Pyridinium saccharinate salts as efficient recyclable acylation catalyst: A new bridge between heterogeneous and homogeneous catalysis

Article abstract of DOI:10.1016/j.tet.2016.04.073

It is important to find a way for separation of concerned chemicals from product mixture after reaction, in order to avoid spreading harmful chemicals to society. The homogeneous nature of DMAP-catalyzed acylation still suffers from the problems of catalyst separation and/or residual DMAP contamination. DMAP causes acute dermal toxicity, whereas the corresponding DMAP salt exhibits only slight irritation to the skin. Very recently, we found that the DMAP saccharinate salt is also great recyclable catalyst, whose acylation of alcohols has been successfully and effectively carried out 10 times without loss in activity. This report covers our comprehensive studies on using the pyridinium saccharinate salts as efficient recyclable acylation catalysts including 4-N,N-dimethylaminopyridinium saccharinate (A), 4-(1-pyrrolidinyl) pyridinium saccharinate (B), 2-N,N-dimethylaminopyridinium saccharinate (C), and pyridinium saccharinate (D). Their structure and reactivity have been studied. The salts A, C, and D contain very interesting seven-membered synthon showing multiple H-bonding interactions for pair of pyridinium cation and saccharinate anion in the solid state. The salt B exhibits H-bonding interaction of N(sac) ... H-N(py) in the solid state, instead of seven-membered synthon. The catalytic reactivity studies show that salts A and B are both very effective, with salt B even better in reactivity, and are both recyclable in the esterification of a variety of alcohols, under solvent-free and base-free conditions at room temperature.

Full text of DOI:10.1016/j.tet.2016.04.073

Tetrahedron 72 (2016) 3468e3476
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pyridinium saccharinate salts as efficient recyclable acylation
catalyst: a new bridge between heterogeneous and homogeneous
catalysis
,
a
a
a
a
Norman Lu a , Wei-Hsuan Chang , Rong-Jyun Wei , Yung-Cheng Fang , Tu-Wen Han ,
*
Guo-Quan Wang b, Jia-Yaw Chang b, Yuh-Sheng Wen c, Ling-Kang Liu c
a Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 106, Taiwan, ROC
b Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
c Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
It is important to find a way for separation of concerned chemicals from product mixture after reaction, in
order to avoid spreading harmful chemicals to society. The homogeneous nature of DMAP-catalyzed ac-
ylation still suffers from the problems of catalyst separation and/or residual DMAP contamination. DMAP
causes acute dermal toxicity, whereas the corresponding DMAP salt exhibits only slight irritation to the
skin. Very recently, we found that the DMAP saccharinate salt is also great recyclable catalyst, whose
acylation of alcohols has been successfully and effectively carried out 10 times without loss in activity. This
report covers our comprehensive studies on using the pyridinium saccharinate salts as efficient recyclable
acylation catalysts including 4-N,N-dimethylaminopyridinium saccharinate (A), 4-(1-pyrrolidinyl) pyr-
idinium saccharinate (B), 2-N,N-dimethylaminopyridinium saccharinate (C), and pyridinium saccharinate
(D). Their structure and reactivity have been studied. The salts A, C, and D contain very interesting seven-
membered synthon showing multiple H-bonding interactions for pair of pyridinium cation and saccha-
rinate anion in the solid state. The salt B exhibits H-bonding interaction of N(sac) . HeN(py) in the solid
state, instead of seven-membered synthon. The catalytic reactivity studies show that salts A and B are both
very effective, with salt B even better in reactivity, and are both recyclable in the esterification of a variety
of alcohols, under solvent-free and base-free conditions at room temperature.
Received 21 March 2016
Received in revised form 24 April 2016
Accepted 26 April 2016
Available online 29 April 2016
Keywords:
Pyridinium saccharinate
DMAP
Homogeneous
Heterogeneous
Organocatalysis
Recoverable
Catalyst
Kinetics
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
and the problem of residual DMAP contamination. Furthermore,
DMAP causes acute dermal toxicity,8 whereas its salts were reportedly
Homogeneous catalysis is a powerful tool in highly active and
stereoselective organic transformations.1 However, the majority of
catalytic processes in industryare still conductedunderheterogeneous
conditions, since separation of the catalyst from product mixture is
easier than under homogeneous conditions. Therefore, in addition to
developing homogeneous catalysts that can be used at high substrate
to catalyst ratio, efforts have also been made to provide the hetero-
geneous counterpart by fixing the catalysts to a solid support.2 Re-
cently, it has been reported that 4-(N,N-dimethylamino)pyridine
(DMAP) is an effective homogeneous catalyst for the esterification3 of
alcohol with acid anhydride,4 the ring-opening polymerization, the
silylation of alcohol, etc.5e7 The homogeneous nature of DMAP-
catalyzed acylation still suffers from the problem of separation, i.e.
only slightly irritating upon the skin contact.8,9 In order to avoid
spreading harmful chemicals to the surroundings, it is important to
find a recoverable DMAP type catalyst that could be easily separated
from the product mixture, for example, by immobilizing DMAP onto
solid supports.10e12 A few immobilized systems have been reported,
but they are not able to show effective catalytic activity with good
recyclability at the same time. Lin et al.12 used the silica nanosphere-
supported DMAP to catalyze the acylation of alcohols. The support
however, was in favor of support molecular weight as small as possible.
Connon et al. reported a recyclable magnetic-nanoparticle-supported
DMAP that can be used and recovered by an external magnet for a few
times.13,14 The fluorous methods15 could offer a useful way to recover
fluorous-tagged compounds from a reaction mixture.16 Legros et al.15
demonstrated a fluorine-containing system to recover the catalyst
salt by addition of a non-polar solvent to precipitate the catalyst
moiety.17,18 However, the high cost of fluorous materials might be
* Corresponding author. Tel.: þ8862 2771 2171x2417; fax: þ8862 2731 7174;
e-mail address: normanlu@mail.ntut.edu.tw (N. Lu).
http://dx.doi.org/10.1016/j.tet.2016.04.073
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
3469
a concern. Very recently, we reported a new protocol concerning the
recyclable catalyst A that is the salt of DMAP and saccharin. The DMAP
saccharinate catalyzed acylation of alcohols was successfully and ef-
fectively carried out for more than 8 times without loss in catalytic
activity. In this manuscript, we report our extended studies on the
general use of pyridinium saccharinate salts as recyclable homoge-
neous catalyst. The pyridine-containing substrates used are 4-N,N-
dimethylaminopyridine (a), 4-(1-pyrrolidinyl)pyridine (b), 2-N,N-
dimethylaminopyridine (c), and pyridine (d). The corresponding pyr-
idinium saccharinate salts19 for aed are 4-N,N-dimethylaminopyr-
idinium saccharinate (A), 4-(1-pyrrolidinyl) pyridinium saccharinate
(B), 2-N,N-Dimethylaminopyridiniumsaccharinate(C)andpyridinium
saccharinate (D), with structures shown in Fig. 1. Two types of supra-
molecular interactions were observed, that of salts A, C, and D being in
contrast to that of salt B. In the reactivity studies described below, we
found that effect of the unique structure of salt B is seemingly corre-
lated to the better catalytic reactivity among the salts AeD.
single crystals obtained by the diffusion crystallization from over-
layering of a saturated methanolic solution with hexane. Prepara-
tions and structures are discussed first, followed by catalytic
activity in acylation of the alcohol with acid anhydride.
