Transition metal free transfer hydrogenation of ketones promoted by 1,3-diarylimidazolium salts and KOH

Article abstract of DOI:10.1016/j.tetlet.2012.06.124

An efficient transition metal free and greener catalytic system was developed for the selective transfer hydrogenation of saturated ketones to alcohols. This was achieved by the use of 1,3-diarylimidazolium salts in the presence of KOH as a promoter for the reaction. When the range of substrates was expanded to include unsaturated ketones, selective reduction of the double bond occurred. The catalyst efficiency was comparable to some established transition metal catalyzed systems. The current system utilizes mild aerobic reaction conditions compared to the inert atmosphere conditions required for the corresponding metal based systems.

Full text of DOI:10.1016/j.tetlet.2012.06.124

Tetrahedron Letters 53 (2012) 4925–4928
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition metal free transfer hydrogenation of ketones promoted
by 1,3-diarylimidazolium salts and KOH
⇑
Monisola Itohan Ikhile, Vincent Onserio Nyamori, Muhammad Dabai Bala
School of Chemistry & Physics, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient transition metal free and greener catalytic system was developed for the selective transfer
hydrogenation of saturated ketones to alcohols. This was achieved by the use of 1,3-diarylimidazolium
salts in the presence of KOH as a promoter for the reaction. When the range of substrates was expanded
to include unsaturated ketones, selective reduction of the double bond occurred. The catalyst efficiency
was comparable to some established transition metal catalyzed systems. The current system utilizes mild
aerobic reaction conditions compared to the inert atmosphere conditions required for the corresponding
metal based systems.
Received 20 April 2012
Revised 14 June 2012
Accepted 27 June 2012
Available online 4 July 2012
Keywords:
Imidazolium salt
Transfer hydrogenation
Metal-free catalyst
Turnover number
Ó 2012 Elsevier Ltd. All rights reserved.
Developing newer or improved methods for the catalytic reduc-
tion of ketones to alcohols is important because the end products
have numerous applications in the pharmaceutical, perfumery,
agrochemical, bulk and fine chemical industries.1 Much of the
work conducted to date on the catalytic transfer hydrogenation
of ketones has utilized transition metals, such as platinum,2 gold,3
iridium,4 rhodium4c,5 and ruthenium.6 Metal-based catalyst sys-
tems have been found to be very effective, although from a view
point of sustainability they have many disadvantages. These in-
clude the fact that they are expensive and toxic to the environ-
ment, especially in the homogeneous environment in which they
are most active.7 Hence, there is a need for an inexpensive and
environmentally friendly catalytic system capable of matching
the activities of transition metal based systems.
Numerous applications of imidazolium salts exist in the litera-
ture.8 Their use as precursors9 towards the synthesis of N-hetero-
cyclic carbene ligands (NHCs), which mimic, and in many
instances have completely replaced phosphines10 as ligands in
organometallic reactions, has made them popular. The reasons
for the superiority of NHCs over phosphines include their ease of
preparation, relative air and moisture stability, low loading and
high efficiency in catalysis.11 Also, the ability of NHCs to be tuned
sterically and electronically has been the driving force that has
facilitated their use as ligands in metal complexes.12 Thus,
NHC-based complexes have been very effective in homogeneous
catalysis and have found application in olefin metathesis,13 hydro-
formylation,14 hydrosilylation,15 epoxidation16 and hydrogenation
reactions.17 Most of these catalyzed reactions also require inert
conditions, in addition to the use of heavy metals. Recently, Royo
and co-workers,18 in their search for less expensive and environ-
mentally friendlier catalyst systems, synthesized iron(II) NHC com-
plexes, which were found to be very effective catalysts for the
transfer hydrogenation of ketones. However, the difficulties
encountered in their synthesis,19 which involved generation of
reactive free carbenes prior to coordination, have greatly limited
their use in catalysis.20
As part of an ongoing search to develop a cheaper, easily acces-
sible, and a simple catalyst system, the imidazolium salts 1–4
(Fig. 1) were synthesized and used in a transition metal free system
for the transfer hydrogenation of ketones. The 1,3-diarylimidazoli-
um tetrafluoroborates with halides substituted at the para-position
were synthesized according to a modified procedure.9 It is also
worth noting that the application of imidazolium-based ionic salts
goes beyond their use as precursors to metal complexes;21 they
have even been applied widely in medicine as antimicrobial
agents.22 However, to our knowledge, their use in a transition me-
tal free environment as organic catalysts for the activation of C@O
and C@C bonds has not been explored.
