of Ti-C bond in a low valent alkyltitanium
species being formed and does not involve the formation
of the corresponding subvalent titanacyclopropane inter-
mediates.
The subvalent titanium species generated by alkylative re-
duction of titanium(IV) isopropoxide with ethylmagne-
sium bromide were tested for the pinacol coupling of
carbonyl compounds.8 As illustrated in Table 2, titani-
um(III) isopropoxide (6) readily reacted with aromatic al-
dehydes 7 (entries 1–6) to afford the corresponding
Synlett 2004, No. 1, 77–80 © Thieme Stuttgart · New York

LETTER
Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr
79
Table 2 Reaction of Carbonyl Compounds with Ti(i-PrO)3
Entry
Substrate
Time (h)
2c,d
0.3d
12
Producta
Yield (%)b
75e
DL-:meso-
36:64
61:39
47:53
47:53
33:67
60:40
–
1
2
C6H5CHO
(C6H5CHOH)2
C6H5CHO
(C6H5CHOH)2
95f
3
p-BrC6H4CHO
p-ClC6H4CHO
p-Me2NC6H4CHO
CH3(CH2)4CHO
(CH2)5CO
(p-BrC6H4CHOH)2
(p-ClC6H4CHOH)2
(p-Me2NC6H4CHOH)2
[CH3(CH2)4CHOH]2
[(CH2)5COH]2
85f
4
12
85f
5
2
95f
6
10
75f
7
15
11g
8
(n-C4H9)2CO
C6H5COCH3
C6H5COCH3
Ph2CO
15
[(n-C4H9)2CHOH)]2
(C6H5CCH3OH)2
(C6H5CCH3OH)2
(Ph2COH)2
<5h
75
–
9
0.2
0.5i
15
80:20
79:21
–
10
11
100
93
a Selected 1H NMR data of the pinacol coupling products, see ref.12
b Was determined by 1H NMR spectra.
c In Et2O.
d 1.5 Equiv of Ti(O-i-Pr)3 was used.
e Near 20% of 1-phenylpropanol was formed.
f The corresponding alcohol 9 was formed as byproduct.
g Isolated yield. The aldol self-condensation product (50%) and cyclohexanol (9) (35%) were isolated by column chromatography on silica gel.
h The starting compound (25%) and the corresponding alcohol 9 (55%) were detected by 1H NMR.
i At reflux.
Remarkably, it was no matter whether the Ti(i-PrO)4 and
EtMgBr were mixed at room temperature10 or at –78 °C,11
with subsequent half an hour reflux in both cases. In other
words, Ti(II) isopropoxide species 4 generated by the
latter procedure, and prepared by Eisch’s procedure5a
completely differ in the reactivity towards benzophenone.
The origin of this difference could be associated with un-
equal influence on the reaction pathway of magnesium
and lithium alkoxides formed during the alkylative reduc-
tion of Ti(IV) with ethylmagnesium bromide or n-butyl-
lithium,5 respectively.
References
(1) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. J. Org. Chem. USSR (Engl. Transl.) 1989,
25, 2027. (b) Kulinkovich, O. G.; Sviridov, S. V.;
Vasilevskii, D. A. Synthesis 1991, 234.
(2) Epstein, O. L.; Savchenko, A. I.; Kulinkovich, O. G. Russ.
Chem. Bull. 2000, 278.
(3) For reviews see: (a) Kulinkovich, O. G. Chem. Rev. 2003,
103, 2597. (b) Kulinkovich, O. G.; de Meijere, A. Chem.
Rev. 2000, 100, 2789.
(4) (a) Kulinkovich, O. G.; Savchenko, A. I.; Sviridov, S. V.;
Vasilevsky, D. A. Mendeleev Commun. 1993, 230.
(b) Epstein, O. L.; Savchenko, A. I.; Kulinkovich, O. G.
Tetrahedron Lett. 1999, 40, 5935.
(5) (a) Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J.
Organomet. Chem. 2001, 624, 229. (b) Eisch, J. J.; Gitua, J.
N. Organometallics 2003, 22, 24.
(6) For physical and spectral data on monomeric (t-Bu3SiO)3Ti,
see: Covert, K. J.; Wolchanski, P. T.; Hill, S. A.; Krusic, P.
J. Inorg. Chem. 1992, 31, 66.
(7) For physical and spectral data on dimeric aryloxide
derivative [(2,6-Ph2C6H3O)2TiCl]2, see: (a) Thorn, M. G.;
Hill, J. E.; Waratuke, S. A.; Johnson, E. S.; Fanwick, P. E.;
Rothwell, I. P. J. Am. Chem. Soc. 1997, 119, 8630. (b) Hill,
J. E.; Fanwick, P. E.; Rothwell, I. P. Polyhedron 1990, 9,
1617.