2.1. Synthesis and structure
2.1.1. Preparation. As a typical example, the salt B was prepared
simply by reacting b and saccharin in 1:1 M ratio at 60 ꢀC. The salt B
consists of a five-membered pyrrolidine at para position on pyri-
dine ring as the N-containing electron donating group. The salt A
and salt C consist of the dimethylamino group at para or ortho
position on pyridine ring, respectively. And the salt D contains the
parent pyridine. A comparison in structure and activity could be
done among salts AeD. The salts A, B, and D were obtained in 95%
yield, whereas salt C was obtained in 61% yield, attributable to the
steric hindrance by ortho dimethylamino group on pyridine ring.
2.1.2. Structure. The four X-ray structures of salts A,21 B, C, and
D20,22 are shown as ion-pairs in the Fig. 1ae d, respectively. The
structures could be summarized that for this type of salts a highly
probable synthon is from interaction between the paired, positively
charged pyridinium cationand negativelycharged saccharinateanion,
with the cationeanion attraction reinforced by two H-bonding in-
teractions embedded in a seven-membered ring. The crystal structure
of parent pyridinium saccharinate (salt D) was a revisit at 100K in the
current study with cell dimensions a 7.3166(3), b 12.8620(5), c
ꢀ
14.0641(5) A,
a 65.294(4), b 75.009(3), g 78.375(3)o. Its seven-mem-
bered synthon could be seen a smooth interface between the plane of
pyridinium cation and the plane of saccharinate anion, as demon-
strated in Fig. 2a. The two reported structures of salt D were all in the
same triclinic space group P-1, one with cell dimensions a 7.4677(7),
ꢀ
b12.9605(12), c14.1895(13) A,
a
65.1760(10),
b
74.752 (2),
g
78.103(2)o
at 292K,22 andtheotherwithcelldimensionsa7.4613(15), b12.954(3),
ꢀ
c 14.179(3) A,
a 65.251(2), b 74.747(3), g
78.160(3)o at 298K.20 When
the temperature of X-ray intensity data changes from 298K, to 292K,
eventually to 100K, the R value improves from 5.05%, to 4.50% and
finally to 3.94%, and the estimated standard deviations of structural
parameters also improves accordingly.
The synthon for pyridinium saccharinate salts serves as the pri-
mary stabilizing forces in the crystalline state. A proton transfer is
noted, from the neutral saccharin to pyridine, and the nature of ma-
terial is changed to charge-carrying pyridinium saccharinate system.
The two H-bonding interactions are located at O(sac) . HeN(py), and
N(sac) . HeC(py), where the former H-bonding parameters are
ꢀ
ꢀ
O(sac) . N(py) 2.630 A, O(sac) . H 1.663 A, and :O(sac) . HeN(py)
178.1ꢀ; and the supportive N(sac) . HeC(py) H-bonding parameters
ꢀ
ꢀ
are N(sac) . C(py) 3.349 A, N(sac) . H 2.261 A, and :N(sac) .
HeC(py) 134.8ꢀ. The seven-membered synthon is planar. Shown in
Fig. 2b is the plane defined by the seven-membered synthon skeleton
thatextendstothemolecularplaneofpyridiniumandtothemolecular
plane of saccharinate, smoothly joining all the planes of salt D.
As briefly mentioned in the introduction, there is noted struc-
ture and reactivity relationship in this study. Salts A, C, and D ex-
hibit in the solid state exactly the seven-membered synthon which
has been viewed as resting state during the catalytic cycles of ac-
ylation in solution (see later). Alternatively in the solid state, salt B
exhibits a H-bonding interaction of N(sac) . HeN(py), instead of
the seven-membered synthon, as a result of the interplanar angle of
33.9ꢀ between pyridinium plane and the molecular plane of sac-
charinate (Fig. 3). This slightly twisted supramolecular structure of
salt B is considered more energetic than a seven-membered syn-
thon, in order to conform well to increased moment of inertia of C2-
symmetric pyrrolidinylpyridinium cation. Thus, it was believed that
with additional resting state for salt B as catalyst in solution, salt B
would be expected to perform better than salts A, C or D.
Fig. 1. The solid state cationeanion pair of the four salts: (a) 4-N,N-dimethylamino-
pyridinium saccharinate, A, (b) 4-(1-pyrrolidinyl)-pyridinium saccharinate, B, (c) 2-
N,N-dimethylaminopyridinium saccharinate, C, and (d) pyridinium saccharinate (D).
Color codes: C, black; N, blue; O, red; S, yellow, and H, white. Salts A, C, and D exhibit
common seven-membered synthon, consisting of H-bonding interactions of O(sac) .
HeN(py) and N(sac) . HeC(py), whereas salt B exhibits H-bonding interaction of
N(sac) . HeN(py) instead of the seven-membered synthon.
2. Results and discussion
All of the pyridinium saccharinate salts AeD can easily be pre-
pared from respective pyridine derivatives aed and saccharin, with

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N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
Fig. 2. (a) Top view and (b) rough side view of the synthon plane in salt D. Color codes: C, gray; N, blue; O, red; S, yellow, and H, white. Red shade indicates the least-squares plane
defined by seven-membered synthon.
Fig. 3. Side view of the saccharinate molecular plane of salt B. Color codes: C, black; N, blue; O, red; S, yellow, and H, white. Red shade indicates the least-squares saccharinate
molecular plane, without protons and two out-of-plane oxygens.
There are many published pyridinium saccharinate structures
in the literature. A search on current version of Cambridge
Structural Data Base revealed many crystal structures readily
available for scrutiny on the synthon. All pyridinium saccharinate
salts adopt the same seven-membered synthon, with the excep-
tion of one instance, namely, the half salt 5-methyl-2-(5-
methylpyridin-2-yl)pyridinium saccharinate saccharin, showing
hydrogen bonding interactions on N(sac) . HeN(py) and O(sac)
. HeC(py) instead.19
pyridinium saccharinate was found to be active also in the catalytic
acylation reaction. We extended the study to salts AeD (Scheme 1).
Two acid anhydrides chosen to react with alcohols were (MeCO)2O
and (iPrCO)2O in order to evaluate these salts on catalytic activity.
For assessment of the catalytic acylation, many 2ꢀ alcohols and one
3ꢀ alcohol were tested. Table 1 gives the results by running the
acylation reactions with 1 mol % loading of salt AeD as catalyst,
without using any solvents or bases.
The ones adopting also the seven-membered synthon in liter-
ature are 1,2-bis(pyridinium-4-yl)ethane (saccharinate)2, trans-1,2-
bis(pyridinium-4-yl)ethene (saccharinate)2,23 2-methylpyridinium
saccharinate,24 4,40-bipyridinium (saccharinate)2, 4-picolinium
saccharinate, and isonicotinamide saccharinate.20
There is presence of other weak interactions in salts AeD con-
Scheme 1. Pyridinium saccharinate salt catalyzed acylation reaction of alcohol with
acid anhydride.
tributing to the stabilization in solid state, for instance the
stacking, CeH .
interaction,25 and the H-bonding interactions on
the eCO and eSO2 groups with the neighboring hydrogen atoms.
