N-Heterocyclic carbene-catalyzed synthesis of acetyltributylcitrate via a transesterification reaction

Article abstract of DOI:10.1016/j.cclet.2013.11.034

A new methodology for the synthesis of a green plasticizer acetyltributylcitrate through a transesterification reaction was developed. Under the catalysis of alkyl-substituted imidazol-type N-heterocyclic carbenes, tributyl citrate can react with vinyl acetate smoothly to give ATBC in high yield.

Full text of DOI:10.1016/j.cclet.2013.11.034

Chinese Chemical Letters 25 (2014) 215–217
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
N-Heterocyclic carbene-catalyzed synthesis of acetyltributylcitrate
via a transesterification reaction
*
*
Lin He , Hao Guo, Xiao-Wei Ma, Jie Zhang, Cheng-Zhi Gu, Wei Wang, Bin Dai
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan and School of Chemistry and Chemical Engineering, Shihezi University,
Shihezi 832000, China
A R T I C L E I N F O
A B S T R A C T
new methodology for the synthesis of
Article history:
A
a green plasticizer acetyltributylcitrate through a
Received 13 July 2013
transesterification reaction was developed. Under the catalysis of alkyl-substituted imidazol-type
N-heterocyclic carbenes, tributyl citrate can react with vinyl acetate smoothly to give ATBC in high yield.
ß 2013 Lin He and Bin Dai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received in revised form 28 September 2013
Accepted 22 October 2013
Available online 27 November 2013
Keywords:
Acetyltributylcitrate
N-Heterocyclic carbenes
Transesterification reaction
Tributyl citrate
Vinyl acetate
1. Introduction
tributyl citrate with HOAc [13] and the acetylation of tributyl
citrate with Ac2O [14]. In line with our continuing interest in NHCs
N-Heterocyclic carbenes (NHCs) have attracted considerable
attention in the past decade, which have been utilized successfully
in both transition-metal-catalyzed reactions [1] and organocata-
lyzed reactions [2]. As versatile nucleophilic organocatalysts, NHCs
can catalyze a variety of important transformations such as
benzoin reaction [3], Stetter reaction [4], homoenolate reactions
[5] via polarity reversal of carbonyl compounds. We and others
have also demonstrated that NHCs can be used as the catalyst for
redox reactions [6], the cyanation reaction [7], the aldol reaction
[8] and several other reactions [9]. Aside from these applications,
NHCs have been used as highly efficient organocatalysts for acyl
transfer reactions. More than ten years ago, the group of Nolan [10]
and Hedrick [11] reported the first two examples of NHC-catalyzed
transesterification reaction independently. Following these semi-
nal findings, great effort has been devoted to the NHC-promoted
transesterifications, including their application in polymerization
reactions [12].
catalysis [15], we found that NHCs can catalyze the transester-
ification reaction between vinyl acetate and tributyl citrate to
afford ATBC in high yield (Scheme 2), which might be used as the
third method for the preparation of this green plasticizer. Herein,
we would like to disclose our preliminary results.
2. Experimental
To a solution of 10 (60 mg, 0.3 mmol) in 0.5 mL THF was added
tBuOK (34 mg, 0.3 mmol) under N2. After the mixture was stirred
for 30 min at rt, tributyl citrate (720 mg, 2.0 mmol) was added
followed by vinyl acetate (1.0 mL). The reaction mixture was then
stirred at 70 8C for 12 h. The solution was filtered through a short
silica pad and concentrated. The crude products were purified
using silica-gel chromatography (ethyl acetate/petroleum ether) to
afford ATBC as a colorless oil. Yield: 81%; Rf = 0.25 (petroleum
ether–EtOAc, 15:1); IR (KBr, cmÀ1): 3498, 2962, 2874, 1740, 1466,
1188; 1H NMR (400 MHz, CDCl3):
d 4.21 (t, 2H, J = 6.7 Hz), 4.09 (m,
4H, J = 6.7 Hz), 2.84 (q, 4H, J = 38.8, 15.5 Hz), 2.05 (s, 3H), 1.71–1.55
(m, 6H), 1.45–1.30 (m, 6H), 0.97–0.88 (m, 9H); GC–MS (EI): m/z
402 (M+).
