Lewis basic ionic liquid as an efficient and facile catalyst for acetylation of alcohols, phenols, and amines under solvent-free conditions

Article abstract of DOI:10.1007/s00706-012-0820-7

The Lewis basic ionic liquid 1,8-diazabicyclo[5.4.0]undec-7-en-8-ium acetate was employed for the acetylation of various phenols, alcohols, and amines in good-to-excellent yields at 50 C under solvent-free conditions in a short time. Compared with existing methods based on conventional catalysts and toxic solvents, the reported method is simple, mild and environmentally viable. Furthermore, the ionic liquid was conveniently separated from the products and easily recycled to catalyze other acetylation reactions with excellent yields. .

Full text of DOI:10.1007/s00706-012-0820-7

Monatsh Chem (2013) 144:369–374
DOI 10.1007/s00706-012-0820-7
ORIGINAL PAPER
Lewis basic ionic liquid as an efficient and facile catalyst
for acetylation of alcohols, phenols, and amines under
solvent-free conditions
•
Li Ji Chao Qian Xin-zhi Chen
•
Received: 4 November 2011 / Accepted: 7 July 2012 / Published online: 16 August 2012
Ó Springer-Verlag 2012
Abstract The Lewis basic ionic liquid 1,8-diazabicy-
clo[5.4.0]undec-7-en-8-ium acetate was employed for the
acetylation of various phenols, alcohols, and amines in
good-to-excellent yields at 50 °C under solvent-free con-
ditions in a short time. Compared with existing methods
based on conventional catalysts and toxic solvents, the
reported method is simple, mild and environmentally via-
ble. Furthermore, the ionic liquid was conveniently
separated from the products and easily recycled to catalyze
other acetylation reactions with excellent yields.
as an efficient catalyst of acetylation. Other catalysts
employed for acylation include nucleophilic agents such as
Bu3P [4], Lewis acids such as metal halides [5–9], metal
triflates [10, 11], perchlorates [12–14], fluoroboric acid
derivates [15, 16], metal triflimide [17], ionic liquids [18–
20], and several solid acids such as zeolite [21], Nafion-H
[22], and HClO4–SiO2 [23]. Most of the above can be used
for the acetylation of various acid/base-sensitive substrates.
However, previously reported methods suffer from at least
one of the following disadvantages: long reaction time;
harsh reaction conditions; a need for expensive, moisture-
sensitive, and toxic reagents as well as toxic solvents; and
the formation of side products. For example, DMAP is
highly toxic (its LD50 value is 56 mg/kg), Bu3P is flam-
mable (its flash point is 37 °C) and air sensitive,
perchlorates are explosive, and triflates are expensive and
moisture sensitive. Many catalysts such as Nafion-H and
N-heterocyclic carbenes require special conditions for their
preparation or are a potential health hazard. Therefore,
there is increasing demand for new catalysts that can help
to overcome the challenges mentioned above, and it is
necessary to develop a mild, efficient, and environmentally
benign acylation reaction.
Keywords Ionic liquid Á [HDBU]OAc Á Acetylation Á
Phenol Á Amine Á Solvent-free condition
Introduction
The protection of heteroatoms—especially those in
hydroxyl and amino groups—as acetyl derivatives is one of
the most frequent transformations used in organic synthesis
because deprotection is relatively easy to achieve [1, 2].
Typically, the protection of alcohols or phenols as acetate
esters and amines as acetamides is realized using acetyl
chloride or acetic anhydride in the presence of a basic
catalyst such as triethylamine or pyridine. In addition,
4-(dimethylamino) pyridine (DMAP) [3] has been used
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was found
to be a far superior catalyst compared to other tertiary
amines, and its nucleophilic nature and utility in organic
synthesis have also been investigated over the past decades.
Recently, Birman et al. [24, 25] successfully intro-
duced nonaromatic amidine derivatives, including DBU, as
catalysts for acylation reactions. However, the associ-
ated procedure suffered from low recyclability and the
unpleasant flavor of DBU, which conflicted with the con-
cept of green chemistry. Thus, a new basic ionic liquid, 1,8-
diazabicyclo[5.4.0]undec-7-en-8-ium acetate ([HDBU]OAc),
was synthesized through the neutralization reaction of DBU
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0820-7) contains supplementary
material, which is available to authorized users.
L. Ji Á C. Qian (&) Á X. Chen
Department of Chemical and Biological Engineering,
Zhejiang University, Hangzhou 310027,
People’s Republic of China
e-mail: chemtec@163.com
123