Salt B shows more short contacts attributable to CeH . in-
pep
p
p
teractions. So does the above mentioned half salt 5-methyl-2-(5-
methylpyridin-2-yl)pyridinium saccharinate saccharin. Both struc-
tures show similar H-bonding interaction of N(sac) . HeN(py).
The salts AeD dissolve in polar solvents, but precipitate from the
non-polar ones.19 We have made use of solubility of the salts and
found that all four can be easily recovered for reuse. Given the
strong binding interactions on cationeanion pair, we believe that
the salts AeD exist in less polar organic solvents as solvated ion-
pairs, likely without solvent molecules separating the cati-
oneanion pair.
Table 1
Results on esterification using salts AeD as catalyst
Entry Catalyst Alcohol
(RCO)2O, Temp, (ꢀC) Time, (h) Yield,a (%)
(R¼)
1
2
3
4
5
6
7
8
A
A
B
B
C
C
D
D
A
A
B
B
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
Me
iPr
Me
iPr
Me
iPr
Me
iPr
25
25
25
25
25
25
25
25
2.5
2
2
2
24
24
24
24
24
24
23
23
99þ
99þ
99þ
99þ
98
97
98
98
90
9
2-Phenyl-2-propanol Me
2-Phenyl-2-propanol iPr
2-Phenyl-2-propanol Me
2-Phenyl-2-propanol iPr
100
100
90
10
11
12
99þ
2.2. Catalysis on esterification
99
90
99þ
It has been known that the acylation of alcohol with acid an-
hydride is easily catalyzed by DMAP. The related conjugated acid
a
The 99þ means the yield is more than 99%.

N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
3471
When 1-cyclohexanol is the reactant, the acylation proceeds
easily to completion in 2e2.5 h at room temperature employing
salts A and B as catalyst, indicating that the catalysis is very facile
(Table 1, entries 1e4). On the other hand, similar acylation
employing salts C and D as catalyst takes 24 h to finish (Table 1,
entries 5e8). For salts A and B as catalyst, the electron-donating
dimethylamino group and pyrrolidinyl group, respectively, at
para position on pyridine ring increase the rate by one order of
magnitude, comparing to the result by the parent pyridinium salt
D. Alternatively the salt C as catalyst exhibits a slowing-down of
the reaction, attributed mainly to the steric hindrance the dime-
thylamino group at ortho position on pyridine ring. The para and
ortho substitution on pyridine ring could also be justified in terms
of intrinsic pKa parameter. The pKa value in aqueous solution for
most basic site of pyridine is 5.23ꢁ0.10, that of 2-(dimethylamino)
pyridine 7.04ꢁ0.10, and that of 4-(dimethylamino)pyridine
(DMAP) 9.52ꢁ0.10. It is reasonable that DMAP is the most reactive
one among the three. Similar reactivity for salts A and B was
predicted on the basis of similar pKa values of salts A and B. In-
terestingly, the reactivity studies show that the salt B as catalyst
was better in reactivity than the salt A, likely correlated to the
difference of structural chemistry in the solid state and corre-
spondingly the difference of resting state during the catalysis
cycles.
completion is faster for salt A as pre-catalyst than free DMAP
only as pre-catalyst. The results from free DMAP-catalyzed ac-
ylation are comparable to those from salt A-catalyzed acylation.
However we feel more important that salt A is safer to handle in
the laboratory than free DMAP, and furthermore, the use of salt A
has an advantage, namely, in catalyst recovering and reuse (see
later).
2.2.1. Salt A-catalyzed esterification. The salt A-catalyzed esterifi-
cation reactions have been discussed in our recent communica-
tion,21 the summarized results here are for comparison with
catalytic esterification by salts BeD. The salt A catalyzed esterifi-
cation was carried out, under solvent-free and base-free conditions
at room temperature (with the exception for esterification of 3ꢀ
alcohol), and after completion of the reaction salt A catalyst was
precipitated by adding hexane (or any other non-polar solvent) to
the product mixture for recovery and reuse that were demon-
strated for 10 runs. Besides acetic anhydride, the more sterically
demanding isobutyric anhydride was run parallel-wise with good
recyclability, also for 10 times.
Using salt A as catalyst, the 2ꢀ alcohols tested were 1-
cyclohexanol, 1-phenyl ethanol, L-menthol, 1-cyclododecanol, and
4-nitrophenol, with satisfactory results both on reactivity and
recyclability listed in Table 3, entries 1e10. The yields were all
greater than or equal to 92% during the recycling experiments ex-
cept in two cases with 87% at the last experiment. The bulky 3ꢀ
alcohol, 2-phenyl-2-propanol, was difficult to acetylate or iso-
butyrate at room temperature. Its A-catalyzed esterification at
100 ꢀC finished in 24 h and the recyclization could proceed for 10
times (Table 3, entries 11e12). It was also noticed that the
heteroatom-containing (N atom) alcohol, 3-pyridyl methanol (en-
try 13), is rapidly esterified for 10 recycling runs without being
influenced by the presence of heteroatom.
We had also compared the catalytic activity of DMAP and
that of salt A, using esterification of -menthol with acid anhy-
L
drides as the model reaction, with results shown in Table 2. The
data from Ishihara’s work with DMAP as catalyst precursor26
(Table 2, entries 3 and 4) and our own results with salt A as
catalyst (Table 2, entries 1 and 2) gave very comparable acyla-
tion results.
Table 2
2.2.2. Salt B-catalyzed esterification.26b In view of the efficient re-
sults from salt A-catalyzed esterification reaction, we extended the
scope of study by using analogous salt B as catalyst using the same
acylation reactions between alcohol and acid anhydride. The salt B
consisted of a para five-membered pyrrolidine on pyridine as the N-
containing electron donating group. The salt was prepared by
reacting equal molar b and saccharin at 60 ꢀC to result in white solid
crystalline materials in high yield.
Comparison of catalytic activity of DMAP and salt A
Entry Catalyst loading Substrate (RCO)2O (R¼) Temp, (ꢀC) Time (h) Yield (%)
1
1 mol % salt A
1 mol % salt A
0.5 mol % DMAP
0.5 mol % DMAP
L
L
L
L
-Menthol Me
-Menthol iPr
-Menthol Me
-Menthol iPr
25
25
25
25
8
8
9
9
97
98
84
98
2
3a
4a
a
The entries 3 and 4 are quoted from Ishihara’s data,26a that we also repeated and
had the same outcome.
