Selective reduction of aromatic ketones in aqueous medium mediated by Ti(III)/Mn: A revised mechanism

Article abstract of DOI:10.1021/jo501141y

An experimental study on the role played by each of the reagents involved in the selective reduction of aromatic ketones in aqueous medium is reported. In this reaction, the reduction of aromatic ketones is mediated by Cp ₂TiCl. Moreover, the presence of Mn in the reaction medium is mandatory. To account for these findings, a substantially revised mechanism is proposed.

Full text of DOI:10.1021/jo501141y

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Selective Reduction of Aromatic Ketones in Aqueous Medium
Mediated by Ti(III)/Mn: A Revised Mechanism
Antonio Rosales,*,§ Juan Munoz-Bascon,† Esther Roldan-Molina,† Mayra A. Castaneda,§
́
̃
̃
Natalia M. Padial,† Andreas Gansauer,‡ Ignacio Rodríguez-García,# and J. Enrique Oltra*,†
̈
†Departamento Química Organ
‡Kekule-
§Centro de Investigacion
Amer
#Química Organ
́
ica, Facultad de Ciencias, Universidad de Granada, Campus Fuentenueva s/n, 18071 Granada, Spain
́
Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Strasse 1, 53127 Bonn, Germany
̈
̈
́
, Estudios y Desarrollo de Ingeniería (CIEDI); Ingeniería Agroindustrial y Alimentos, Universidad de las
icas, 170513 Quito, Ecuador
́
́
ica, CeiA3, Universidad de Almería, Almería E-04120, Spain
ABSTRACT: An experimental study on the role played by
each of the reagents involved in the selective reduction of
aromatic ketones in aqueous medium is reported. In this
reaction, the reduction of aromatic ketones is mediated by
Cp2TiCl. Moreover, the presence of Mn in the reaction
medium is mandatory. To account for these findings, a
substantially revised mechanism is proposed.
Scheme 1. Original Mechanism Proposed for the Titanocene
(III)-Promoted Reduction of Aromatic Ketones in Aqueous
Media10a
itanium is the seventh most abundant metal on earth, and
T
many titanium compounds are nontoxic and environ-
mentally friendly.1 Among titanium catalysts, Cp2TiCl
(Nugent’s reagent) has emerged as a powerful tool in organic
synthesis.2 In fact, this single-electron-transfer (SET) reagent
has been shown to be capable of promoting and/or catalyzing
transformations as useful as the radical opening of epoxides,3
radical cascade cyclizations,4 Barbier-type allylations and
propargylations,5 Michael-type additions of aldehydes to
conjugated enals,6 Reformatsky-type reactions,7 pinacol cou-
plings,8 reduction of radicals by hydrogen-atom transfer from
water to alkenes,9 alkynes,9 ketones,10 and free radicals,11 THF-
ring formation reactions,12 regiodivergent epoxide opening
(REO) processes,13 homolytic opening of ozonides,14 and the
synthesis of exocyclic allenes.15 A detailed knowledge of
mechanisms involved in these reactions is desirable to provide
a platform for the design of novel and more efficient processes
and catalysts. In this paper, we report on the reagents and
experimental conditions necessarily required for the titanocene-
(III)-promoted reduction of ketones in aqueous medium.10
Our results suggest that the previously proposed reduction
mechanisms are not accurate and must be revised.
The observation that tertiary radicals can be efficiently
reduced in the presence of titanocene(III) and water11a
suggested to us that toxic and relatively expensive hydrogen-
atom donors such as 1,4-cyclohexadiene are not required for
the reduction of radicals under these conditions. Based on this
finding, we devised a novel procedure for the selective
reduction of aromatic ketones in aqueous medium.10a The
originally proposed reaction mechanism was based on the
assumption that, even in the presence of water, the reduction of
ketones by SET from a trinuclear species of titanocene(III)
such as 1 should provide titanoxy radicals such as 2 (Scheme
1). The considerable steric demand of these tertiary radicals
would delay potential pinacol coupling processes, and thus, 2
could evolve to give the alkyl−TiIV complex 3 by radical
coupling with a second equivalent of Cp2TiCl. Subsequently,
the organometallic derivative 3 in aqueous medium would be
hydrolyzed in an irreversible step to 4, which eventually results
in the formation of the corresponding secondary alcohol after
acidic quenching (Scheme 1).