X
N
N
X
+
-
BF4
X = F (1); Cl (2); Br (3); I (4)
⇑
Corresponding author. Tel.: +27 31 260 2616; fax: +27 31 260 3091.
E-mail address: bala@ukzn.ac.za (M.D. Bala).
Figure 1. 1,3-Diarylimidazolium salts 1–4.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.124

4926
M. I. Ikhile et al. / Tetrahedron Letters 53 (2012) 4925–4928
Table 1
The current study was inspired by our general interest in the
incorporation of greener procedures in catalysis; hence transfer
hydrogenation under metal-free conditions was investigated. In
exploratory experiments, the transfer hydrogenation of cyclohexa-
none was examined with imidazolium salts 1–4 as the catalysts
and isopropanol as the hydrogen source (and solvent) in a basic
KOH environment. A typical experimental procedure for the trans-
fer hydrogenation is described.23,24 A very low catalyst loading of
0.5 mol % of the 1,3-diarylimidazolium salts (Fig. 1) was used in
an aerobic environment and later in pure water, although very
low conversion of the product was obtained in water. The salts
1–4 showed high activity toward the conversion of cyclohexanone
into cyclohexanol with 1 showing the highest substrate conversion
(Table 1). A turnover number (TON) up to 194 was observed which
is higher than some of the metal-catalyzed reactions reported to
date.4a This can be attributed to the negative inductive effect on
the imidazolium carbon center due to the para-fluorine substitu-
ent. In general, the reactivity pattern can easily be attributed to
the inductive effect which renders the imidazolium carbon more
susceptible to attack by an electrophile such as the ketone C@O
bond, or the alkene C@C bond (as observed for unsaturated
ketones).
Transfer hydrogenation of cyclohexanone catalyzed by imidazolium salts 1–4
OH
O
KOH, 1–4
i-PrOH, 82 oC, 12 h
Imidazolium salt
Conversiona (%)
TONb
1
2
3
4
97
81
80
77
194
162
160
154
a
Conversion was determined by GC analysis after 10 h for 1 and 12 h for 2–4.
Turnover number (TON) = mol product/mol catalyst.
b
Moderate to high conversions of cyclohexanone into cyclohexa-
nol were recorded as shown in Table 1. It was important from the
onset to establish the role of the various components, notably the
imidazolium salt, the KOH promoter and the solvent/hydrogen
source in the catalytic transfer hydrogenation process. Evidence
for the involvement of the carbene in facilitating reduction of the
ketone was obtained from the results presented in Figure 2. When
a blank run (no KOH or salt added) was conducted, there was no
reaction observed, but when only KOH was added a 40% conversion
of cyclohexanone into cyclohexanol was observed after 12 hours.
Figure 2. Relative conversions of cyclohexanone into cyclohexanol via transfer
hydrogenation from isopropanol with key reagents (KOH and 1).
H
R1
O
R2
H
+
X
N
X
N
BF4
-
H
KOH
X
N
N
X
O
R1
H
K
8
O
R2
X
N
X
N
H
K
5
O
H
O
R1
R2
O
X
N
N
X
X
N
N
O
X
O
R2
O
R1
K
H
7
6
O
H
R1
R2
Scheme 1. Proposed mechanism for the transfer hydrogenation of ketones using 1,3-diarylimidazolium salts promoted by KOH in isopropanol.

M. I. Ikhile et al. / Tetrahedron Letters 53 (2012) 4925–4928
4927
Table 1
This was consistent with similar reactions that have established
Transfer hydrogenation of ketones catalyzed by imidazolium salt 1
the role of KOH and other basic media for promoting catalytic
transfer hydrogenation reactions. However, it is noted that these
reactions rely on the use of high concentrations of the base and
long reaction times.25 Without base initiated deprotonation, the
imidazolium salt 1 on its own initiated very negligible conversion
(2%) of the ketone. However, combining the base and 1, the conver-
sion increased to 97% after a reaction time of 10 h.