The experimental results of salt B as acylation catalyst were
recorded in Table 4. Similar to salt A, the salt B was a very effective,
recyclable acylation catalyst for the esterification of 1-cyclohexanol
with acetic anhydride as well as with isobutyric anhydride (Table 4,
entries 1e2), which were successfully carried out under solvent-free
andbase-freeconditionatroom temperatureandbothreactionswere
Based on the results on Tables 1 and 2, the catalysis proceeds
smoothly with salts A and B as catalyst and to a less degree with
salts C and D as catalyst. The catalyst loading of salt A is slightly
greater than the loading of DMAP only, yet the time to
Table 3
Salt A-catalyzed esterification of alcohols with anhydrides under solvent- and base-free conditions
Entry
1b
2
3
4
5
6
7
8
Alcohol
(RCO)2O (R¼)
T (ꢀC)
T (h)
Yielda (%)
1-Cyclohexanol
1-Cyclohexanol
1-Phenyl ethanol
1-Phenyl ethanol
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
25
25
25
25
25
25
25
25
25
2.5
2
2
99þ
99þ
99þ
99þ
97
98
99
95
99þ
99þ
99þ
99þ
96
99þ
99þ
99þ
99þ
96
97
97
97
98
99
99þ
99þ
95
94
99
99þ
99þ
98
93
98
99þ
99þ
92
87
98
99þ
99þ
87
99þ
99þ
99þ
96
99þ
99þ
99þ
95
99þ
99þ
99þ
92
2
L
-Menthol
-Menthol
8e12
8e12
8
L
98
96
96
97
95
97
99
95
92
1-Cyclododecanol
1-Cyclododecanol
4-Nitrophenol
98
99
97
97
97
96
97
97
96
8
95
95
95
94
94
95
95
94
94
9
2e4
2e4
24
24
0.5
99þ
99þ
90
99þ
99þ
90
99þ
99þ
88
98
99þ
99þ
88
99þ
99þ
88
96
96
96
96
10
11
12
13
4-Nitrophenol
25
99þ
99þ
99þ
99þ
99þ
2-Phenyl-2-propanol
2-Phenyl-2-propanol
3-Pyridyl methanol
100
100
25
85
88
88
85
80
99þ
99þ
99þ
99
99þ
96
99þ
94
99þ
93
99þ
91
99þ
90
99þ
89
99þ
99þ
99þ
99þ
a
99þ means the yield is more than 99%.
b
Rate law is ln[cyclohexanol]¼ꢂ0.24te0.58. (see Supplementary data D).

3472
N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
completed within 2 h. Salt B exhibited a solubility property the same
as that of salt A and was easily precipitated by addition of hexane to
the product mixture. Its recycling and reuse have been demonstrated
10 times, keeping yields all above 88% for either acetic anhydride or
for sterically more hindered isobutyric anhydride with good recy-
2.2.3. Salt C-catalyzed esterification. The reaction of equal molar 2-
(N,N-dimethylamino)pyridine and saccharin resulted in 61.4%
yield of salt C, whose catalytic activity was also studied. The NMe2
group at ortho position imposed a steric hindrance on acylation,
and thus much longer time was required to reach completion.
Shown in Table 5 entries 1e2 for example, the salt C-catalyzed
esterification of 1-cyclohexanol with acetic anhydride and with
isobutyric anhydride, respectively, took both 24 h at room tem-
perature, with yields of 98% and 97%, respectively. The esterifica-
tion of 1-phenyl ethanol exhibited similar results (Table 5 entries
3e4) whereas the esterification of 1ꢀ alcohol, the 3-phenyl prop-
anol, was much faster and needed only 6e7 h to complete (Table 5
entries 5e6). At room temperature, without adding the catalyst
salt C, the yield is around 20% which is significantly lower than
those with the catalyst added. Because the catalytic activity of salt
C was too much inferior to that of salts AeB, we decided that it
won’t gain meaningful advantage from extra recycling experi-
ments with salt C as catalyst. Accordingly no recovery and reuse
was attempted.
clability. Furthermore, other 2ꢀ alcohols, i.e. 1-phenyl ethanol,
L-
menthol, and 1-cyclododecanol all proceeded easily to the recyclable
acylation with salt B as shown in Table 4, entries 3e8. When the less
nucleophilic 4-nitrophenol was used as substrate, the reaction com-
pleted in 2.5 h; and its recycling and reuse was also successfully re-
peated 10 times with a quantitative yield every run (Table 4, entries
9e10). As for the sterically hindered 2-phenyl-2-propanol, a 3ꢀ alco-
hol, the recycling experiments could also be effectively carried out at
90 ꢀC for 10 times. The heteroatom-containing 3-pyridyl methanol
could also be quickly esterified without being influenced by the het-
eroatom for 10 times. Overall, the salt B appeared to be an even better
catalystonacylationreactionofalcoholwithacidanhydridesthansalt
A, in particular on the acylation of tertiary 2-phenyl-2-propanol
(Table 4, entries 11e12), which requires only 90 ꢀC and 23 h instead
of 100 ꢀC and 24 h (vide infra, Scheme 2).
Table 4
Salt B-catalyzed esterification of alcohols with anhydrides under solvent- and base-free conditions
Entry
1b
2
3
4
5
6
7
8
Reactant
(RCO)2O (R¼)
T (ꢀC)
t (h)
Yielda (%)
1-Cyclohexanol
1-Cyclohexanol
1-Phenyl ethanol
1-Phenyl ethanol
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
22
22
22
22
22
22
22
22
22
22
90
90
22
2
2
1
1
5
5
6
6
2
99þ
99þ
99þ
99þ
99
99
92
99
99þ
99þ
99
99
99þ
99þ
99þ
99þ
99þ
95
99þ
99þ
99þ
99þ
92
99þ
99þ
99þ
99þ
94
99þ
99þ
99þ
99þ
95
98
98
95
94
95
97
94
90
93
97
89
88
88
98
89
89
99þ
99þ
99þ
91
99þ
L
-Menthol
-Menthol
90
90
90
88
L
99
91
91
90
91
88
87
85
84
1-Cyclododecanol
1-Cyclododecanol
4-Nitrophenol
92
92
92
90
91
91
91
90
90
99
96
97
94
94
92
94
94
93
9
99þ
99þ
99
99þ
99þ
99
99þ
99þ
98
99þ
99þ
96
99þ
99þ
96
99þ
99þ
95
99þ
99þ
95
99þ
99þ
95
99þ
99þ
95
10
11
12
13
4-Nitrophenol
2
2-Phenyl-2-propanol
2-Phenyl-2-propanol
3-Pyridyl methanol
23
23
0.5
98
95
93
92
91
92
90
90
89
99þ
99þ
99þ
99þ
99þ
99þ
99þ
99þ
99þ
a
99þ means the yield is more than 99%.
b
Rate law is ln[cyclohexanol]¼ꢂ0.35xe0.50. (see Supplementary data D).
Table 5
N
Salt C-catalyzed esterification of alcohols with anhydrides under solvent- and base-
free conditions
Yielda (%)
O
O
O
Entry
Reactant
(RCO)2O (R¼)
T (ꢀC)
t (h)
H
N
N
O
R
1
2
3
4
5
6
1-Cyclohexanol
1-Cyclohexanol
1-Phenyl ethanol
1-Phenyl ethanol
3-Phenyl propanol
3-Phenyl propanol
Me
iPr
Me
iPr
Me
iPr
25
25
25
25
25
25
24
24
24
24
6
98 (49)
97
99 (17)
99
98 (19)
96
N
N
N
R
R
R
H
+
O2S
O
O
R
O
H
N
N
H
H
N
c
7
HO
a
H
O
The numbers inside the parenthesis are the yields from the trials without adding
R'
O
O
O2S
the catalysts.
