Pinacol coupling of aromatic aldehydes catalysed by a titanocene complex: a
transition metal catalysed radical reaction
Andreas Gans a¨ uer
Institut f u¨ r Organische Chemie der Georg-August-Universit a¨ t, Tammannstr. 2, D-37077 G o¨ ttingen, Germany
A trinuclear complex derived from titanocene chloride and
magnesium bromide is an efficient catalyst for the pinacol
coupling of aromatic aldehydes; the 1,2-diols are obtained
with good diastereoselectivity and a wide variety of sensitive
functional groups are tolerated.
pathway operated. It is known that titanium alkoxides are less
8
selective stoichiometric reagents in pinacol couplings and that
5 5 2 2
both coupling and reduction of (C H ) TiCl are fast at and
below room temperature.2 Thus, silylation is the rate determin-
,6
ing step in the catalytic cycle. To improve the diastereo-
selectivity a solution of benzaldehyde and Me
slowly added to a mixture of (C TiCl and Zn in THF. The
selectivity increased and the yield remained high. Selectivity is
further improved by adding 1 equiv. of MgBr to the
3
SiCl in THF was
The reductive coupling of carbonyl compounds is the most
direct way to 1,2-diols by forming a functionalized carbon–
5
H
5
)
2
2
1
carbon bond. Many stoichiometric reagents for this reaction
2
2
have been developed and the pinacol coupling has also been
benzaldehyde solution. This gave a tighter dimeric titanium
catalyst by replacing Zn with Mg.
applied as a key step in the synthesis of several natural
3
products. To avoid the use of expensive and toxic reagents the
Diethyl ether and dichloromethane gave inferior results.
t
development of an efficient transition metal catalysed pinacol
coupling is desirable. Here the first titanocene dichloride
catalysed pinacol coupling of aromatic aldehydes is described
yielding the corresponding 1,2-diols at room temperature in
good yields with good diastereoselectivities. Pinacol coupling is
not only a shortcut of the otherwise existing two-step sequence,
coupling of the aldehydes to an (E)-stilbene with stoichiometric
amounts of titanium reagents as in McMurry coupling reactions,
and a syn,vic-dihydroxylation of the central double bond. More
importantly the pinacol route to 1,2-diols tolerates certain
functional groups that are sensitive to the McMurry reagent and/
or to the dihydroxylation reaction. The pinacol coupling used
here catalytically uses cheap, readily available, non-toxic
reagents.
Other silylating reagents, e.g. Me
2
Bu SiCl, did not give any
reaction.
Under the optimised conditions a variety of symmetrical
1,2-diols were synthesised in good yields and selectivities and
could be obtained diastereomerically pure after a single
recrystallisation. Functional groups interfering with McMurry
couplings or dihydroxylation reactions such as chlorides,
double bonds, phenolate esters and a,b-unsaturated esters are
readily tolerated. Although initial experiments were performed
on a small scale, the reaction can be readily scaled up and gave
the same results using 0.5, 5 or 50 mmol of substrate. In the
latter case 320 mg of catalyst was used. This compared
favourably with the use of 24.9 g of (C
stoichiometric reaction. In effect (C TiCl
the cheaper Me SiCl. A stoichiometric reductant was needed in
both cases. Other stoichiometric or catalytic reagents, e.g. SmI
5
H
2
5
)
2
TiCl
2
in the
5
H
5
)
2
is replaced by
The only reported catalytic pinacol couplings involve harsh
reaction conditions, low selectivities and low functional group
3
2
,
4
4a
tolerance. The catalysts, ruthenium complexes or samarium
iodide,4b do not allow control of diastereoselectivity or
enantioselectivity by ligand variations.
are even more expensive and less selective. The cheapest source
of inherently toxic osmium for a dihydroxylation reaction is
about 40 times more expensive than the essentially non-toxic
Based on the ability of cyclopentadienyl-bonded titanium(iii)
(C
5
H
5
)
2
TiCl
2
.
reagents2
a,c
to induce stoichiometric pinacol couplings it
Mechanistically it seems reasonable to assume that the
seemed possible to develop a catalytic cycle. For this purpose
catalytically active species in the catalytic cycle is a dimeric
the formed diol has to be removed from titanium with
5
concomitant regeneration of (C
5
H
5
)
2
TiCl
2
. In situ reduction to
Ar HH Ar
6
the titanium(iii) reagent then finishes the catalytic cycle.
Benzaldehyde coupling in the presence of Zn and Me SiCl
with 10% (C TiCl gives complete conversion to pinacol
after hydrolysis in less than 10 min. Me SiCl as additive also
gives clean product formation. Without the catalyst, conversion
was not observed with Me SiCl as additive. Me SiCl and Zn
•
•
2
2
5 5
H )
2
2
C5H5
C5H5
O
O
C5H5
C5H5
3
Ti
Mg
Ti
Cl
Cl
2
2
3
Fig. 1 Likely catalytically active species for the dimerisation of ketyl
radicals both bound to the dimeric titanium catalyst
react to give pinacol over 20 h albeit without diastereo-
selectivity. Catalylic acceleration of the reaction was therefore
7
significant as was the improvement in diastereoselectivity.
Interestingly, however, lowering the temperature at which the
catalytic coupling was performed leads to reduced selectivity
and pronouncedly longer reaction times. One step in the
catalytic cycle was slow and thus a competing, less selective
2 2
Table 1 Coupling of benzaldehyde at 0.1 m in the presence of Me SiCl or
Me
3
SiCl
Amount of
catalyst (%)
10
t/h
T/°C
Yield (%)
1:2
O
OH
R
OH
R
1.2
22
0.25
3
3
0
240
25
25
25
93
92
96
88
90
86:14
3
% (C5H5)2TiCl2, Zn
1
0
3
3
3
70:30
Ar
Ar
+
Ar
R
H
Ar
R
Ar
R
84:16a
MgBr2, Me3SiCl
a,b
89:11
95:5
OH
OH
a,c
>
91
<9
Ar = Ph, furyl, R = vinyl, halide, ester
1
2
a
SiCl. b Slow addition of PhCHO and Me
SiCl. c Slow
1
.5 equiv. of Me
3
3
Scheme 1 Titanocene catalysed pinacol coupling of aromatic aldehydes
addition in the presence of MgBr
2
Chem. Commun., 1997
457