370
L. Ji et al.
and acetic acid. This DBU salt is a ionic liquid with weak
basicity at room temperature. [HDBU]OAc has been used for
various organic transformations because of its ease of prep-
aration and high activity [26–28]. The main aim of the work
described in this paper was to employ [HDBU]OAc to cat-
alyze the acetylation of alcohols, phenols, and amines under
mild conditions.
Table 2 Yield of the acetylation of 4-nitrophenol with different
amounts of [HDBU]OAc
Entry
Cat./mol%
Time/h
Yielda/%
1
2
3
4
5
6
7
8
9
–
2.0
5
20b
20c
5
2.0
82
8
2.0
0.75
0.75
0.75
0.75
0.75
0.75
22
35
78
95
95
96
10
15
20
25
30
Results and discussion
Effect of the solvent
Initially to optimize the reaction conditions, we tried to
convert 4-nitrophenol (10.0 mmol) to 4-nitrophenyl acetate
in the presence of a catalytic amount of [HDBU]OAc
(20 mol%) and acetic anhydride (10.1 mmol) in various
solvents and also under solvent-free conditions. As shown
in Table 1, in comparison to conventional methods per-
formed in solvents such as 1,2-dichloroethane, acetonitrile,
toluene, THF, and n-hexane, the yield of the reaction
realized under solvent-free conditions is higher and the
reaction time is shorter. Therefore, we employed solvent-
free conditions for the conversion of various alcohols,
phenols, and amines to the corresponding acetates or
acetamides.
The substrate was treated with Ac2O (1.01 equiv.) at 50 °C
Yield determined by GC
a
b
The catalyst was replaced with DBU
c
The catalyst was replaced with HOAc
the rate-limiting step when a small amount of [HDBU]OAc
is available (\20 mol%). However, when the amount of
[HDBU]OAc increases (more than 30 mol%), the acetyla-
tion of substrates becomes the rate-limiting step. Therefore,
we decided to use 20 mol% [HDBU]OAc in subsequent
experiments.
Effect of the reaction temperature
Effect of the amount of [HDBU]OAc
The reaction temperature was varied from 20 to 70 °C to
study its effect on the acetylation of 10.0 mmol 4-nitro-
phenol with 10.1 mmol acetic anhydride (Table 3). The
reactions were carried out at 20, 30, 40, 50, 60, and 70 °C.
We observed that the yield increased rapidly as the tem-
perature was increased (up to 50 °C). When the
temperature was higher than 60 °C, the substrate trans-
formed into acetate rapidly with a violent release of heat
and the yield decreased slightly, probably due to the partial
The amount of [HDBU]OAc was varied from 5 to
30 mol% to study its effect on the acetylation of
10.0 mmol 4-nitrophenol with 10.1 mmol acetic anhydride
(Table 2). The reactions were carried out with 5, 10, 15,
20, 25, and 30 mol% of [HDBU]OAc. The yield of
4-nitrophenyl acetate was measured after 0.75 h of stirring
the mixture at 50 °C. We observed that the yield increased
rapidly as the amount of [HDBU]OAc was increased (up to
20 mol%), and then slowed down. These results show that
the reaction of [HDBU]OAc and acetic anhydride could be
Table 3 Yield of the acetylation of 4-nitrophenol at different reac-
tion temperatures
Table 1 Effect of the solvent during the [HDBU]OAc-catalyzed
acetylation of 4-nitrophenol with Ac2O using different solvents
Entry
Temperature/°C
Time/h
Yielda/%
Entry
Solvent
Time/h
Yielda/%
1
2
3
4
5
6
7
20
30
40
50
60
70
80
2.0
5
1
2
3
4
5
6
1,2-Dichloroethane
Acetonitrile
Toluene
2
68
25
11
62
16
97
2.0
45
85
95
93
90
87
2
1.0
2
0.75
0.40
0.20
0.10
THF
2
n-Hexane
Neat
2
0.75
The substrate was treated with Ac2O (1.01 equiv.) and [HDBU]OAc
(0.20 equiv.) at 50 °C
The substrate was treated with Ac2O (1.01 equiv.) and [HDBU]OAc
(0.20 equiv.)
a
a
Yield determined by GC
Yield determined by GC
123