O2S
R
N
_
HO
R'O
O
2.2.4. Salt D-catalyzed esterification. Prepared directly from re-
action of parent pyridine and saccharin, salt D was also studied on
its catalytic activity on esterification of alcohol with acid anhydride,
as shown in Table 6. Relative to salts AeB, salt D showed much
poorer results, which were expected, because of weaker basicity of
d compared to a and b. For salts A and B, the NMe2 group and the
pyrrolidynyl group at para position on pyridine ring, respectively,
donate electron density to the ring, whereas for salt D no such
auxiliary donating group is available. Thus, the poor catalytic ac-
tivity of salt D-catalyzed esterification was attributed to electronic
effect. Shown in Table 6, the esterification reaction for the 2ꢀ
b
a
H
N
O
R
O
H O
N
O2S
R'
d
Scheme 2. Proposed mechanism27 of pyridinium saccharinate salt A catalyzed acyla-
tion reaction based on synthon connectivity as the resting state with O(sac)
HeN(py)/O(sac)-H . N(py) for propagation.
.

N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
3473
alcohols including 1-cyclohexanol, 1-phenyl ethanol, and
thol, took 24 h to finish at room temperature (Table 6, entries 1e2,
5e8).
L
-men-
pyridinium saccharinate are ion-pairs in solution. Thus, based on
this ion-pairs concept, we think the mechanism is more likely as
the one proposed below.
At the molecular level, taking advantage of the cationeanion
pair, the pyridinium saccharinate catalyzed esterification reaction
is consistent to a mechanism proposed in Scheme 2. The pyr-
idinium saccharinate salt is an internally self-buffering system
because the seven-membered synthon effectively interfaces more
than one negative centers for one proton. The salt B, as derived
from b and saccharine, is used for illustration: the pKa of acidic
most proton of saccharine is 2.2 and the pKa of the basic most
proton of pyrrolidinyl-pyridine (b) is 9.5. The isoelectronic point pI
of salt B is then (2.2þ9.5)/2¼5.9, which is within reasonably range
of pKa values of acetic acid and isobutyric acid, the by-products in
the esterification of alcohols with acid anhydrides.
Shown in Scheme 2 the pyridinium saccharinate salt A stays in
the static form of cationeanion and in the static form with neutral
saccharine and pyridine, the latter being considered the more ac-
tivated to react with acid anhydride and the form with ion pair
serves as the resting. That is, the generation of transient DMAP in
system is important for the catalytic activity, whereas the N-acyl
pyridinium cation is also transient in the rate determining step that
is followed by reaction with the alcohol substrate. Salts A, C, and D
as catalyst, with their X-ray structures in mind, likely utilize path-
way of Scheme 2. For salt B, the pathway of Scheme 2 is also rea-
sonable. In addition, a pathway with N(sac) . HeN(py) as resting
state may give an alternative route for salt B, also with its X-ray
structure under consideration.
Table 6
D-catalyzed esterification of alcohols with anhydrides under solvent- and base-free
conditions
Entry
Reactant
(RCO)2O; (R¼)
T (ꢀC)
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Cyclohexanol
1-Phenyl ethanol
1-Phenyl ethanol
3-Phenyl propanol
3-Phenyl propanol
Me
iPr
Me
iPr
Me
iPr
Me
iPr
Me
iPr
25
25
60
60
25
25
25
25
100
100
24
24
8
98 (49)
98
97 (95)b
95
8
24
24
8
8
24
24
99 (17)
99
99 (29)
98
L
-Menthol
-Menthol
91 (90)b
88
L
a
The numbers inside the parenthesis are the yields from the trials without adding
the catalysts.
b
At higher temperature (60 or 100 ꢀC; entries 3&9), the catalytic activity from the
catalyst shows only the very minor effect.
For the esterification of 1-cyclohexanol with acid anhydrides
with salt D as catalyst, the reactions finished in 8 h if temperature
was raised to 60 ꢀC (Table 6, entries 3e4). With less steric influence
the primary 3-phenyl propanol (Table 6, entries 7e8) could be ac-
ylated at room temperature in 8 h. The esterification of L-menthol
with acid anhydrides took 24 h at 100 ꢀC (Table 5, entries 9e10).
Due to poor catalytic activity on esterification results, no attempts
were made on recovery and reuse on salt D.
Search for pyridinium carboxylate structures in Cambridge
Structural Data Base didn’t reveal statistical importance on similar
seven-membered synthon in that carboxylate replaces saccha-
rinate. It cannot be ruled out however that the carboxylate anion
exchanges positions with the saccharinate anion, to play a role
during conversion of the acid anhydride to N-acyl cation and con-
currently to carboxylic acid.
2.3. Mechanism of acylation of alcohols
As mentioned above, DMAP is an effective homogeneous cata-
lyst for the esterification of alcohols. To overcome the major
problem associated with the use of soluble catalysts, i. e. the re-
covery of the catalyst from the reaction medium, Ishihara et al. had
3. Conclusion
immobilized the catalyst on
a
polymeric matrix by using
Four pyridinium saccharinate salts were prepared and their
crystal structures studied. The structures all contain important H-
bonding interactions between ion pair of pyridinium and saccha-
rinate in the solid state. Salts A, C, and D showed the seven-
membered synthon with embedded double H-bonding interactions
whereas salt B exhibited only the N(sac) . HeN(py) H-bonding not
the seven-membered synthon. The reactivity of salts AeD as cat-
alyst on esterification has been studied. Salt C was a poor catalyst
for esterification due to its steric hindrance and salt D without
donating substituent on pyridine ring was also proved a poor cat-
alyst. Salts A and B, whose kinetics have been studied, are very
efficient recyclable catalysts for the acylation of a variety of 2ꢀ and
3ꢀ alcohols, and both salts could be recycled in the esterification
reaction for 10 times without decreasing catalytic activity. From the
kinetic studies, salt B turned out to be the best catalyst, even better
than salt A in this esterification.
polystyrene-supported DMAP. The catalyst loading was at the level
of 5e10 mol %, with the residual polystyrene-supported DMAP
carboxylate salt being recovered as residues from distillation of
product mixture. This recovered precatalyst was reportedly reused
more than three times.
The current method of recovery utilized the precipitation of the
saccharinate salts from product mixture, by addition of hexane or
other non-polar solvents to the soup and the saccharinate salts
separated quantitatively, ready for reuse in next acylation reaction.
The recovery and reuse were demonstrated for 10 runs with salts A
and B as catalyst. We strongly favor to enter the catalytic cycle from
the saccharinate salts side.
In order to improve on recovery and reuse of the catalyst, in-
sights on mechanism as well as equilibria in reaction mixture are
helpful. Following the original mechanism on DMAP catalyzed ac-
ylation of alcohol with acid anhydride, the rate-determining step is
the reaction of N-acyl pyridinium carboxylate with the alcohol; free
DMAP does not enter the kinetic equation directly.26 The equilib-
ria21 involved are believed to be mainly the molecular processes on
relocation of active proton between the reactant alcohol and the
product carboxylic acid.
Given that the majority of pyridinium saccharinate structures
reveals a seven-membered synthon in the solid state, and that
collectively the strongeweak O(sac) . HeN(py) and N(sac) .