Closely related to the above reaction, Oltra et al. reported the
titanocene(III)-catalyzed reduction of free radicals, generated
from epoxides in aqueous medium, by hydrogen-atom transfer
(HAT) from water.11 To rationalize this unusual reaction, the
authors proposed the formation of a titanocene(III) aqua-
complex, Cp2Ti(OH2)Cl, in which the H−OH bond
Received: May 22, 2014
Published: July 14, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/jo501141y | J. Org. Chem. 2014, 79, 7672−7676

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Table 1. Relative Ratio of Compounds Obtained after 60 h of Stirring of 5 with Cp2TiCl2, Mn, and/or Water at 25 °C
Cp2TiCl2 (equiv)
Mn (equiv)
MnCl2 (equiv)
2
H2O (equiv)
5 (%)
6 (%)
7 (%)
8 (%)
a
1
8
8
8
8
8
100
100
100
100
100
100
100
100
100
100
a
2
100
a
a
3
1
2
3
60
40
a
a
4
24
76
b
b
5
4
94
c
a
6
Cp2TiCl 3 eq.
100
a
7
3
3
3
3
3
3
1
2
4
8
8
8
100
a
8
100
a
a
9
15
85
b
10
11
12
98
a
a
a
50
31
52
17
a
a
D2O 100
12
88
a
b
Relative ratio determined on the basis of the 1H NMR spectrum of the reaction crude. Yields of pure products isolated by flash chromatography.
c
Once titanocene(III) was formed (green solution) by reaction between Cp2TiCl2 and Mn dust, the solution was filtered under an inert atmosphere
to remove residual Mn before addition to 5.
Scheme 2. Revised Mechanism for the Titanocene(III)/Mn-Promoted Reduction of Ketones in Aqueous Medium
dissociation energy (BDE) would be considerably lower than
the BDE of water.11b The effect of a Lewis acid on the BDE of
water was first described by Wood et al.16 and Renaud et al.17
This observation suggested us a partially revised mechanism for
ketone reduction in aqueous medium by HAT from Cp2Ti-
obtained from EPR techniques, cyclic voltammetry, and
calculations.18
Here, we report new results which cannot be explained with
the mechanisms previously proposed for the titanocene(III)-
catalyzed reduction of ketones in aqueous medium. To avoid
the mechanistic complexity arising from the Cp2TiCl
regenerating reagents required in the catalytic version, we
(OH2)Cl.10b Subsequently, Gansauer et al. revised the structure
̈
of the titanocene(III) aqua-complex on the basis of the results
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decided to study the stoichiometric Cp2TiCl-mediated
reduction of acetophenone 5 in aqueous media. These findings
would provide a solid basis for the understanding of the related
catalytic systems. Our results are summarized in Table 1.
After 60 h stirring of 5 with Mn dust and water in the
absence of titanocene, 5 was recovered unchanged (entry 1),
strongly supporting the original assumption that Cp2TiCl is a
key reagent in the reduction process.10a Under the usual
conditions, Cp2TiIIICl is generated in situ by reduction of
commercial Cp2TiIVCl2 by Mn (or Zn) dust. This results in the
formation of 0.5 equiv of MnCl2 per Cp2TiCl in the reaction
mixture.19 Therefore, we performed a second control experi-
ment, in the absence of titanocene, by adding Mn dust, water,
and MnCl2 to 5 (entry 2). Under these conditions, 5 was
recovered quantitatively, too. This definitively confirms that
Cp2TiCl is essential for the reduction process. We determined
the exact amount of Cp2TiCl needed to complete the reduction
process by means of three experiments with increasing amounts
of Cp2TiCl2 (entries 3−5). It turned out that at least 3 equiv of
titanocene is needed to complete the process and to obtain an
excellent 94% yield of alcohol 6 (entry 5).
We subsequently investigated the role played by manganese
in a series of five experiments with increasing amounts of this
metal (entries 6−9). We decided to start with a control
experiment in the absence of Mn. To this end, we prepared a
green suspension of Cp2TiCl by stirring Cp2TiCl2 with Mn
dust, filtered of the excess of Mn and added the filtrate, the
typical and transparent green solution of Cp2TiCl devoid of
Mn, to 5 under an inert atmosphere. After 60 h of stirring, 5
was recovered unchanged (entry 6), showing that Mn is
required not only for the reduction of Cp2TiCl2 to Cp2TiCl but
also for the step in which the reduction of ketone 5 to 6 takes
place. The results summarized in entries 7 and 8 suggest that
with less than 2 equiv of Mn the metal is completely consumed
in the reduction of Cp2TiCl2 to Cp2TiCl, and therefore,
reduction of 5 to 6 cannot take place. Nevertheless, with 4
equiv of Mn in aqueous THF a significant quantity of reduction
6 (85%) was obtained (entry 9). The optimum yield (94%) of
6, however, was obtained with 8 equiv of Mn (entry 5). It
should be noted that the excess of Mn can be easily recovered
at the end of the experiment by simple filtration. Nevertheless,
the most important observation is that in the absence of Mn
neither reduction nor pinacol-coupling products were detected
(entry 6), suggesting that Mn is needed to efficiently generate a
key species involved in the reduction processes.