Lewis basic ionic liquid as an efficient and facile catalyst
371
volatilization of acetic anhydride and the occurrence of
some side reactions at higher reaction temperatures. Based
on these results and the generality of the method, 50 °C
was chosen for further experiments.
was transformed to the corresponding acetate without
affecting the carbon–carbon double bond (entry 16), and
benzylic alcohol was acetylated without the formation
of any oxidative side products (entry 17). The efficacy of
the catalyst can be clearly visualized in the acetylation
of polyhydroxy compounds under similar conditions
(entries 14, 15, 19, 30). Obviously, the acetylation of
amines was much faster than that of alcohols and phe-
nols, which may be due to the higher nucleophilicity of
amines than phenols (entries 20–29). Another noteworthy
feature of this methodology is that carbohydrates such as
D-glucose and valienamine underwent exhaustive acety-
lation (entries 19, 30), demonstrating the practical utility
of this method in carbohydrate chemistry and pharma-
ceutical chemistry.
Reusability of the catalyst
The reusability of the catalyst was also investigated. For
this purpose, the same model reaction was studied again
under optimized conditions. After the completion of the
reaction, the reaction mixture was cooled to room tem-
perature and diluted with diethylether and water. The
aqueous layer was concentrated under reduced pressure to
remove the acetic acid and water, and the catalyst
[HDBU]OAc was recovered as an oily residue and reused
for a similar reaction after drying in vacuo. As shown in
Fig. 1, the catalyst could be reused at least five times
without any significant loss of activity.
The possible mechanism of acetylation catalyzed
by [HDBU]OAc
Acetylation of alcohols, phenols, and amines
Based on all of the results that obtained above, we pin-
pointed the catalysis cycle is shown in Scheme 2, which is
similar to the mechanism of acetylation catalyzed by pyr-
idine and DMAP [48].
To explore the generality and scope of the method, var-
ious phenols, primary, secondary, and benzylic alcohols,
and amines with various groups were acetylated with
acetic anhydride using the optimized reaction conditions
(Scheme 1), and the results are listed in Table 4. No
competitive Fries rearrangement was observed for phe-
nolic substrates (entries 1–7), which is very common in
the presence of a Lewis acid. Catechol and hydroquinone
were also not oxidized to the corresponding benzoqui-
nones (entries 9, 10). Prenyl alcohol, an allylic alcohol,
Conclusion
In summary, [HDBU]OAc was found to be a new, highly
efficient, and chemoselective catalyst for the acylation of
primary and secondary alcohols, phenols, and amines.
Given the continual tightening of legislation on the release
of waste and use of toxic substances as a measure to control
environmental pollution, the use of a stoichiometric
amount of acetylating agent and the solvent-free conditions
employed in the present method make it environmentally
friendly and suitable for industrial applications.
Experimental
All chemicals were of reagent grade and used without
further purification. All yields refer to isolated products
after purification. Products were characterized by com-
parison with authentic samples and by spectroscopic data
(1H NMR and 13C NMR spectra) and melting points. H
1
Fig. 1 Reuse of [HDBU]OAc for the acetylation of 4-nitrophenol
under optimized conditions
NMR spectra were recorded at 400 MHz on a Bruker
(Karlsruhe, Germany) AC-P400 spectrometer. The spectra
were measured in CDCl3, relative to TMS (0.00 ppm). GC
analysis was performed using an Agilent (Santa Clara, CA,
USA) 1705A GC. All reactions were carried out in pre-
dried glassware (150 °C, 5 h) cooled under a vacuum. The
Lewis basic ionic liquid [HDBU]OAc was prepared
according to a method described in a previous work [20].
Scheme 1
123