Acetyltributylcitrate (ATBC) is an ester derived from citric acid,
which can be used to replace phthalate esters as a green and
nontoxic plasticizer in many plastic products such as toys, child
care articles, food packages, medicinal instruments and so on. To
date, this environmentally friendly plasticizer is mainly prepared
by two methods (Scheme 1), namely, the direct esterification of
3. Results and discussion
Our investigation commenced with the transesterification
between vinyl acetate and tributyl citrate in the presence of a
*
Corresponding authors.
E-mail addresses: helin@shzu.edu.cn (L. He), db_tea@shzu.edu.cn (B. Dai).
1001-8417/$ – see front matter ß 2013 Lin He and Bin Dai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.11.034

216
L. He et al. / Chinese Chemical Letters 25 (2014) 215–217
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
O
O
O
Table 2
direct esterification
acetylation
NHC-Catalyzed transesterification reaction of vinyl acetate with tributyl citrate.a
+
HO
H3CCO
(a)
(b)
OH
Entry
1
Imizadolium salt
Time (h)
12
ATBC
conversionb (%)
O
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
O
73
H3CCO
+
HO
BF4
O
N
N
6
Scheme 1. The synthetic method of ATBC.
2
12
71
CO Bu
2
O
O
CO Bu
BF4
2
NHCs
+
HO
CO Bu
2
H CCO
3
CO Bu
2
N
N
O
solvent, r.t
CO Bu
2
CO Bu
2
7
ATBC
3
4
5
24
12
12
36
76
81
Cl
Ad
N
N
-
-
Ad
Cl
8
Cl
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
Ar
I
2
3
1, IPr
N
N
9
Ar=2,4,6-Me C H
Ar=2,6-(i-Pr) C H
Ar=2,6-(i-Pr) C H
6 3
3
6
2
2
6
3
2
BF4
BF4
Cl
Ph
N
-
N
N
N
N
X
R
N
10
OH
N
S
N
6
7
8
12
12
12
78
74
52
4
5
R = Bn, X = Cl
11
Scheme 2. NHCs-catalyzed synthesis of ATBC.
BF4
N
N
catalytic amount of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene (IPr, a stable NHC) [16]. To our delight, under the catalysis
of 20 mol% IPr, the reaction proceeded smoothly in THF at room
temperature, giving 21% conversion of ATBC (Table 1, entry 1).
Encouraged by this result, a range of simple NHC precursors such
as imidazolium 2, imidazolinium 3, thiazolium 4 and triazolium 5
were tested for the reaction. The results indicated that NHCs
generated from 2 or 3 can promote the reaction with low efficiency
(Table 1, entries 2 and 3), whereas NHCs generated from 4 and 5
cannot catalyze the transesterification (Table 1, entries 4 and 5).
tKOBu, DBU, Et3N and Cs2CO3 all can react with the azolium salts to
produce the corresponding NHC catalyst in situ, but no obvious
differences were observed (Table 1, entries 6–8). Other reaction
12
I
N
N
13
a
Reaction conditions: tributyl citrate (2.0 mmol), vinyl acetate (2.0 mL), 15 mol%
imidazolium salt, 15 mol% tBuOK, 70 8C.
b
Determined by GC–MS analysis.
media, such as toluene, diethyl ether, DCM were also surveyed
briefly and the results showed that vinyl acetate was the best
choice with respect to the conversion of ATBC (Table 1, entry 9–12).
When the reaction temperature was elevated to 40 8C and 70 8C,
the conversion of ATBC can be increased to 32% and 41%
respectively (Table 1, entries 13 and 14). Lowering the catalyst
loading to 15 mol% had no obvious effects on the reaction (Table 1,
entry 15). However, further reduction of NHC to 10 mol% led to a
dramatic decrease of the conversion of ATBC (Table 1, entry 16).
