Aromatic carbonyl compound reduction and pinacol coupling processes mediated by titanocene(III)/Zn in water

Article abstract of DOI:10.1055/s-2005-872163

A novel procedure for the reduction and pinacol coupling of aromatic aldehydes and ketones mediated by titanocene(III)/Zn in water is described. The titanocene-catalyzed version in sea water proved to be especially convenient for the reduction of aryl ketones. Mechanistically, the reaction presumably proceeds via free-radical chemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872163

SPECIAL TOPIC
2619
Aromatic Carbonyl Compound Reduction and Pinacol Coupling Processes
Mediated by Titanocene(III)/Zn in Water
T
itanoce
n
u
e/Zn-Mediat
a
n
l
R
eactions in
Wat
L
er . Oller-López, Araceli G. Campaña, Juan M. Cuerva,* J. Enrique Oltra*
Department of Organic Chemistry, Faculty of Sciences, University of Granada, Campus Fuentenueva s/n, 18071 Granada, Spain
Fax +34(958)248437; E-mail: joltra@ugr.es; E-mail: jmcuerva@ugr.es
Received 7 July 2005
moting not only the reduction of aromatic carbonyl com-
pounds but also their pinacol coupling.
Abstract: A novel procedure for the reduction and pinacol coupling
of aromatic aldehydes and ketones mediated by titanocene(III)/Zn
in water is described. The titanocene-catalyzed version in sea water
proved to be especially convenient for the reduction of aryl ketones.
Mechanistically, the reaction presumably proceeds via free-radical
chemistry.
Thus, when we treated acetophenone (1) during 24 hours
with a blue mixture prepared by stirring Cp2TiCl2 (2
equiv) and Zn dust (8 equiv) in deoxygenated water, we
obtained alcohol 2 and the pinacol coupling product 3 in
similar proportions and a 74% overall yield (Scheme 1).
The 1H NMR spectrum of 3 indicated a mixture of the dl
and meso stereoisomers in a 7:3 ratio respectively.10 The
experiment was subsequently repeated without Cp2TiCl2
but then we only recovered unchanged acetophenone,
showing the crucial role played by the titanocene species.
Moreover, when the blue mixture of titanocene(III) and
zinc in water was filtered to remove the remaining Zn dust
in suspension, the filtrate turned green and was inactive
against acetophenone, thus indicating that an excess of
zinc was also necessary for the reaction.
Key words: green-chemistry, radical reactions, titanium, water,
zinc
Water has many potential advantages in order to replace
more familiar organic solvents. It is for example a no-cost,
safe and environmental friendly substance and has unique
chemical properties as solvent.1 Water, however, has con-
siderable reactivity against both carbanion and carboca-
tion intermediates and, for this and other reasons, it has
been scarcely used as solvent in organic synthesis. On the
other hand, water is stable against free-radical intermedi-
ates because of its strong O–H bonds.2 Therefore, in the
cases where the solubility and stability of reagents and
products could allow it, water might become an ideal sol-
vent for free-radical chemistry.
OH
OH
O
Cp2TiCl2/Zn
H2O, 24 h
Ph
+
Ph
Ph
2 (38%)
Ph
OH
3 (36%)
7:3 dl:meso
1
With this idea in mind, we decided to study the behavior
in water of radical reactions promoted by bis(cyclopenta-
dienyl)titanium(III) chloride,3 an organometallic single-
electron transfer reagent which, in our laboratory, proved
to be compatible with this solvent.4 This titanocene(III)
complex is usually generated in situ by stirring commer-
cial Cp2TiIVCl2 with Mn or Zn in anhydrous THF, where
it exists as a green mixture of the dimeric (Cp2TiIIICl)2 and
the monomeric Cp2TiIIICl forms5 and is capable of cata-
lyzing the pinacol coupling of aromatic aldehydes6 and
other C–C bond forming reactions via radical chemistry.7
In 1996 Barden and Schwartz8observed that in THF–H2O
(4:1) green titanocene(III) hydrolyzed to a blue species,
formulated as [Cp2TiIII(H2O)]+ by the authors, which in
our hands proved to be capable of catalyzing the selective
reduction of aromatic ketones using water as proton
source.9 Now we have found that blue titanocene(III) can
be directly generated in H2O (including distilled, tap and
sea water), by stirring Cp2TiCl2 with Zn in the absence of
oxygen, giving stable solutions which are capable of pro-
Scheme 1 Titanocene(III)/Zn-promoted transformation of 1 in
water
The result depicted in Scheme 1 suggests that blue ti-
tanocene in water might afford synthetic applications
complementary to those of (Cp2TiCl)2, which shows low
reactivity toward pinacol coupling of aromatic ketones.8
Moreover, the above observations can be rationalized if
the mechanism proposed in Scheme 2 is accepted.
First, zinc would catalyze the hydrolysis of Cp2TiCl2 to
the ionic green TiIV species 4.11 The chloride ion of 4
should be strongly solvated by water and, therefore, the
first step would be practically irreversible. Subsequently,
Zn would react with 4 in an equilibrium leading to the ac-
tive blue TiIII species 5 (if Zn is removed from the medium
the equilibrium reverses to the inactive green species 4).
The trimetallic nature of 5 is reminiscent of that observed
for the crystalline form of related titanocene(III) complex-
es.12 In addition, 5 has a ionic character that warrants its
solubility in water. Single-electron transfer from 5 to 1
would give the alkoxy-TiIV complex 6, which would spon-
taneously evolve towards the free radical 7 by protonation
of the Ti–O bond. Finally 7 could undergo radical cou-
pling toward 3 or Zn-mediated reduction to 2. An alterna-
SYNTHESIS 2005, No. 15, pp 2619–2622
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872163; Art ID: C04305SS
© Georg Thieme Verlag Stuttgart · New York