372
L. Ji et al.
Table 4 [HDBU]OAc-catalyzed acetylation of phenols, alcohols, amines, and sugars
Entry
Substrates
Productsa
Yieldb/%
Time/h
Ref.
1
PhOH
PhOAc
94
95
94
94
90
91
90
89
95
96
88
85
87
0.75
0.75
0.75
0.75
0.75
0.75
0.75
1.0
[29]
[29]
[17]
[29]
[29]
[29]
[30]
[31]
[29]
[32]
[33]
[29]
[34]
2
p-NO2-PhOH
o-NO2-PhOH
p-Cl-PhOH
p-NO2-PhOAc
o-NO2-PhOAc
p-Cl-PhOAc
3
4
5
p-Me-PhOH
p-(t-Bu)-PhOH
2,6-(t-Bu)2-PhOH
2,4-(NO2)2-PhOH
1,2-(HO)2C6H4
1,4-(HO)2C6H4
n-BuOH
p-Me-PhOAc
p-(t-Bu)-PhOAc
2,6-(t-Bu)2-PhOAc
2,4-(NO2)2-PhOAc
1,2-(AcO)2C6H4
1,4-(AcO)2C6H4
n-BuOAc
6
7
8
9c
10c
11
12
13
1.0
1.0
1.0
t-BuOH
t-BuOAc
1.5
1.0
14c
15d
91
92
1.5
1.5
[35]
[36]
16
86
1.0
[37]
17
18
BnOH
BnOAc
92
89
1.0
1.0
[19]
[23]
19e
95
3.0
[38]
20
21
22
23
24
25
26
27
BnNH2
BnNHAc
92
95
94
93
95
96
96
93
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
[39]
[40]
[40]
[40]
[41]
[42]
[43]
[44]
PhNH2
PhNHAc
p-Me-PhNH2
o-Me-PhNH2
o-NO2-PhNH2
m-MeO-PhNH2
o-CF3-PhNH2
o-Cl-PhNH2
p-Me-PhNHAc
o-Me-PhNHAc
o-NO2-PhNHAc
m-MeO-PhNHAc
o-CF3-PhNHAc
o-Cl-PhNHAc
123

Lewis basic ionic liquid as an efficient and facile catalyst
373
Table 4 continued
Entry
Substrates
Productsa
Yieldb/%
Time/h
Ref.
28
p-Cl-PhNH2
p-F-PhNH2
p-Cl-PhNHAc
p-F-PhNHAc
94
96
92
0.5
0.5
2.0
[45]
[46]
[47]
29
30e
a
All products were identified by their 1H NMR and 13C NMR spectra. All spectral data and melting point data for solid products are provided in
the ‘‘Electronic supplementary material’’
b
Yields of the corresponding acetylated products refer to isolated yields obtained at 50 °C using [HDBU]OAc (0.20 equiv.) and Ac2O (1.01
equiv.), except in special cases
c
Reaction carried out with 2.02 equivalents of Ac2O
d
Reaction carried out with 3.03 equivalents of Ac2O
e
Reaction carried out with 5.05 equivalents of Ac2O
the catalyst [HDBU]OAc was recovered as a pale yellow
oily residue that could be reused after drying in vacuo at
80 °C for 12 h.
Acknowledgments We thank the National Natural Science Foun-
dations of China (21076183, 21006087) for financial support.
References
1. Greene TW, Wuts PGM (1999) Protective groups in organic
synthesis, 3rd edn. Wiley, New York
2. Hanson JR (1999) Protective groups in organic synthesis.
Blackwell, Malden
3. Steglich W, Hofle G (1969) Angew Chem Int Ed 8:981
4. Vedejs E, Bennett NS, Conn LM, Diver ST, Gingras M, Lin S,
Oliver PA, Peterson MJ (1993) J Org Chem 58:7286
Scheme 2
5. Torregiani E, Seu G, Minassi A, Appendino G (2005) Tetrahe-
dron Lett 46:2193
6. Bhattacharya AK, Diallo MA, Ganesh KN (2008) Synth Commun
38:1518
7. Meshram G, Patil VD (2009) Synth Commun 39:4384
Typical procedure for acetylation using [HDBU]OAc
To a stirred solution of 1.39 g 4-nitrophenol (10 mmol) in
1.03 g of freshly distilled acetic anhydride (10.1 mmol)
were added 0.42 g of [HDBU]OAc (20 mol%), and the
reaction mixture was stirred at 50 °C for 45 min. The
reaction was monitored by TLC (EtOAc/hexane = 1:4,
v/v) and GC. After the reaction had completed, the mixture
was diluted with EtOAc and water. The organic layer was
washed with saturated NaHCO3 solution and water and
then dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give an oil, which was purified by
column chromatography (EtOAc/hexane = 1:15, v/v) if
necessary. The aqueous layer was concentrated under
reduced pressure to remove the acetic acid and water, and
8. Chakraborti AK, Gulhane R (2004) Synlett 15:627
9. Chakraborti AK, Gulhane R (2003) Tetrahedron Lett 44:6749
10. Kamal A, Khan MNA, Reddy KS, Srikanth YVV, Krishnaji T
(2007) Tetrahedron Lett 48:3813
11. Shirini F, Zolfigol MA, Aliakbar AR, Albadi J (2010) Synth
Commun 40:1022
12. Bartoli G, Bosco M, Dalpozzo R, Marcantoni E, Massaccesi M,
Sambri L (2003) Eur J Org Chem 4611
13. Chakraborti AK, Sharma L, Gulhane R, Shivani (2003) Tetra-
hedron 59:7661
14. Chakraborti AK, Gulhane R, Shivani (2003) Synlett 1805
15. Chakraborti AK, Gulhane R (2003) Tetrahedron Lett 44:3521
16. Chakraborti AK, Gulhane R, Shivani (2004) Synthesis 111
17. Chakraborti AK, Shivani (2006) J Org Chem 71:5785
18. Wang WJ, Cheng WP, Shao LL, Yang JG (2008) Catal Lett
121:77
123