HeC(py) hydrogen bonds become a robust recognition motif, we
may reasonably assume that the presence of such a synthon is also
in the solution state and use it as working hypothesis so that the
4. Experimental
4.1. General
Gas chromatographic/mass spectrometric data were obtained
using an Agilent 6890 Series gas chromatograph with a series 5973
mass selective detector. The GC monitoring employed a HP 6890 GC
using a 30 mꢃ0.250 mm HP-1 capillary column with a 0.25
mm
stationary phase film thickness. Infrared spectra were obtained on
a Perkin Elmer RX I FT-IR Spectrometer. NMR spectra were recorded
on Bruker AM 500 and 300 using 5 mm sample tubes. The residual

3474
N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
3
ꢀ
peaks of D2O or CDCl3 was used as the reference peaks for 1H or 13
C
13.6575(4) A,
b
112.260(2) , V 1511.20(8) A , Z¼4, T¼100.0(1)K, No
ꢀ
ꢀ
NMR spectra. Elemental Analysis was done by the staff of the Na-
tional Taiwan University Elemental Analysis Laboratory. The X-ray
diffraction data of salts AeD were collected at 100 or 200K
employing a Bruker (including Nonius BV) CCD diffractometer; the
structure was solved by successive Fourier maps.
of refln.¼3088, GoF¼1.111, R¼2.99%, [I>2
s(I)].
4.5. Preparation of salt C
2-(N,N-Dimethylamino)pyridine (4.09 mmol, 500 mg) and
equimolar of saccharin (4.09 mmol, 749.21 mg) followed by the
addition of 20 mL THF as solvent.
4.2. General procedure for the salt preparation
Yield (purified): 61.4%, white solid, mp: 149.1 ꢀC.
The 100 mL round bottomed flask was charged with pyridine
derivatives (or pyridine) (4.09 mmol) and equimolar of saccharin
(4.09 mmol, 500 mg) followed by the addition of 20 mL THF as
solvent. Then the reaction mixture was set to react in THF, at ca.
60 ꢀC for overnight. After the reaction, the solvent was removed by
vacuum. The crude product was then obtained. Recrystallization
proceeded with dissolution of crude product in methanol to form
a saturated solution, to which a hexane overlayer (ca. 10 cm high)
was added. Solvent diffusion over a period of a week at room
temperature afforded white crystals of the desired salt.
1H NMR (500 MHz, D2O)
d 7.76e7.72 (m, 2H, C5H4Ne), 7.67e7.63
(m, 4H, C6H4e; Saccharin H), 6.90 (d, H, J¼9.2 Hz, C5H4Ne), 6.71 (t,
H, J¼6.7 Hz, C5H4Ne), 3.07 (s, 6H, CH3).
13C NMR (126 MHz, D2O)
d 38.5, 111.4, 111.8, 141.9, 143.0, 151.9
(C’s on the DMAP) 120.2, 123.5, 132.3, 133.2, 133.7, 135.1, 172.1 (C’s
on the Saccharin).
FTIR n
(cmꢂ1) 3040 (NeH), 1646s (C]O, stretch), 1573s, 1456 m
(pyridine), 1333, 1146s (ReSO2eN), 1266s (NeCH3).
EA: Calcd for C14H15N3O3S: C, 55.07; H, 4.95; N, 13.76; S, 10.50.
Anal. Found: C, 54.76; H, 4.85; N, 14.00; S, 10.89.
X-ray crystallographic data of salt
C
(CCDC 892061):
8.4058(4), c
4.3. Preparation of salt A21
C
14H15N3O3S, Mr 305.35, P21/c, 7.1952(4),
a
b
3
ꢀ
ꢀ
23.5390(11) A,
b
96.981(2), V 1413.12(12) A , Z¼4, T¼200(2)K, No.
The 100 mL round bottomed flask was charged with 4-(N,N-
dimethylamino)pyridine (DMAP; 4.09 mmol, 500 mg) and equi-
molar of saccharin (4.09 mmol, 749.21 mg) followed by the addition
of 20 mL THF as solvent. Then the reaction mixture was set to react
in THF, at ca. 60 ꢀC for overnight. After the reaction, the solvent was
removed by vacuum. The crude product (1.24 g; yield¼99%) was
then obtained. Recrystallization proceeded with dissolution of
crude product in methanol to form a saturated solution, to which
a hexane overlayer (ca. 10 cm high) was added. Solvent diffusion
over a period of a week at room temperature afforded white
needle-shaped crystals of salt A.
of refln.¼2480, GoF¼0.951, R¼3.90%, [I>2
s(I)].
4.6. Preparation of salt D
Pyridine (4.09 mmol, 323.11 mg) and equimolar of saccharin
(4.09 mmol, 749.21 mg) followed by the addition of 20 mL THF as
solvent.
Yield (purified): 95.2%, white solid, mp: 131.0 ꢀC.
1H NMR (500 MHz, D2O)
d
8.78 (dd, 2H, J¼5.5 Hz and J¼1.4 Hz,
C5H4Ne), 8.60 (tt, H, J¼7.8 Hz and J¼1.8 Hz, C5H4Ne), 8.06 (dd, 2H,
J¼7.8 Hz and J¼6.9 Hz, C5H4Ne), 7.88e7.80 (m, 4H, C6H4e; Sac-
Analytical data of salt A: Yield (purified): 95%, mp: 218.0 ꢀC.
charin H). 13C NMR (126 MHz, D2O)
d 126.7, 141.1, 146.4 (C’s on the
1H NMR (500 MHz, D2O)
d
7.90 (d, 2H, J¼7.5 Hz, C5H4Ne),
7.76e7.71 (m, 4H, C6H4e; Saccharin H), 6.72 (d, 2H, J¼7.59 Hz,
C5H4Ne), 3.12 (s, 6H, CH3); 13C NMR (126 MHz, D2O)
39.6, 107.0,
Pyridine) 119.7, 123.0, 131.5, 132.8, 133.2, 140.4, 171.5 (C’s on the
Saccharin).
d
FTIR n
(cmꢂ1) 3086 (NeH), 1630s (C]O, stretch), 1583, 1460
142.3,157.6 (C’s on the DMAP) 120.6,123.9,132.7,133.6, 134.1, 138.3,
172.6 (C’s on the Saccharin).
(pyridine), 1336s, 1173s, 1143 (ReSO2eN).
EA: Calcd for C12H10N2O3S: C, 54.95; H, 3.84; N, 10.68; S, 12.23.
Anal. Found: C, 54.44; H, 3.76; N, 10.81; S, 12.50.
FTIR n
(cmꢂ1) 3077s (NeH), 1646s (C]O, stretch), 1542, 1443 m
(pyridine), 1329, 1163, 1130, (ReSO2eN), 1270s (NeCH3).
EA: Calcd for C14H15N3O3S: C 55.07; H 4.95; N 13.76. Anal.
Found: C 54.50; H 4.85; N 13.50.
X-ray crystallographic data of salt
12H10N2O3S, Mr 262.28, P-1, a 7.3166(3), b 12.8620(5), c 14.0641(5)
D (CCDC 1037131):
C
A,
3
ꢀ
ꢀ
a
65.294(4),
b
75.009(3),
g
78.375(3), V 1154.85(8) A , Z¼4,
X-ray study was detailed in Ref. 21.