1
O
KOH,
OH
i-PrOH, 82 oC, 12 h
R1
R2
TONb
R1
Entry
R2
Ketone
Conversiona (%)
A plausible mechanism is proposed to account for the roles of
the components as shown in Scheme 1. The mechanism is similar
to that proposed by Ouali et al.25 for the base-catalyzed transfer
hydrogenation of ketones, which was also related to the mecha-
nism proposed for the hydride transfer from a metal-coordinated
alkoxide to a ketone in the Meerwein–Ponndorf–Verley reduction
of ketones catalyzed by aluminum(III).26
The first step involved deprotonation of the imidazolium salt in
the basic KOH-isopropanol mixture, followed by potassium coordi-
nation to the reactive carbene species and subsequent generation
of an NHC potassium isopropoxide, 5 (Scheme 1). The ketone
was then activated by 5 through coordination to the K-NHC, and
concerted hydrogen transfer to yield intermediate 6 followed by
rearrangement to 7. The subsequent release of acetone afforded
the alkoxide 8 which coordinates a new isopropanol moiety and
eliminates the alcohol product.
1
27
54
O
O
2
3
4
5
96
192
74
37
O
100c
19
200
38
O
O
O
This mechanism hinges on the isopropanol/ketone proton inter-
change and its interaction with the KOH/imidazolium salt. As
shown in Figure 2, the marked improvement in catalytic activity
was obtained when both KOH and the imidazolium salt 1 were uti-
lized in the reaction points to the definite involvement of the imi-
dazolium salt. This contrasts to the situations when only KOH or
imidazolium salt 1 was used. Coordination of the ketone to K-
NHC to yield 6 is usually favored by the stability of the M-O bond.
For the base-catalyzed transfer hydrogenation a trend has been
established for the base which is a function of the charge density
of the alkali metal thus: Li > Na > K.25 The assertion is that the imi-
dazolium salts contribute to a stronger K-O bond initially and also
influence product elimination due to a combination of the ability
of the NHC as a ligand to exhibit both high basicity and strong
nucleophilicity.14
6
7
20
37
40
74
O
O
8
3
6
O
9
7
14
22
O
10
11
The question arises of the possible influence of transition metal
contaminants in the KOH base. The KOH was supplied by Merck as
99.995% pure by metal content. Our assay by ICP-OES (Inductively
Coupled Plasma-Optical Emission Spectroscopy)27 confirmed the
absence of contamination from precious metals commonly used
in conjunction with NHCs for catalysis (Pt, Au, Ir, Rh and Ru).2–6
In order to understand the scope and generality of this catalytic
system, imidazolium salt 1 was further tested with a set of ketones
chosen to explore the effects of electronic and steric variations of
the substrate backbone on the ketone C@O bond. The results of this
study are presented in Table 2.23,24 The imidazolium salt 1 was
effective in the activation of the C@O bond in all the substrates
studied. In this instance also, TON values were obtained that were
in some cases comparable to or higher than those reported for Ru-
catalyzed transfer hydrogenation reactions.4a The cyclic aliphatic
ketones (entries 1–4) generally yielded higher conversions into
alcohols than the acyclic examples (entries 5–10) with cyclobuta-
none showing the best conversion of 100% after 6 hours. A general
trend attributable to steric hindrance with respect to access to the
O
11
12
13
61
47
84
122
94
O
F
O
Cl
168
O
14d
15d
16
55
78
32
110
156
64
O
O
a
b
c
C@O bond was observed to be dependent on the size of the group
a
Conversion was determined by GC analysis.
Turnover number (TON) = mol product/mol catalyst.
Conversion determined after 6 h.
to the C@O bond, for example the isopropyl-containing ketone (en-
try 8) showed the least susceptibility to reduction. The trend may
also be attributed to the relative ease of formation and stability of
the carbocation, with terminal examples being less stable and
more reactive towards reduction. Also, due to steric reasons, the ef-
fect of changing the location of a substituent from the 2- to 4-posi-
tion on the cycloalkane resulted in a significant increase in
d
Converted into a saturated ketone.
catalytic activity (entries 1 and 2) for the C@O group. A similar
trend was also reported by Enthaler and co-workers.6a The
2-substituted ketone resulted in the least reactivity of the cyclic

4928
M. I. Ikhile et al. / Tetrahedron Letters 53 (2012) 4925–4928
compounds due to a combination of steric interference of the sub-
stituent to the reactive C@O bond and poor electronic contribu-
References and notes
a
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Crabtree, R. H. Organometallics 2009, 28, 321; (b) Wylie, W. N. O.; Lough, A. J.;
Morris, R. H. Organometallics 2012, 31, 2152; (c) Binobaid, A.; Iglesias, M.;
Beetstra, D.; Dervisi, A.; Fallis, I.; Cavell, K. J. Eur. J. Inorg. Chem. 2010, 5426.