Cp2TiCl and 9. We propose this equilibrium because in the
absence of Mn 5 is recovered unchanged (entry 6). Then, Mn
present in the reaction medium would reduce Cp2TiCl
coordinated to 9 in an irreversible process leading to the
titanaoxirane 11. This type of metallaoxiranes is well-known. In
fact, both zirconaoxiranes and titanaoxiranes closely related to
11 have been reported previously.20 In the absence of Mn, the
key intermediate 11 is not formed, and consequently, neither
pinacol-coupling nor reduction products are observed (entry
6). In the presence of Mn, but absence of water, formation of
11 and subsequent coordination to a second molecule of 9
would lead to pinacol-coupling products such as 15 (7 when R
= Me, entry 10) via five-membered titanadioxolanes as
previously reported.20c In aqueous medium, however, a Ti(III)
aqua-complex such as 12 is formed.11b,18 It is known that this
aqua-complex can act as an efficient H atom donor for the
reduction of carbon-centered free radicals.11 Nevertheless, in
the absence of radicals, aqua-complex 12, which would
probably be more acidic than uncomplexed water, could
promote the hydrolysis of 11 to alkyl-TI(IV) products such as
13, precursors of reduction products like 6 or 8 (when D2O is
used instead of H2O). Formation of 12 from Cp2TiCl would be
an equilibrium reaction, and thus, when the proportion of water
increases, a higher amount of the reduction product 9 is
obtained (compare entries 5 and 11).
In conclusion, a detailed experimental study of the role
played by each of the reagents involved in the selective
reduction of aromatic ketones in aqueous medium, promoted
by Cp2TiCl2/Mn, is reported. Thus, we have observed that Mn
is required not only to reduce Cp2TiIVCl2 to Cp2TiIIICl but also
for the irreversible generation of a key intermediate, the
titanaoxirane 11. In the presence of water, this intermediate
undergoes hydrolysis toward alcohols, such as 6 or 8.
Nevertheless, under anhydrous conditions the intermediate is
transformed into pinacol-coupling products such as 15. Thus,
the free-radical character conventionally assumed for these
chemical processes should be reconsidered.
EXPERIMENTAL SECTION
General Methods. General details have been described else-
where.11c Silica gel was used as solid support for flash chromatography.
Compounds 6 and 7 are commercial.
■
Treatment of Acetophenone (5) with Mn and H2O (Entry 1).
Deoxygenated THF (18 mL) was added to Mn (438 mg, 8 mmol)
under an argon atmosphere. The suspension was stirred, and then a
solution of acetophenone (5) (120 mg, 1 mmol) and water (1.8 mL,
100 mmol) in THF (12 mL) was added. The solution was stirred for
60 h at 25 °C. The reaction was then quenched with 2 N HCl and
extracted with Et2O. The organic layer was washed with brine and
dried (anhyd Na2SO4), and the solvent was removed to afford starting
material 5. The relative ratio (see entry 1 in Table 1) was determined
Finally, we corroborated the role played by water. As above,
we started with a control experiment in the absence of water
(dry THF, entry 10). Under these conditions, only 7 was
detected. In contrast, when we added 50 equiv of water, 6
(52%) was the main product (entry 11). The optium yield of 6
(94%), however, was obtained with 100 equiv of water (entry
5). Finally, we treated 5 with Cp2TiCl2, Mn, and D2O (entry
12). In this manner, we obtained deuterium labeled 8 with a
90% deuterium incorporation (DI).
The observations mentioned above cannot be explained by
the originally proposed mechanism (see Scheme 1).10a
Moreover, the partially revised mechanism reported by Paradas
et al.10b does not account for the direct participation of Mn as
mandatory reagent. On the other hand, the revised mechanism
depicted in Scheme 2 suitably accommodates all experimental
observations reported to date.
1
on the basis of their H NMR spectra.
Treatment of Acetophenone (5) with Mn, MnCl2, and H2O
(Entry 2). Deoxygenated THF (18 mL) was added to a mixture of
MnCl2 (251 mg, 2 mmol) and Mn (438 mg, 8 mmol) under an argon
atmosphere. The suspension was stirred, and then a solution of
acetophenone (5) (120 mg, 1 mmol) and water (1.8 mL, 100 mmol)
in THF (12 mL) was added. The solution was stirred for 60 h at 25
°C. The reaction was then quenched with 2 N HCl and extracted with
Et2O. The organic layer was washed with brine and dried (anhyd
Na2SO4) and the solvent removed to afford starting material 5. The
relative ratio (see entry 2 in Table 1) was determined on the basis of
1
their H NMR spectra.
