Ruthenium(III) acetylacetonate [Ru(acac)3] -An efficient recyclable catalyst for the acetylation of phenols, alcohols, and amines under neat conditions

Article abstract of DOI:10.1139/V06-191

A catalytic amount of ruthenium(III) acetylacetonate (2 mol%) [Ru(acac)₃] enables solvent-free acetylation of phenols, alcohols, and amines at ambient temperature in good to excellent yields. Furthermore, the catalyst could be recovered and reused at least three times without a significant loss in yields.

Full text of DOI:10.1139/V06-191

148
COMMUNICATION / COMMUNICATION
Ruthenium(III) acetylacetonate [Ru(acac)3] — An
efficient recyclable catalyst for the acetylation of
phenols, alcohols, and amines under neat
conditions
Ravi Varala, Aayesha Nasreen, and Srinivas R. Adapa
Abstract: A catalytic amount of ruthenium(III) acetylacetonate (2 mol%) [Ru(acac)3] enables solvent-free acetylation
of phenols, alcohols, and amines at ambient temperature in good to excellent yields. Furthermore, the catalyst could be
recovered and reused at least three times without a significant loss in yields.
Key words: acetylation, protecting groups, ruthenium(III) acetylacetonate, phenols, alcohols, amines.
Résumé : L’utilisation d’une quantité catalytique d’acétylacétonate de ruthénium(III) (2 mol %) [Ru(acac)3] permet de
réaliser l’acétylation, sans solvant, de phénols, d’alcools et d’amines à la température ambiante, avec des rendements
allant de bons à excellents. De plus, il est possible de récupérer le catalyseur et de le réutiliser au moins trois fois sans
diminution significative des rendements.
Mots-clés : acétylation, groupes protecteurs, acétylacétonate de ruthénium(III), phénols, alcools, amines.
[Traduit par la Rédaction] Varala et al. 152
Introduction
the catalysts (e.g., triflates); (iv) special efforts required to
prepare the catalysts (Bi(OTf)3, Nafion-H, yttria–zirconia,
and AlPW12O40); (v) lack of atom economy (use of excess of
acetylating agents); (vi) stringent reaction conditions and the
requirement of prolonged reaction times; (vii) in many cases,
the reported acylation methodologies are applicable to only
alcohols and are not suitable for acid-sensitive substrates;
and (viii) in addition, the metal triflates may involve com-
petitive side reactions (e.g., dehydration and rearrangement)
with acid-sensitive substrates because of the large negative
Acetylation of phenol, alcohol, and amine functionalities
is one of the most frequently used transformations in organic
synthesis (1). Among the various protecting groups used for
the hydroxyl function, acetyl is the most common because it
is easy to introduce, stable in acidic reaction conditions, and
easily removable by mild alkaline hydrolysis. In general, this
can be achieved by treating alcohols with acid anhydrides or
acid chlorides in the presence of stoichiometric amounts of
amine bases such as tertiary amines (2), 4-(dimethylamino)py-
ridine (DMAP), 4-(1-pyrrolidino)pyridine (PPY) (3), and
Bu3P (4). Acylation of alcohols can also be achieved under
an acid-catalyzed condition by treating alcohols with acid
anhydrides in presence of several protic acids (5) and by us-
ing various metal salts as Lewis acids (6).
Certain reported methodologies suffer from one or more
of the following disadvantages (5, 6): (i) potential health
hazard (DMAP is highly toxic (e.g., intravenous LD50 in the
rat is 56 mg/kg), and Bu3P is flammable (flash point is
37 °C)); (ii) difficult handling (Bu3P undergoes aerial oxida-
tion, and triflates are moisture sensitive); (iii) high cost of
H value of TfOH. Furthermore, the use of large amounts of
B
acylating agents and activators should be avoided to pro-
mote green chemistry and atom efficiency.
Despite a number of precedents, a catalytically efficient
practical alternative that can be used under milder and cost-
effective conditions for this very important transformation is
highly desirable, and there is still scope for further improve-
ment. Another promising approach to environment-friendly
chemistry is to minimize or completely eliminate the use of
harmful organic solvents in organic syntheses. This is be-
cause organic reactions run under solvent-free conditions are
advantageous because of their enhanced selectivity, effi-
Received 16 September 2006. Accepted 07 December 2006. Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 7 February 2007.
R. Varala,1 A. Nasreen, and S.R. Adapa. Indian Institute of Chemical Technology, Hyderabad 500 007, India.
1Corresponding author (e-mail: rvarala_iict@yahoo.co.in).
Can. J. Chem. 85: 148–152 (2007)
doi:10.1139/V06-191
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Varala et al.
149
Scheme 1.
Table 1. Effect of acylating agent in [Ru(acac)3]-catalyzed
acetylation of phenols, alcohols, and amines.
ciency, ease of manipulation, cleaner product formation, and
the avoidance of toxic or volatile solvents (7). Thus, a para-
digm shift from using solvents toward solvent-free reactions
not only simplifies organic synthesis but also improves pro-
cess conditions for large-scale synthesis.2
Recently, we have reported [Ru(acac)3] as an efficient
Lewis acid (LA) catalyst for chemoselective tetrahydropy-
ranylation (THP) of alcohols and phenols under solvent-free
conditions (8).
Table 2. Results of the recycling and
reuse of [Ru(acac)3] in the acetylation
of aniline, as a model substrate.