Therefore, the optimized conditions were determined as follows:
Table 1
Evaluation of conditions for transesterification reaction.a
Entry
NHC
Solvent
Time (h)
ATBC
conversionb
(%)
1
1, IPr (20 mol%)
THF
12
12
12
24
24
24
12
12
12
12
12
12
12
12
12
12
21
24
12
/
2
2, tBuOK (20 mol%)
3, tBuOK (20 mol%)
4, tBuOK (20 mol%)
5, tBuOK (20 mol%)
2, DBU (20 mol%)
2, Et3N (20 mol%)
2, Cs2CO3 (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (20 mol%)
2, tBuOK (15 mol%)
2, tBuOK (10 mol%)
THF
t
15 mol% imidazolium salt as precatalyst and 15 mol% KOBu as
base to generate NHC in situ in vinyl acetate at 70 8C for a given
period of time.
3
THF
4
THF
5
THF
/
6
THF
23
22
24
21
22
23
29
32
41
43
9
Since the steric and electronic properties of the N-substituents
in NHCs had an obvious effect on their nucleophilicity, a series of
imidazolium salts with different N-substituents were then
investigated for the transesterification reaction under the optimal
reaction conditions as mentioned above. Using more nucleophilic
alkyl-substituted NHC 6 or 7 as catalyst precursors instead of
IMesÁHCl, the catalytic efficiency of NHC increased significantly,
giving >70% conversion of ATBC (Table 2, entries 1 and 2). The
stable NHC IAd, owing to the large bulky adamantyl group, only
catalyzed the reaction with moderate efficiency with 36%
conversion of ATBC (Table 2, entry 3). Several alkyl-substituted
ionic liquids such as 9, 10, 11 and 12 were also evaluated for the
reaction (Table 2, entries 4–7). In the presence of tKOBu, the ionic
liquid converted to the corresponding NHC in situ, which can
promote the transesterification efficiently. Benzimidazolium salt
7
THF
8
THF
9
Toluene
Et2O
10
11
12
13c
14d
15d,e
16d,f
CH2Cl2
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
a
Reaction conditions: tributyl citrate (2.0 mmol), vinyl acetate (2.0 mL), 20 mol%
precatalyst, 20 mol% tBuOK, room temperature.
b
Determined by GC–MS analysis.
c
Performed the reaction at 40 8C.
Performed at 70 8C.
Using 15 mol% catalyst.
d
e
f
Using 10 mol% catalyst.

L. He et al. / Chinese Chemical Letters 25 (2014) 215–217
217
(b) Y.M. Zhao, Y. Tam, Y.J. Wang, Z. Li, J. Sun, N-heterocyclic carbene-catalyzed
internal redox reaction of alkynals: an efficient synthesis of allenoates, Org. Lett.
14 (2012) 1398–1401;
13 was also tested for the reaction as a precatalyst, which can give
52% conversion of the desired product (Table 2, entry 8).
(c) F.G. Sun, L.H. Sun, S. Ye, N-heterocyclic carbene-catalyzed enantioselective
annulation of bromoenal and 1,3-dicarbonyl compounds, Adv. Synth. Catal. 353
(2011) 3134–3138;
4. Conclusion
(d) X.B. Wang, X.L. Zou, G.F. Du, Z.Y. Liu, B. Dai, Nucleophilic carbene-catalyzed
redox-esterification reaction of a-halo-a,b-unsaturated aldehyde, Tetrahedron
68 (2012) 6498–6503.
In conclusion, we have developed a NHC-promoted transester-
ification reaction between tributyl citrate and vinyl acetate. The
mild conditions and simple procedures provide a new approach for
the synthesis of ATBC. Further studies on the scale-up and
applications of this methodology are ongoing in our laboratory.