5. Aupoix, A.; Bournaud, C.; Vo-Thanh, G. Eur. J. Org. Chem. 2011, 2772.
6. (a) Enthaler, S.; Jackstell, R.; Hagemann, B.; Junge, K.; Erre, G.; Beller, M. J.
Organomet. Chem. 2006, 691, 4652; (b) Ohara, H.; Wylie, W. N. O.; Lough, A. J.;
Morris, R. H. Dalton Trans. 2012. http://dx.doi.org/10.1039/C2DT30994G; (c)
Rautenstrauch, V.; Hoang-Cong, X.; Churlaud, R.; Abdur-Rashid, K.; Morris, R. H.
Chem. Eur. J. 2003, 9, 4954.
7. Junge, K.; Schroder, K.; Beller, M. Chem. Commun. 2011, 47, 4849.
8. Yong, G.; Zhang, Y.; Ying, Y. Angew. Chem., Int. Ed. 2008, 47, 9345.
9. Arduengo, A. J., III; Dias, H. V.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1992,
114, 5530.
10. Dragutan, I.; Dragutan, V.; Delaude, L.; Demonceau, A. Arkivoc 2005, x, 206.
11. Occhipinti, G.; Bjørsvik, H. R.; Jensen, V. R. J. Am. Chem. Soc. 2006, 128, 6952.
12. Gusev, D. G. Organometallics 2009, 28, 6458.
tion from the methyl group. Ketones in which the reactive C@O
group was b to a CH3 (terminal) were found to be more reactive
than internal C@O groups (bonded by ethyl and propyl groups).
This showed that steric interactions, rather than electronic interac-
tions were the dominant factors for this catalysis. For the para-
substituted acetophenones, replacing the substituent with a less
electrophilic group (entries 12 vs 13) gave a significant increase
in substrate conversion into product. This suggests that the induc-
tive effect (positive or negative) of the group para to the aromatic
C@O group was an important determinant of the extent of the
reaction.
In addition, the scope and selectivity of the catalyst system was
further extended to unsaturated ketones (entries 11–16). The a,b-
unsaturated ketones, 3-penten-2-one (entry 14), and 4-hexen-3-
one (entry 15) were reduced selectively to the corresponding satu-
rated ketones, instead of C@O reduction to the alcohols as observed
in previous entries. Martin and List have shown that the catalyzed
13. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783.
14. Bortenschlager, M.; Schutz, J.; Von Preysing, D.; Nuyken, O.; Hermann, W. A.;
Weberskirch, R. J. Organomet. Chem. 2005, 690, 6233.
transfer hydrogenation of
a,b-unsaturated ketones results in con-
version into the corresponding saturated ketones with high enanti-
oselectivity.28 Also, Sakaguchi et al.29 reported the selectivity of
their iridium-catalyzed system for the transfer hydrogenation of
unsaturated ketones into saturated products. They further con-
firmed the preferred selectivity of their catalytic system toward
reduction of the C@C double bond over the C@O bonds. On the other
hand, there are numerous examples in the literature of the reduc-
15. Herrmann, W. A.; Kulpe, J. A.; Konkol, W.; Bahrmann, H. J. Organomet. Chem.
1990, 389, 85.
16. Krishna, M. V. V.; Kandepi, M.; Cardoso, J. M. S.; Royo, B. Catal. Lett. 2010, 136,
222.
17. Yigit, M.; Yigit, B.; Ozdemir, I.; Cetinkaya, E.; Cetinkaya, B. Appl. Organomet.
Chem. 2006, 20, 322.
18. Kandepi, V. V. K. M.; Cardoso, J. M. S.; Peris, E.; Royo, B. Organometallics 2010,
29, 2777.
19. Liu, B.; Xia, Q.; Chen, W. Angew. Chem., Int. Ed. 2009, 48, 5513.
20. Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844.