Cycle
Yield (%)a
Results and discussion
1
2
3
4
99
99
97
96
In a continuation of our recent efforts to develop new syn-
thetic routes for carbon–carbon and carbon–heteroatom bond
formation and heterocycles (9), we herein present our pre-
liminary results using an efficient recyclable [Ru(acac)3]-cat-
alyzed solvent-free acetylation of hydroxy and amine
functions (Scheme 1). The procedure, based on the Lewis
acid catalytic activity of the [Ru(acac)3], represents an envi-
ronmentally benign alternative to current chemical processes
that use water-intolerant Lewis acids.
Initially, we have screened a few available acetylaceto-
nates, such as [VO(acac)2], [Pd(acac)2], [Ru(acac)3], and
[Co(acac)3], for the model reaction between aniline
(1 mmol) and acetyl chloride (1.1 mmol) under neat condi-
tions at ambient temperature. Among the catalysts tested,
[Ru(acac)3] proved to be the most efficient LA catalyst in
terms of yields and reaction time (the corresponding acety-
lated product was obtained in 5 min with quantitative iso-
lated yield >99%). An optimum concentration of 2 mol% of
[Ru(acac)3] is sufficient to afford the acetylated product in
an excellent yield. While optimizing the acylating agent,
several features that deserved comment are shown in Ta-
ble 1.
In case of alcohols and phenols (Table 1, entries 1 and 2),
acetic anhydride was preferred over the corresponding acid
chloride or acetic acid. It is significant to note that acetyl
chloride was preferred over acetic anhydride with the
acetylation reaction of amines (Table 1, entry 3). This is in
complete contrast with the observations reported by Yadav et al.
(6c). This clearly demonstrates that the acetylation reaction
behaviour is completely dependent on the chosen catalyst.
Acetylation of amines, using acetic acid at ambient tempera-
ture, with our catalyst did not give acetylated product.
The direct condensation of acetic acid with alcohols is
generally avoided because the equilibrium between the sub-
strates and the products require the elimination of water
aIsolated yields with reused catalyst (recov-
ered catalyst 99%, 99%, and 98%
respectively).
from the reaction mixture, using a dehydrant or azeotro-
pically, to shift the equilibrium in favor of the product.
Intrigued by the observations in hand, we have studied the
scope and the generality of this process for a wide range of
aromatic and aliphatic phenols, alcohols and amines.
One of the important features of the present developed
protocol for the formation of acetylated products is that ab-
solute anhydrous conditions are not required. The reactions
are clean and devoid of unwanted products and gave the cor-
responding acetylated products in moderate to excellent
yields. Very importantly, this protocol allowed us to adopt a
simple work-up procedure by employing ether to dissolve
the organic material not the catalyst, which could be easily
removed by filtration. The recovered catalyst is oven dried at
60 °C for 2 h and then reused for the model reaction without
significant loss of yield for at least three cycles (Table 2; Ta-
ble 3, entry 27).
As evident from Table 3, the described methodology illus-
trates a fine acetylation procedure that has wide applicability,
extending the scope to alkyl (1°, 2°, and 3°), allyl, pro-
pargylic, aryl, and benzylic alcohols (Table 3, entries 1–36).
Under optimized reaction conditions, secondary and ter-
tiary alcohols do not experience any competitive dehydration
(Table 3, entries 3, 4, and 12). Acid-sensitive functionalities,
such as allylic and propargylic substrates (Table 3, entries 5–
8 and 14), are tolerated, and no rearrangement took place for
those substrates. Chiral alcohols and amines (Table 3, entries
9 and 36) were easily acetylated with complete retention of
2 Exothermicity of a large-scale reaction should be controlled by maintaining the temperature and using an appropriate solvent, if necessary.
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Can. J. Chem. Vol. 85, 2007
Table 3. Ruthenium(III) acetylacetonate-catalyzed acetylation of phenols, alcohols, and amines.
the optical purity. Steric factors played vital role in affecting
acetylation (Table 3, entries 34 and 35), and the reaction
completion took longer times with moderate yields.
Next, the scope of the present methodology was extended
to other anhydrides and acid chlorides to test the efficacy of
the catalyst, and the results are quite satisfactory. From Ta-
ble 4, solid anhydrides, such as benzoic, maleic, succinic,
and phthalic anhydrides, also reacted well in the acylation
reaction with the model substrates chosen.
hols and phenols, initially, electrophilic activation by
[Ru(acac)3] for possible coordination to both carbonyl oxy-
gen atoms of the anhydride 2 to form a six-membered transi-
tion state, and then nucleophilic attack by the alcohol 1 to
give the desired acetylated product 3. For amines,
[Ru(acac)3] first activates the acyl halide 4 and then polar-
izes it on the nucleophilic amine 5 to form the correspond-
ing acetylated product 6 and regenerates back.
The efficiency and generality of the present [Ru(acac)3]-
catalyzed protocol can be realized at a glance by comparing
our results for the chosen model substrates with those of
The present [Ru(acac)3]-catalyzed acetylation may proba-
bly follow the mechanism depicted in Scheme 2: For alco-
© 2007 NRC Canada