In conclusion, the simple procedure for the generation of
putative titanium(III) isopropoxide (6) described in this
work, as well as the alternative way to Ti(II) isopropoxide
species (4) early reported by Eisch5 and coworkers are
flexible tools for the elaboration of synthetically useful ti-
tanium alkoxide reductive agents in variable valent state.
Investigations on the use of these reagents for the reduc-
tive cleavage of carbon-halogen and nitrogen-oxygen co-
valent bonds in organic molecules are in progress in our
laboratory.
Acknowledgment
(8) For a recent review, see: Gansäuer, A.; Bluhm, H. Chem.
Rev. 2000, 100, 2771; and references therein.
This work was carried out with support of the INTAS programme
and Belarussian Fund for Scientific research.
Synlett 2004, No. 1, 77–80 © Thieme Stuttgart · New York

80
E. A. Matiushenkov et al.
LETTER
(11) The treatment of benzophenone with 1 equiv of Ti(II)
(9) Procedure for Pinacol Coupling: To a solution of Ti(i-
PrO)4 (2.05 g, 7.3 mmol) in THF (6 mL) under argon
atmosphere, a solution of EtMgBr prepared from Mg (0.19
g, 7.9 mmol) and EtBr (0.9 g, 8.2 mmol) in THF (8 mL) was
added for a 2 min. The initially colorless solution turned
blue, green-brown and black-brown over the course of
EtMgBr addition. The reaction mixture was stirred and
refluxed for 30 min under argon, then a solution of carbonyl
compound in THF (2 mL) was added in one portion at r.t. or
at reflux. The reaction mixture was stirred for a denoted time
(Table 2) and then diluted with 20 mL of Et2O and quenched
with 20 mL of 10% H2SO4 (in the case of the example in
entry 5 the reaction mixture was quenched with aq NH4CI
and filtered). Organic layer was separated, washed with
H2O, aq NaHCO3 and dried over MgSO4. After removing of
the solvent in vacuo the resulting reaction mixtures were
analyzed by 1H NMR and then crystallized from CCI4 or
EtOH.
isopropoxide, prepared by alkylative reduction of Ti(IV)
isopropoxide with EtMgBr in THF at –78 °C, led to 58% of
pinacol 8, 1% of benzhydrol 9, and 21% of the starting
compound was recovered.
(12) Selected NMR data for pinacol coupling products:
dl- and meso-1,2-bis(4¢-Chlorophenyl)ethane-1,2-diol. 1H
NMR (lit.13) (400 MHz, CDCI3), dl: d = 2.93 (s, 2 H, OH),
4.61 (s, 2 H, CH), 7.00 (d, 4 H, J = 8.6 Hz), 7.20 (d, 4 H,
J = 8.6 Hz); meso: d = 2.36 (s, 2 H, OH), 4.83 (s, 2 H, CH),
7.09 (d, 4 H, J = 8.6 Hz), 7.25 (d, 4 H, J = 8.6 Hz).
dl- and meso-2,3-Diphenylbutane-2,3-diol. 1H NMR
(lit.14) (400 MHz, CDCI3), dl: d = 1.50 (s, 6 H, CH3), 2.59 (s,
2 H, OH), 7.17–7.26 (m, 10 H, Ph-H); meso: d = 1.58 (s, 6
H, CH3), 2.29 (s, 2 H, OH), 7.17–7.26 (m, 10 H, Ph-H).
dl- and meso-Dodecane-6,7-diol.15 1H NMR (400 MHz,
CDCI3), dl: d = 0.85–0.93 (m, 6 H, CH3), 1.21–1.54 (m, 16
H, CH2), 1.92–2.05 (s, 2 H, OH), 3.37–3.41 (m, 2 H, CH);
meso: d = 0.85–0.93 (m, 6 H, CH3), 1.21–1.54 (m, 16 H,
CH2), 1.92–2.05 (s, 2 H, OH), 3.57–3.63 (m, 2 H, CH).
(13) Trahanovsky, W. S.; Gilmore, J. R.; Heaton, P. C. J. Org.
Chem. 1973, 38, 760.
(10) The treatment of benzophenone with 1 equiv of Ti(II)
isopropoxide, prepared by alkylative reduction of Ti(IV)
isopropoxide with EtMgBr in THF at r.t., led to 39% of
pinacol 8, 3% of benzhydrol 9, and 47% of the starting
compound was recovered.
(14) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748. (b) Fürstner, A.; Csuk, R.; Rohrer, Ch.; Weidmann, H.
J. Chem. Soc., Perkin Trans. 1 1988, 1729.
(15) Criegee, R.; Höger, E.; Huber, G.; Kruck, P.; Marktscheffel,
F.; Schellenberger, H. Liebigs Ann. Chem. 1956, 599, 6.
Synlett 2004, No. 1, 77–80 © Thieme Stuttgart · New York