2620
J. L. Oller-López et al.
SPECIAL TOPIC
Zn
show once more the special behaviour of titanocene(III)
complexes in water and confirm the role played by the
methyl group in the stereoselectivity observed for the pi-
nacol coupling of acetophenone reported here.
2 H2O
Zn
[Cp TiIV(OH2)Cl]+ Cl–
2 Cp2TiIVCl2
+
+
2
2
4 (green)
[(Cp2TiIIIOH2)2ZnCl2]2+ 2Cl–
2
4 (green)
5 (blue)
To check the scope and limitations of the method, we as-
sayed the reaction with other aromatic and aliphatic alde-
hydes and ketones 11,13 and 16 (Figure 2) under the same
conditions employed for acetophenone (see above). The
results are summarized in Table 1.
+
H2O
Cp
O
TiIV
Cl–
2
ZnCl2
O
5 + 2
+
Cp
Ph
1
Ph
6
HO
OH
X
pinacolization
OH
Ph
2
6
2
Ph
R
Ph
Ph
R
R
HO
7
2 Cp2Ti(OH)Cl
8, X = O; R = H
Zn + 2 H2O
2 Zn(OH)2
OH
3 (dl)
reduction
9, X = H, OH; R = H
11, X = O; R = Ph
12, X = H, OH; R = Ph
10, R = Ph
15, R = C9H19
OH
2
X
Ph
t-Bu
X
2
H
8
Scheme 2 Hypothetical formation of 5 in H2O and reaction with 1
16, X = O
17, X = H, OH
13, X = O
14, X = H, OH
tive pathway towards the pinacol coupling product via a
carbanion-type intermediate seems quite unlikely in wa-
ter.
Figure 2 Chemical structure of compounds 8–17
Table 1 Reduction and Pinacol Coupling Products from Substrates
1,8,11,13 and 16a
The moderate stereoselectivity observed in the pinacol
coupling reaction probably derives from both steric and
electronic factors. Thus, in the radical-radical approach
leading to the dl stereoisomer, the steric repulsion be-
tween the methyl groups can be minimized in an arrange-
ment where the proximity between two phenyl and two
hydroxyl groups provides stabilizing p/p interaction13 and
gauche effect14 respectively. On the other hand, stabiliz-
ing effects must be lost to avoid steric hindrance in the
radical approach leading to the meso isomer (see
Figure 1).
Substrate
R.P.b (yield, %)
P.C.P.c (yield, %)
1
2 (38)
3 (36)
dl:meso = 7:3
8
9 (11)
10 (41)
dl:meso = 1:1
11
13
16
12 (61)
14 (21)
n.d.d
15 (14)
n.d.d
17 (26)
cis:trans = 1:2
preferred approach
a Reactions were carried out with Cp2TiCl2/Zn in distilled water.
b R.P. = reduction product.
Ph OH
HO Ph
Me
Me
c P.C.P. = pinacol coupling product.
d n.d. = not detected.
Me
Me
Ph OH
Ph OH
The results in Table 1 suggest that the process is faster for
aromatic aldehydes and ketones than for aliphatic ones, a
phenomenon which could be rationalized by the stabiliz-
ing delocalization of benzyl radicals such as 7. This prop-
erty might be exploited for selective reductions of aryl
ketones and pinacol couplings of aromatic aldehydes in
the presence of aliphatic carbonyl groups.
Me
Me
OH
OH
Ph
Ph
Ph
HO
Ph
OH
Me
Me
3 dl isomer
3 meso isomer
Figure 1 Stereoselective radical-radical approach towards 3
Very recently, Enemærke et al. have invoked stabilizing
p/p interaction and gauche effect to justify the high stereo-
selectivity observed in the synthesis of hydrobenzoin
(dl:meso = 97:3) from benzaldehyde mediated by
Cp2TiCl2/Zn in THF.15 Nevertheless, when we treated
benzaldehyde (8) with a blue mixture prepared by stirring
Cp2TiCl2 and Zn in water, besides an 11% of benzyl alco-
hol (9), we obtained a 41% yield of hydrobenzoin (10) as
a 1:1 mixture of stereoisomers (Table 1). These results
In all reactions in water presented above, Cp2TiCl2 was
the most costly reagent.16 Therefore, the development of a
new version catalytic in titanocene seemed desirable, es-
pecially for large-scale preparations. On the basis of the
presumable formation of Cp2Ti(OH)Cl during the process
(see Scheme 2), we deemed that the quantity of Cp2TiCl2
required might be substantially reduced by adding 2,4,6-
collidine hydrochloride (col·HCl), the titanocene-regener-
ating agent developed by Gansäuer et al.6b,17 This reagent
Synthesis 2005, No. 15, 2619–2622 © Thieme Stuttgart · New York