374
L. Ji et al.
19. Hajipour AR, Khazdooz L, Ruoho AE (2009) J Chin Chem Soc
56:398
20. Yue CB, Liu QQ, Yi TF, Chen Y (2010) Monatsh Chem 141:975
21. Ballini R, Bosica G, Carloni S, Ciaralli L, Maggi R, Sartori G
(1998) Tetrahedron Lett 39:6049
35. Tanoue Y, Hamada M, Kai N, Nagai T, Sakata K, Hashimoto M,
Morishita SI (2000) J Heterocycl Chem 37:1351
36. Satam JR, Gawande MB, Deshpande SS, Jayaram RV (2007)
Synth Commun 37:3011
37. Dubovyk I, Watson IDG, Yudin AK (2007) J Am Chem Soc
129:14172
38. Grugel H, Minuth T, Boysen MMK (2010) Synthesis 3248
39. Barbero M, Bazzi S, Cadamuro S, Dughera S (2009) Eur J Org
Chem 430
40. Lee YM, Moon ME, Vajpayee V, Filimonov VD, Chi KW (2010)
Tetrahedron 66:7418
22. Kumareswaran R, Pachamuthu K, Vankar YD (2000) Synlett
1652
23. Chakraborti AK, Gulhane R (2003) Chem Commun 1896
24. Birman VB, Li XM, Han ZF (2007) Org Lett 9:37
25. Yang X, Birman VB (2009) Org Lett 11:1499
26. Ying AG, Liu L, Wu GF, Chen G, Chen XZ, Ye WD (2009)
Tetrahedron Lett 50:1653
27. Ying AG, Wang LM, Wang LL, Chen XZ, Ye WD (2010) J
Chem Res 30
28. Yang ZZ, He LN, Miao CX, Chanfreau S (2010) Adv Synth Catal
352:2233
29. Das R, Chakraborty D (2011) Synthesis 1621
30. Simion AM, Hashimoto I, Mitoma Y, Egashira N, Simion C
(2011) Synth Commun 42:921
31. Neuvonen H, Neuvonen K, Koch A, Kleinpeter E, Pasanen P
(2002) J Org Chem 67:6995
32. Zarei A, Hajipour AR, Khazdooz L (2011) Synth Commun
41:1772
33. Iuchi Y, Obora Y, Ishii Y (2010) J Am Chem Soc 132:2536
34. Chakraborti AK, Singh B, Chankeshwara SV, Patel AR (2009) J
Org Chem 74:5967
41. dos Santos CMG, McCabe T, Watson GW, Kruger PE, Gunnl-
augsson T (2008) J Org Chem 73:9235
42. Karimi B, Behzadnia H (2010) Synlett 2019
43. Strekowski L, Patterson SE, Janda L, Wydra RL, Harden DB,
Lipowska M, Cegla MT (1992) J Org Chem 57:196
44. Bedford RB, Engelhart JU, Haddow MF, Mitchell CJ, Webster
RL (2010) Dalton Trans 39:10464
45. Liu LF, Liu H, Pi HJ, Yang S, Yao M, Du WT, Deng WP (2011)
Synth Commun 41:553
46. Kajihara K, Arisawa N, Shuto S (2008) J Org Chem 73:9494
47. Shing TKM, Li TY, Kok SHL (1999) J Org Chem 64:1941
48. Xu SJ, Held I, Kempf B, Mayr H, Steglich W, Zipse H (2005)
Chem Eur J 11:4751
123