T¼100.0(1)K, No. of refln.¼5624, GoF¼1.031, R¼3.94%, [I>2s(I)].
Because the synthesis employed a general procedure described
in the preparation of salt A, only salient amounts and yields are
given for salts BeD.
4.7. General procedure for the salt-catalyzed esterification
The alcohol (2 mmol) and the anhydride (2.2 mmol) were mixed
in a 10 mL test tube and 1 mol % of salt A (0.02 mmol) was added.
The tube was then capped (or under N2 purge) and the reaction
mixture was stirred at room temperature (except for 1-
methylcyclopentanol at 60 ꢀC). After a couple of hours the acid
effluent was evaporated in vacuum. The residue was then allowed
to cool to room temperature and the salt was precipitated by
adding 2 mL hexane (or toluene). After filtration, salt was re-
covered, and then evaporating solvent from the filtrate afforded the
crude ester product. The recovered salt was charged with the
substrates, and the reaction mixture was then proceeded to the
next run. The products were quantified with GC analysis by com-
parison to NMP as an internal standard. The products from the 1st
run were further purified by column chromatography, and the
isolated yields were compared with the GC/MS yields. They were all
in good agreement.
4.4. Preparation of salt B
4-(1-Pyrrolidinyl)pyridine (4.09 mmol, 606.18 mg) and equi-
molar of saccharin (4.09 mmol, 749.21 mg) followed by the addition
of 20 mL THF as solvent.
Yield (purified): 95%, white solid, mp: 184.5 ꢀC.
1H NMR (500 MHz, D2O)
d
7.86 (d, 2H, J¼7.3 Hz, C5H4Ne),
7.83e7.70 (m, 4H, C6H4e; Saccharin H), 6.57 (d, 2H, J¼7.8 Hz,
C5H4Ne), 3.39 (t, 4H, J¼6.9 Hz, NCH2e), 2.04 (m, 4H, CH2e); 13C
NMR (126 MHz, D2O)
d 24.0, 47.5, 106.6, 141.2, 153.9 (C’s on the
Pyrrolidine) 119.6, 123.0, 131.8, 132.7, 133.2, 137.2, 171.7 (C’s on the
Saccharin). FTIR
n
(cmꢂ1) 3053 (NeH), 2866 (ReCH2eR), 1650s (C]
O, stretch), 1553s, 1450 m (pyridine), 1326, 1206, 1146s (ReSO2eN),
1276s (NeCH3).
EA: Calcd for C16H17N3O3S: C, 57.99; H, 5.17; N, 12.68; S, 9.68.
Anal. Found: C, 57.65; H, 5.22; N, 12.68; S, 9.74.
All the salt-catalyzed esterification products listed in Tables are
mostly known compounds. The products (Esters 1e15) have been
checked by GC/MS, NMR spectrometer (mp if the product is a solid).
X-ray crystallographic data of salt
B
(CCDC 892062):
8.9063(3),
C
16H17N3O3S, Mr 331.39, P21/n, 13.4242(4),
a
b
I

N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
3475
Esters 1e15 exhibited spectroscopic data exactly identical to those
O]CCHe), 1.71 (hex, 2H, J¼6.8 Hz, CH2e), 1.54e1.28 (m, 20H,
CH2e), 1.16 (d, 6H, J¼6.8 Hz, CH3).
reported in the literature.15,28e34
C
12H23OC(O)CH(CH3)2, GC/MS (m/z; EI): 254 (Mþ), 211
4.7.1. (a)15 Ester 1 (Cyclohexyl acetate): colorless liquid. 1H NMR
(MþꢂjꢂC3H7), 167 (MþeC4H7O2), 71 (C4H7Oþ), 43 (C3Hþ7 ).
(500 MHz, CDCl3)
d 4.72 (m, H, OCHe), 2.01 (s, 3H, CH3), 1.87e1.85
(m, 2H, CHe), 1.75e1.71 (m, 2H, CHe), 1.57e1.54 (m, 2H, CH2e),
1.45e1.22 (m, 4H, CH2e).
4.7.9. (i)34 Ester 9 (4-nitrophenyl acetate): pale yellow solid, m.p:
77 ꢀC. 1H NMR (500 MHz, CDCl3)
d
8.25 (d, 2H, J¼8.7 Hz, C6H4e),
C6H11OC(O)CH3, GC/MS (m/z; EI): 142 (Mþ), 99 (MþeC2H3O), 83
(MþeC2H3O2), 43 (C2H3Oþ).
7.26 (d, 2H, J¼8.7 Hz, C6H4e), 2.32 (s, 3H, CH3).
4-NO2PhOC(O)CH3, GC/MS (m/z; EI): 181 (Mþ), 138
(MþeC2H3O), 122 (MþeC2H3O2), 92 (MþeC2H3NO3), 43 (C2H3Oþ).
4.7.2. (b)28 Ester 2 (Cyclohexyl isobutyrate): colorless liquid. 1H
NMR (500 MHz, CDCl3)
d
4.71 (m, H, OCHe), 2.46 (sept, H, J¼6.8 Hz,
4.7.10. (j)26 Ester 10 (4-nitrophenyl isobutyrate): pale yellow solid,
O]CCHe), 1.83e1.78 (m, 2H, CHe), 1.72e1.68 (m, 2H, CHe),
1.53e1.49 (m, 2H, CH2e), 1.44e1.23 (m, 4H, CH2e), 1.11 (d, 6H,
J¼6.8 Hz, CH3).
m.p: 39.4 ꢀC. 1H NMR (500 MHz, CDCl3)
d
8.26 (d, 2H, J¼8.6 Hz,
C6H4e), 7.25 (d, 2H, J¼8.6 Hz, C6H4e), 2.81 (sept, H, J¼6.8 Hz, O]
CCHe), 1.30 (d, 6H, J¼6.8 Hz, CH3).
C6H11OC(O)CH(CH3)2, GC/MS (m/z; EI): 170 (Mþ), 127
(MþꢂjꢂC3H7), 99 (MþeC4H7O), 83 (MþeC4H7O2), 71 (C4H7Oþ), 43
(C3Hþ7 ).
4-NO2PhOC(O)CH(CH3)2, GC/MS (m/z; EI): 209 (Mþ), 138
(MþeC4H7O), 122 (MþeC4H7O2), 92 (MþeC2H3NO3), 71 (C4H7Oþ),
43 (C3Hþ7 ).
4.7.3. (c)29 Ester 3 (1-phenylethyl acetate): colorless liquid. 1H
4.7.11. (k)26 Ester 11 (dimethylbenzyl acetate): colorless liquid. 1H
NMR (500 MHz, CDCl3)
d
7.33 (m, 4H, C6H5-), 7.27 (m, H, C6H5e), 5.88
NMR (500 MHz, CDCl3)
d
7.38 (m, 4H, C6H5e), 7.28 (t, H, J¼6.8 Hz,
(q, H, J¼6.8 Hz, OCHe), 2.05 (s, 3H, CH3), 1.53 (d, 3H, J¼6.8 Hz, CH3).
PhCH(CH3)OC(O)CH3, GC/MS (m/z; EI): 164 (Mþ), 121
(MþeC2H3O), 105 (MþeC2H3O2), 77 (MþeC4H7O2), 43 (C2H3Oþ).