SPECIAL TOPIC
Titanocene/Zn-Mediated Carbonyl Reactions in Water
2621
should be capable of regenerating Cp2TiCl2 from water, becomes especially convenient for the reduction of
Cp2Ti(OH)Cl releasing 2,4,6-collidine (Scheme 3), which aryl ketones. Mechanistically the reaction presumably
might be recovered after work-up by simple acid-base ex- proceeds via radical intermediates. In the practice the pro-
traction.6b,17
cess has significant advantages as it takes place at room
temperature under mild conditions using inexpensive,
safe and environmental friendly reagents and solvents.
These characteristics fit several principles of ‘green
chemistry’.19 Presently we are studying the possibility of
developing an enantioselective version of our method.
Cl–
Cp2TiCl2
+
+ H2O
Cp2Ti(OH)Cl
+
N
H
N
Scheme 3 Cp2TiCl2 regeneration from Cp2Ti(OH)Cl by col·HCl
Titanocene(III)-Catalyzed Reduction of Acetophenone (1) in
Sea Water; Typical Procedure
Strictly deoxygenated Mediterranean Sea water20 (25 mL) was add-
ed to a mixture of Cp2TiCl2 (41 mg, 0.17 mmol), Zn (433 mg, 6.68
mmol), and 2,4,6-collidine hydrochloride (388 mg, 2.5 mmol), and
the mixture was stirred until the color turned blue (about 5 min).
To check our hypothesis, we treated acetophenone (1)
with a mixture of a substoichiometric quantity of
Cp2TiCl2, Zn and 2,4,6-collidine hydrochloride in dis-
tilled water. Thus we obtained 1-phenylethanol (2) (51%)
and 2,3-diphenylbutane-2,3-diol (3, dl:meso = 7:3) (9%). Then, acetophenone (1; 100 mg, 0.84 mmol) was added and the
mixture was stirred at r.t. for 24 h, diluted with EtOAc, washed with
When the experiment was carried out starting from benz-
brine, dried (Na2SO4) and the solvent removed. The residue was
aldehyde, we obtained benzyl alcohol (30%) and
subjected to flash chromatography (hexane–EtOAc, 9:1) to give 92
mg of a mixture of products 2 and 3 in a 85:15 ratio (1H NMR).
hydrobenzoin (46%, dl:meso = 1:1), confirming that alde-
hydes are more prone to undergo pinacol coupling than
ketones under our conditions. Moreover, we observed that
Acknowledgment
addition of some salts (NaCl, KCl, NaOAc) improved the
yield of reduction products. Therefore, we assayed the ti-
tanocene(III)-catalyzed reduction of acetophenone in
Mediterranean Sea water (Scheme 4), which might be-
come an interesting solvent at industrial level in Mediter-
ranean countries. The results obtained (77% yield of 2 and
13% of 3) confirmed the viability of the catalytic version
and the increase of selectivity towards reduction products
under these conditions, thus reinforcing the potential in-
terest of the method for the large-scale reduction of aro-
matic ketones.
To the ‘Junta de Andalucía’ for the financial support to our group
(FQM339). J.L.O-L. thanks the Spanish Ministry of Science and
Technology for his grant.
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OH
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Ph
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Synthesis 2005, No. 15, 2619–2622 © Thieme Stuttgart · New York

2622
J. L. Oller-López et al.
SPECIAL TOPIC
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Synthesis 2005, No. 15, 2619–2622 © Thieme Stuttgart · New York