Varala et al.
151
Table 4. Acylation of n-butanol, aniline, and piperidine with different anhydrides and acyl chlorides.
Entry
1
Substrate
Acylating agent
Conditions
RT
Time
Yield (%)a
n-butanol
Benzoic anhydride
Maleic anhydride
Succinic anhydride
Phthalic anhydride
Boc anhydride
Propionic anhydride
Butyric anhydride
Benzoic anhydride
Succinic anhydride
Boc anhydride
3.0 h
3.0 h
3.0 h
3.5 h
1.0 h
1.0 h
1.0 h
3.5 h
4.0 h
2.5 h
20 min
30 min
90
80
82
78
92
95
98
88
62
85
95
78
2
2-Naphthol
RT
RT
3
4
Aniline
Benzoyl chloride
CH2=CHCOCl
Piperidine
Benzoyl chloride
CH2=CHCOCl
RT
10 min
15 min
92
88
aIsolated yields.
Scheme 2. Proposed mechanism for the [Ru(acac)3]-catalyzed acetylation of phenols, alcohols, and amines.
some recently developed procedures (as shown in Table 5).
The reactions have been compared with respect to the reac-
tion times, mol% of the catalyst used, and the yields.
lyst. We believe that this protocol will be a valuable addition
to acetylation-related modern synthetic methodologies.
Typical experimental procedure
Conclusion
The hydroxy or amine compound (Table 3, entries 1–36;
1.0 mmol), acylating agent (1.1 mmol), [Ru(acac)3] (2
mol%) were placed, successively, in a flask under neat con-
ditions at room temperature. After stirring, the reaction mix-
ture was treated with Et2O (2 × 5 mL), and the catalyst was
removed by filtration. The filtrate extracts were concentrated
under reduced pressure, and the crude product was then pu-
rified by silica-gel chromatography (hexane – ethyl acetate).
All the obtained acylated products were characterized by IR,
In summary, we have developed a mild, efficient, and
highly selective methodology for the acetylation of alcohols
using [Ru(acac)3] as LA catalyst (2 mol%). Notable features
of the protocol are clean and simple solvent-free reaction
conditions, non-aqueous workup, and the use of recyclable
and environmentally benign catalyst. This work widens the
scope of using transition-metal salts and complexes in or-
ganic synthesis because of the nontoxic nature of the cata-
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Can. J. Chem. Vol. 85, 2007
Table 5. Comparison of the catalytic efficiency of [Ru(acac)3] with some recently reported catalysts.
Entry
Catalyst
mol%
AAa
Time (min)
Yield (%)b
For the reaction of aniline with an acylating agent
1
2
3
4
[Ru(acac)3] (neat)
2
A
C
C
C
5
1
99
96
77
95
AlPW12O40 (neat)
0.5
10
20
I2
105
60
NbCl5
5
6
7
Zeolite
Fe+3-Montmorillonite
Gd(OTf)3–[bmim][BF4]
5
20
0.2
B
B
C
30
180
120
73
98
96
For the reaction of n-butanol with an acylating agent
1
2
3
[Ru(acac)3] (neat)
CuSO4·5H2O (neat)
Sn(tpp)(OTf)2
2
C
C
C
30
1440
60
90
93
87
10
1
For the reaction of phenol with an acylating agent
1
2
3
4
5
6
[Ru(acac)3] (neat)
2
C
C
C
C
C
C
120
90
91
92
95
88
90
83
CuSO4·5H2O (neat)
10
H14[NaP5W30O110
]
0.1
0.2
10
60
Gd(OTf)3–[bmim][BF4]
120
30
I2
K-10–DCM
100c
120
aAcylating agent.
bIsolated yields.
cmg/1 mmol.
1H NMR spectroscopy, and mass spectrometry, and their
structures are consistent with their published physical data
(6).
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Lin, P.A. Oliver, and M.J. Peterson. J. Org. Chem. 58, 7286
(1993).
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Acknowledgments
We thank Dr. J.S. Yadav, Director, Indian Institute of
chemical technology, and Council of Scientific Industrial
Research (CSIR, India) for financial support. A. Nasreen
thanks the Department of Sciene and Technology, New
Delhi for sponsoring project (GAP-0128).
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© 2007 NRC Canada