[7] (a) J.J. Song, F. Gallou, J.T. Reeves, et al., Activation of TMSCN by N-heterocyclic
carbenes for facile cyanosilylation of carbonyl compounds, J. Org. Chem. 71 (2006)
1273–1276;
(b) Y. Suzuki, A. Bakar, K. Muramatsu, M. Sato, Cyanosilylation of aldehydes
catalyzed by N-heterocyclic carbenes, Tetrahedron 62 (2006) 4227–4231;
(c) J. Zhang, G.F. Du, Y.K. Xu, L. He, B. Dai, N-heterocyclic carbene catalyzed
cyanation reaction of carbonyl compounds with ethyl cyanoformate and acetyl
cyanide, Tetrahedron Lett. 52 (2011) 7153–7156.
Acknowledgments
[8] (a) J.J. Song, Z.L. Tan, J.T. Reeves, N.K. Yee, C.H. Senanayake, N-heterocyclic
carbene-catalyzed Mukaiyama aldol reactions, Org. Lett. 9 (2007) 1013–1016;
(b) G.F. Du, L. He, C.Z. Gu, B. Dai, N-heterocyclic carbene catalyzed vinylogous
aldol reaction of 2-(trimethylsilyloxy) furan and aldehydes, Synlett (2010) 2513–
2517.
We are gratefully acknowledge the financial support of the
Doctor Foundation of Bingtuan (No. 2011BB011) and Shihezi
University.
[9] (a) T.Y. Jian, L. He, C. Tang, S. Ye, N-heterocyclic carbene catalysis: enantioselec-
tive formal [2+2] cycloaddition of ketenes and N-sulfinylanilines, Angew. Chem.
Int. Ed. 50 (2011) 9104–9107;
References
[1] S. Dı´ez-Gonza´lez, N. Marion, S.P. Nolan, N-heterocyclic carbenes in late transition
metal catalysis, Chem. Rev. 109 (2009) 3612–3676.
[2] (a) D. Enders, O. Niemeier, A. Henseler, Organocatalysis by N-heterocyclic car-
benes, Chem. Rev. 107 (2007) 5606–5655;
(b) X.D. Zhao, K.E. Ruhl, T. Rovis, N-heterocyclic-carbene-catalyzed asymmetric
oxidative hetero-Diels–Alder reactions with simple aliphatic aldehydes, Angew.
Chem. Int. Ed. 51 (2012) 12330–12333;
(c) J. Dugal-Tessier, E.A. O’Bryan, T.B.H. Schroeder, D.T. Cohen, K.A. Scheidt, An N-
heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of
spirooxindole lactones, Angew. Chem. Int. Ed. 51 (2012) 4963–4967;
(d) L. Candish, D.W. Lupton, N-heterocyclic carbene-catalyzed Ireland-coates
Claisen rearrangement: synthesis of functionalized b-lactones, J. Am. Chem.
Soc. 135 (2013) 58–61.
´
´
(b) N. Marion, S. Dıez-Gonzalez, S.P. Nolan, N-heterocyclic carbenes as organo-
catalysts, Angew. Chem. Int. Ed. 46 (2007) 2988–3000;
(c) V. Nair, S. Vellalath, B.P. Babu, Recent advances in carbon–carbon bond-
forming reactions involving homoenolates generated by NHC catalysis, Chem.
Soc. Rev. 37 (2008) 2691–2698;
(d) D. Enders, A. Grossmann, N-heterocyclic carbene catalyzed domino reactions,
Angew. Chem. Int. Ed. 51 (2012) 314–325.
[10] G.A. Grasa, R.M. Kissling, S.P. Nolan, N-heterocyclic carbenes as versatile nucleo-
philic catalysts for transesterification/acylation reactions, Org. Lett. 4 (2002)
3583–3586.
[11] G.W. Nyce, J.A. Lamboy, E.F. Connor, R.M. Waymouth, J.L. Hedrick, Expanding the
catalytic activity of nucleophilic N-heterocyclic carbenes for transesterification
reactions, Org. Lett. 4 (2002) 3587–3590.
