Cp2TiCl-mediated selective reduction of α,β-unsaturated ketones

Article abstract of DOI:10.1016/S0040-4039(02)00170-3

A mild method for the selective reduction of α,β-unsaturated ketones is reported. The process described herein involves, as the active species, the low-valent titanium complex Cp₂TiCl.

Full text of DOI:10.1016/S0040-4039(02)00170-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2013–2015
Cp2TiCl-mediated selective reduction of a,b-unsaturated ketones
Lionel Moisan, Christophe Hardouin, Bernard Rousseau and Eric Doris*
CEA/Saclay, Service des Mole´cules Marque´es, De´partement de Biologie Cellulaire et Mole´culaire, 91191 Gif sur Yvette Cedex,
France
Received 13 December 2001; accepted 23 January 2002
Abstract—A mild method for the selective reduction of a,b-unsaturated ketones is reported. The process described herein involves,
as the active species, the low-valent titanium complex Cp2TiCl. © 2002 Elsevier Science Ltd. All rights reserved.
The chemoselective reduction of a,b-unsaturated
ketones has been extensively studied.1 However, while
the reduction of the carbonyl group is often achieved
with relative ease,2 the selective transformation of the
adjacent double bond remains limited. Numerous
methodologies have been developed to perform this
conversion and include H2/cat.-,3 hydride-,4 SmI2-,5
Sn-6 and chalcogenide-based7 reductions. In this paper
we disclose a novel reaction for the selective reduction
of a,b-unsaturated ketones to the corresponding satu-
rated ketones. Our approach is based on the utilization
of Cp2TiCl as the active species8 where the low-valent
titanocene reagent operates via a single electron trans-
fer (SET) process similar to the pinacol coupling of
aldehydes and ketones.9 In addition, Cp2TiCl promotes
the selective reduction of a,b-epoxy ketones to aldols.10
With these results in mind, we examined the reactivity
of a,b-unsaturated ketones towards Cp2TiCl, and
found that, upon treatment with 2 equiv. of Cp2TiCl in
THF/MeOH, conjugated enones could be selectively
reduced to saturated ketones (Scheme 1).
powdered zinc for 45 min at room temperature. Results
are summarized in Table 1.
In most cases, the overall yields were satisfactory. The
selective reduction of 1-phenylprop-2-en-1-one (entry 1)
afforded the expected 1-phenylpropan-1-one in 89%
yield. The reaction was successfully extended to di-
(entry 2) and trisubstituted (entry 3) olefinic systems.
Treatment of chalcone (entry 4) under the above-men-
tioned conditions led not only to reduced 1,3-diphenyl-
propan-1-one, but also to the cyclo-dimerized product
in a stereoselective fashion. This dimerization has previ-
ously been observed by others when SmI2 is used as the
reducing agent.11 The procedure worked equally well on
aliphatic ketones (entry 5), as well as in the case of a
1,2-ynone system (entry 6). However, in addition to the
saturated ketone, the pinacol coupling product was
obtained in a 65/35 ratio. Our attempts to selectively
reduce an a,b-unsaturated ester (e.g. ethyl b-methylcin-
namate) were unsuccessful as the starting ester
remained unaffected by Cp2TiCl.
To gauge the scope and limitations of this methodol-
ogy, various 1,2-enones were reacted with Cp2TiCl at
−25°C (see experimental procedure). The low-valent
titanium(III) complex was readily prepared by the in
situ reduction of 2.5 equiv. of Cp2TiCl2 with 5 equiv. of
A postulated reaction mechanism is illustrated in
Scheme 2 for the selective reduction of 3-methyl-1-
phenylbut-2-en-1-one 1. In the first step, the single
electron transfer from Cp2TiCl to the carbonyl gener-
ates a radical intermediate 2 which, upon reaction with
a second equivalent of Cp2TiCl, produces enolate 3.
Subsequent protonation of 3 by methanol then affords
3-methyl-1-phenylpropan-1-one 4.
O
R3
O
R3
2 Cp2TiCl
R4
R1
R4
THF/MeOH
R1
R2
R2
The emergence of 3 as an intermediate during this
transformation was upheld by the observation that
when methanol-d was used as co-solvent instead of
methanol, the reduced product 5 (analogous to 4) was
labeled both a and b to the carbonyl (>90% isotopic
enrichment) (Scheme 3).
Scheme 1.
Keywords: enone; reduction; titanium.
* Corresponding author. E-mail: eric.doris@cea.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00170-3

2014
L. Moisan et al. / Tetrahedron Letters 43 (2002) 2013–2015
Table 1. Example of selective reduction of a,b-unsaturated ketones
yield (%)b
89
substrate
ratioa
entry
products
O
O
1
Ph
Ph
O
O
2
3
70
56
Ph
Ph
O
O
Ph
Ph
Ph
Ph
O
O
4
5
6
OH
55/45
65/35
68
77
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
OH
Ph
71c
n-Pr
n-Pr
Ph
n-Pr
Ph
2
a
Ratios determined by 1H NMR analysis of the crude reaction mixture. b Combined isolated yields. c The reaction was run with 4.5 equiv. of
Cp2TiCl.
Cp2TiCl
ClCp2TiO
Ph
Cp2TiCl
O
2 Cp2TiCl
Ph
THF/MeOH
1
2
ClCp2TiO
Ph
O
MeOH
TiCp2Cl
Ph
4
3
Scheme 2.
dropwise over a period of 1 h. The reaction was
warmed to room temperature and the stirring was
continued until completion of the reaction (1 h as
In conclusion, we have shown that the low-valent
Cp2TiCl selectively reduces selected a,b-unsaturated
ketones to the corresponding saturated ketones under
mild conditions.
O
ClCp2TiO
Ph
Typical experimental procedure: THF (5 mL) was added
to a mixture of Cp2TiCl2 (0.47 g, 2.5 equiv.) and
powdered Zn (0.25 g, 5 equiv.) in an oven-dried flask
purged with N2. The heterogeneous solution was
degassed under vacuum, purged with N2 (this operation
was repeated three times) and stirred vigorously for 45
min at room temperature. The green slurry of Cp2TiCl
was cooled to −25°C. Anhydrous MeOH (1 mL) was
added. A solution of 1-phenylprop-2-en-1-one (0.1 g,
0.76 mmol, 1 equiv.) in 5 mL of THF was then added
2 Cp2TiCl
THF
Ph
TiCp2Cl
1
3
O
MeOD
Ph
D
D
5
Scheme 3.

L. Moisan et al. / Tetrahedron Letters 43 (2002) 2013–2015
2015
monitored by TLC). The excess of zinc was decanted.
The organic phase was transferred to a flask and
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aqueous layer was extracted three times with Et2O. The
combined organic layers was filtered through a fritted
glass funnel, dried over Na2SO4, filtered and concen-
trated under reduced pressure. The residue was sub-
jected to column chromatography over silica
(hexane:EtOAc, 9:1).
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