21. Schuster, O.; Yang, L.; Raubenheimer, H. G.; Albrecht, M. Chem. Rev. 2009, 109,
3445.
22. Hindi, K. M.; Panzner, M. J.; Tessier, C. A.; Cannon, C. L.; Youngs, W. J. Chem. Rev.
2009, 109, 3859.
tion of the carbonyl group of
a,b-unsaturated ketones into the
corresponding alcohols.30 Thus, this system is one of the
few28,29,31 exhibiting high selectivity for the reduction of the C@C
double bond in
the aliphatic
a
,b-unsaturated ketones (entries 14 and 15). For
23. The reactions were monitored by GC analysis with an Agilent capillary gas
chromatograph (GC) model 6820 fitted with a DB wax polyethylene column
a
,b-unsaturated ketones (entries 14 and 15), the
conjugated keto-ene resonance facilitated hydrogenation of the
C@C bond in preference to the C@O bond. On the other hand uncon-
jugated, 5-hexen-2-one (entry 16) was converted into the corre-
sponding alcohol. In this instance the selectivity was in favor of
reduction of the C@O bond, which can be attributed to the (CH2)2
spacer (between the C@C and C@O bonds) that disrupted the
keto-ene conjugation and resonance stabilisation. Aromatic ke-
tones were also converted into the corresponding alcohols even
(0.25 mm in diameter, 30 m in length), and
a flame ionization detector.
Nitrogen gas was used as carrier gas at a flow rate of 2 mL/min. The oven
temperature for the aromatic (except 4-fluoroacetophenone) and the cyclic
(except cyclobutanone) ketones was 70 °C, while for the remaining ketones the
oven temperature was 50 °C. Samples (0.1 lL) were injected at 260 °C front
inlet temperature for the aromatic (except 4-fluoroacetophenone) and the
cyclic ketones (except cyclobutanone). For the remaining ketones the front
inlet temperature was 180 °C.
24. A typical procedure for the transfer hydrogenation reaction is described: 1,3-
diarylimidazolium salt 1 (0.0105 mmol, 3.6 mg) and KOH (0.112 g, 10 ml, 0.2 M
in i-PrOH) were added to a round-bottom flask followed by the addition of
cyclohexanone (2.1 mmol, 0.21 mL). The mixture was refluxed at 82 °C for
12 h. The reaction progress was monitored by taking aliquots at time intervals
which were passed through a pad of silica and injected into a GC. The identities
of the products were assessed by comparison of their retention times with
commercially available (Aldrich Chemical Co.) samples. The percentage
conversions were obtained from integration values of the GC peaks which
were related to residual unreacted ketones.
25. Ouali, A.; Majoral, J.-P.; Caminade, A.-M.; Taillefer, M. ChemCatChem 2009, 1,
504.
26. Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999,
121, 9580.
27. The KOH base was assayed using a Perkin Elmer Optima 5300DV ICP-OES.
28. Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
29. Sakaguchi, S.; Yamaga, T.; Ishii, Y. J. Org. Chem. 2001, 66, 4710.
30. Mizugaki, T. J.; Kanayama, Y.; Ebitani, K.; Kaneda, K. J. Org. Chem. 1998, 63,
2378.
though they also contain a,b-conjugation involving the C@O bond
(entries 11–13). In these cases the C@C bonds form part of the phe-
nyl ring system, which due to electron delocalization is very stable
and difficult to reduce, thus leading to the selective reduction of the
aromatic ketones to the corresponding alcohols instead.
In conclusion, for the first time, 1,3-diarylimidazolium salts
have successfully been used as catalysts in the absence of transi-
tion metals for the selective reduction of ketone C@O and alkenyl
C@C bonds. Moderate to excellent conversions were obtained for
various ketones including aliphatic, aromatic, cyclic and unsatu-
rated examples. The reaction does not require the usual inert con-
ditions commonly associated with transition metal based catalysis.
When all the permutations are combined together, it can be
concluded that the best substrate for these catalytic systems is
an aromatic ketone containing an electron-donating para
substituent.
31. Gonzalez, S. D.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem. Eur. J. 2006, 12, 7558.
Acknowledgements
We thank the University of KwaZulu-Natal and the National
Research Foundation (NRF) for financial support.