[3] (a) D. Enders, A. Grossmann, J. Fronert, G. Raabe, N-heterocyclic carbene cata-
lysed asymmetric cross-benzoin reactions of heteroaromatic aldehydes with
trifluoromethyl ketones, Chem. Commun. 46 (2010) 6282–6284;
(b) D. Enders, A. Henseler, A direct intermolecular cross-benzoin type reaction:
N-heterocyclic carbene-catalyzed coupling of aromatic aldehydes with trifluor-
omethyl ketones, Adv. Synth. Catal. 351 (2009) 1749–1752.
[12] (a) G.A. Grasa, R. Singh, S.P. Nolan, Transesterification/acylation reactions cata-
lyzed by molecular catalysts, Synthesis (2004) 971–985;
[4] (a) T. Jousseaume, N.E. Wurz, F. Glorius, Highly enantioselective synthesis of a-
amino acid derivatives by an NHC-catalyzed intermolecular Stetter reaction,
Angew. Chem. Int. Ed. 50 (2011) 1410–1414;
`
(b) M. Fevre, J. Pinaud, Y. Gnanou, J. Vignolle, D. Taton, N-heterocyclic carbenes
(NHCs) as organocatalysts and structural components in metal-free polymer
synthesis, Chem. Soc. Rev. 42 (2013) 2142–2172.
(b) X.Q. Fang, X.K. Chen, H. Lv, Y.R. Chi, Enantioselective Stetter reactions of enals
and modified chalcones catalyzed by N-heterocyclic carbenes, Angew. Chem. Int.
Ed. 50 (2011) 11782–11785;
[13] A. Sakakura, S. Nakagawa, K. Ishihara, Bulky diarylammonium arenesulfonates as
mild and extremely active dehydrative ester condensation catalysts, Tetrahedron
62 (2006) 422–433.
(c) D.A. DiRocco, T. Rovis, Catalytic asymmetric intermolecular Stetter reaction of
enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional
additives, J. Am. Chem. Soc. 133 (2011) 10402–10405.
[14] A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, Widely useful DMAP-
catalyzed esterification under auxiliary base- and solvent-free conditions, J. Am.
Chem. Soc. 129 (2007) 14775–14779.
[5] (a) X.K. Chen, X.Q. Fang, Y.R. Chi, cis-Enals in N-heterocyclic carbene-catalyzed
reactions: distinct stereoselectivity and reactivity, Chem. Sci. 4 (2013) 2613–
2618;
[15] (a) Z.H. Cai, G.F. Du, L. He, C.Z. Gu, B. Dai, N-heterocyclic carbene catalyzed
hydrophosphonylation of aldehydes, Synthesis (2011) 2073–2078;
(b) Y.C. Fan, G.F. Du, W.F. Sun, W. Kang, L. He, N-heterocyclic carbene-catalyzed
cyanomethylation of aldehydes with TMSAN, Tetrahedron Lett. 53 (2012) 2231–
2233;
(b) D.T. Cohen, K.A. Scheidt, Cooperative Lewis acid/N-heterocyclic carbene
catalysis, Chem. Sci. 3 (2012) 53–57;
(c) J.M. Mo, X.K. Chen, Y.R. Chi, Oxidative, g-Addition of enals to trifluoromethyl
ketones: enantioselectivity control via Lewis acid/N-heterocyclic carbene coop-
erative catalysis, J. Am. Chem. Soc. 134 (2012) 8810–8813.
(c) X.L. Zou, G.F. Du, W.F. Sun, et al., N-heterocyclic carbene mediated Refor-
matsky reaction of aldehydes with a-trimethylsilylcarbonyl compounds, Tetra-
hedron 69 (2013) 607–612.
[6] (a) D.A. DiRocco, T. Rovis, Catalytic asymmetric a-acylation of tertiary amines
mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox
catalysis, J. Am. Chem. Soc. 134 (2012) 8094–8097;
[16] A.J. Arduengo III, R. Krafczyk, R. Schmutzler, Imidazolylidenes, imidazolinylidenes
and imidazolidines, Tetrahedron 55 (1999) 14523–14534.