General Procedure for Ti(III)/Mn-Mediated Reduction of
Acetophenone (5) in Aqueous Media (Entries 3−5). Deoxy-
genated THF (18 mL) was added to a mixture of Cp2TiCl2 (247 mg, 1
The coordination between 9 and Cp2TiCl would provide the
intermediate 10 in an equilibrium reaction shifted toward
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mmol (entry 3); 494 mg, 2 mmol (entry 4) or 741 mg, 3 mmol (entry
5 and 11)) and Mn (438 mg, 8 mmol) under an argon atmosphere,
and the suspension was stirred at 25 °C until it turned lime green
(after about 15 min). Then a solution of acetophenone (5) (120 mg, 1
mmol) and water (1.8 mL, 100 mmol (entries 3−5) or 0.9 mL, 50
mmol (entry 11)) in THF (12 mL) was added, and the solution (it
turned blue when water was used) was stirred for 60 h at 25 °C. The
reaction was then quenched with 2 N HCl and extracted with Et2O.
The organic layer was washed with brine and dried (anhyd Na2SO4)
and the solvent removed. The residue of the entry 5 was submitted to
flash chromatography (hexane/AcOEt 9:1) affording the products
indicated in Table 1. NMR data of 6 are identical that reported from
commercial sample. For the other entries (3, 4, and 11 in Table 1), the
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: a.rosales.martinez@gmail.com.
*E-mail: joltra@ugr.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
We thank the Spanish “Ministerio de Economıa y Compet-
itividad” (Project CTQ2011-24443) and the “Junta de
́
Andalucıa” (Project P10.FQM.6050) for their generous
1
relative ratio of products was determined on the basis of their H
NMR spectra.
financial support. A.R. acknowledges University of the Americas
for his position as Professor−Researcher.
Treatment of Acetophenone (5) with Cp2TiCl and H2O (Entry
6). Deoxygenated THF (18 mL) was added to a mixture of Cp2TiCl2
(741 mg, 3 mmol) and Mn (438 mg, 8 mmol) under an argon
atmosphere, and the suspension was stirred at 25 °C until it turned
lime green (after about 15 min). Once titanocene(III) was formed
(green solution), the solution was filtered under an inert atmosphere,
to remove residual Mn. Then, a solution of acetophenone (5) (120
mg, 1 mmol) and water (1.8 mL, 100 mmol) in THF (12 mL) was
added, and the solution was stirred for 60 h at 25 °C. The reaction was
then quenched with 2 N HCl and extracted with Et2O. The organic
layer was washed with brine and dried (anhyd Na2SO4) and the
solvent removed to afford starting material 5. The relative ratio (see
entry 6 in Table 1) was determined on the basis on the basis of the 1H
NMR spectra.
REFERENCES
■
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(Entries 7−9). Deoxygenated THF (18 mL) was added to a mixture
of Cp2TiCl2 (741 mg, 3 mmol) and Mn (54.7 mg, 1 mmol (entry 7);
109.4 mg, 2 mmol (entry 8) or 219 mg, 4 mmol (entry 9)) under an
argon atmosphere, and the suspension was stirred at 25 °C for 15 min.
Then, a solution of acetophenone (5) (120 mg, 1 mmol) and water
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turned blue when water was used) was stirred for 60 h at 25 °C. The
reaction was then quenched with 2 N HCl and extracted with Et2O.
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and the solvent removed to afford the products indicated in entries 7−
9 in Table 1. The relative ratio (see entries 7−9 in Table 1) was
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1
determined on the basis of their H NMR spectra.
̈
Pinacolization of Acetophenone (5) with Cp2TiCl and Mn
(Entry 10). Deoxygenated THF (18 mL) was added to a mixture of
Cp2TiCl2 (741 mg, 3 mmol) and Mn (438 mg, 8 mmol) under an
argon atmosphere, and the suspension was stirred at 25 °C until it
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acetophenone (5) (120 mg, 1 mmol) in THF (12 mL) was added,
and the solution was stirred for 60 h at 25 °C. The reaction was then
quenched with 2 N HCl and extracted with Et2O. The organic layer
was washed with brine and dried (anhyd Na2SO4) and the solvent
removed. The crude of reaction was submitted to flash chromatog-
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7 are identical to those reported for a commercial sample.
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about 15 min.). Then, a solution of acetophenone (5) (120 mg, 1
mmol) and D2O (1.9 mL, 100 mmol) in THF (12 mL) was added,
and the solution (it turned blue when water was used) was stirred for
60 h at 25 °C. The reaction was then quenched with 2 N HCl and
extracted with Et2O. The organic layer was washed with brine and
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identical to those reported for a commercial sample.
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