C6H5e), 2.07 (s, 3H, CH3), 1.82 (s, 6H, CH3).
PhCH(CH3)2OC(O)CH3, GC/MS (m/z; EI): 178 (Mþ), 135
(MþeC2H3O), 119 (MþeC2H3O2), 91 (MþeC4H7O2), 77
(MþeC5H9O2), 43 (C2H3Oþ).
4.7.4. (d)30 Ester 4 (1-phenylethyl isobutyrate): colorless liquid. 1H
NMR (500 MHz, CDCl3)
d
7.33 (m, 4H, C6H5e), 7.27 (m, H, C6H5e),
4.7.12. (l)26 Ester 12 (dimethylbenzyl isobutyrate): pale yellow
5.87 (q, H, J¼6.8 Hz, OCHe), 2.57 (sept, H, J¼6.8 Hz, O]CCHe), 1.53
(d, 3H, J¼6.8 Hz, CH3), 1.19 (d, 3H, J¼7.1 Hz, CH3), 1.17 (d, 3H,
J¼7.1 Hz, CH3).
solid, m.p: 72.4 ꢀC. 1H NMR (500 MHz, CDCl3)
d 7.38 (m, 4H, C6H5e),
7.27 (t, H, J¼6.8 Hz, C6H5e), 2.57 (sept, H, J¼6.8 Hz, O]CCHe), 1.81
(s, 6H, CH3), 1.20 (d, 6H, J¼6.8 Hz, CH3).
PhCH(CH3)OC(O)CH(CH3)2, GC/MS (m/z; EI): 192 (Mþ), 121
(MþeC4H7O), 105 (MþeC4H7O2), 77 (MþꢂjꢂC6H11O2), 43 (C3Hþ7 ).
PhCH(CH3)2OC(O)CH(CH3)2, GC/MS (m/z; EI): 206 (Mþ), 135
(MþeC4H7O), 119 (MþeC4H7O2), 91 (MþꢂjꢂC6H11O2), 71 (C4H7Oþ),
43 (C3Hþ7 ).
4.7.5. (e)31 Ester
colorless liquid. 1H NMR (500 MHz, CDCl3)
5
(2-isopropyl-5-methylcyclohexyl acetate):
4.60 (dt, H, J¼4.3 Hz
d
4.7.13. (m) Ester 13 (3-pyridinylmethyl acetate): pale yellow liq-
and 11.1 Hz, OCHe), 1.95 (s, 3H, CH3), 1.92 (d, H, J¼11.9 Hz, CHe),
1.79 (dsept, H, J¼2.6 Hz and 6.8 Hz, CHe), 1.63e1.57 (m, 2H, CH2e),
1.44e1.37 (m, H, CHe), 1.28 (tt, H, J¼2.6 Hz and 11.1 Hz, CHe), 0.99
(dq, H, J¼3.4 Hz and 9.4 Hz, CHe), 0.88 (q, H, J¼11.1 Hz, CHe), 0.83
(d, 3H, J¼3.4 Hz, CH3), 0.82 (d, 3H, J¼3.4 Hz, CH3), 0.81 (m, H, CHe),
0.69 (d, 3H, J¼7.7 Hz, CH3).
uid. 1H NMR (500 MHz, CDCl3)
d 8.53 (s, H, C5H4Ne), 8.48 (d, H,
J¼4.3 Hz, C5H4Ne), 7.60 (d, H, J¼7.9 Hz, C5H4Ne), 7.20 (dd, H,
J¼7.3 Hz and 4.9 Hz, C5H4Ne), 5.02 (s, 2H, CH2OC]O), 1.99 (s, 3H,
O]CCH3).
C5H4NCH2OCOCH3, GC/MS (m/z; EI): 151 (Mþ),108 (MþeC2H3O),
92 (MþeC2H3O2), 78 (MþeC3H5O2), 43 (C2H3Oþ).
2-CH(CH3)2-5-CH3C6H9OC(O)CH3, GC/MS (m/z; EI): 198 (Mþ),
139 (MþeC2H3O2), 124 (MþeC3H6O2), 96 (MþꢂjꢂC5H10O2), 81
(MþeC6H13O2), 43 (C2H3Oþ).
Acknowledgements
N. Lu thanks National Taipei University of Technology and the
Ministry of Science and Technology of Taiwan (MOST 104-2113-M-
027-004-MY1) for the financial supports.
4.7.6. (f) Ester 6 (2-isopropyl-5-methylcyclohexyl isobutyrate):
colorless liquid. 1H NMR (500 MHz, CDCl3)
d 4.60 (m, H, OCHe), 2.43
(sept, H, J¼6.8 Hz, O]CCHe), 1.89 (d, H, J¼11.9 Hz, CHe), 1.81
(dsept, H, J¼2.6 Hz and 6.8 Hz, CHe), 1.63e1.57 (m, 2H, CH2e),
1.43e1.39 (m, H, CHe), 1.31 (tt, H, J¼2.6 Hz and 11.1 Hz, CHe), 1.08
(d, 3H, J¼3.4 Hz, CH3), 1.07 (d, 3H, J¼3.4 Hz, CH3), 0.98 (dq, H,
J¼3.4 Hz and 9.4 Hz, CHe), 0.87 (q, H, J¼11.1 Hz, CHe), 0.83 (d, 3H,
J¼3.4 Hz, CH3), 0.81 (d, 3H, J¼3.4 Hz, CH3), 0.75 (m, H, CHe), 0.68 (d,
3H, J¼6.8 Hz, CH3).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.04.073.
References and notes
2-CH(CH3)2-5-CH3C6H9OC(O)CH(CH3)2, GC/MS (m/z; EI): 226
(Mþ), 139 (MþeC4H7O2), 124 (MþeC5H10O2), 96 (MþꢂjꢂC7H14O2),
81 (MþeC8H17O2), 71 (C4H7Oþ), 43 (C3Hþ7 ).
1. Baker, R. T.; Thomas, W. Science 1999, 284, 1477e1479.
2. (a) Bergbreiter, D. E.; Sung, S. D. Adv. Synth. Catal. 2006, 348, 1352e1366; (b)
Baker, D. E.; Osburn, P. L..; Wilson, A. and Sink, E. M.. J. Am. Chem. Soc. 2000,
9058e9064.
4.7.7. (g)32 Ester 7 (cyclododecyl acetate): colorless liquid. 1H NMR
3. (a) Asymmetric Heterogeneous Catalysis; Ding, K., Uozomi, Y., Eds.; Wiley-VCH:
Weinheim, 2008; (b) Recoverable and Recyclable Catalysts; Benaglia, M., Ed.;
(500 MHz, CDCl3)
d 5.02 (m, H, OCHe), 2.04 (s, 3H, CH3), 1.72 (hex,
ꢁ
ꢁ
John Wiley and Sons Ltd: 2009; (c) Marques-Lopez, E.; Herrera, R. P.; Christ-
mann, M. Nat. Prod. Rep. 2010, 1138e1167; (d) Ishihara, K.; Ohara, S.; Yamamoto,
H. Science 2000, 290, 1140e1142.
2H, J¼6.8 Hz, CH2e), 1.52e1.29 (m, 20H, CH2e).
C
12H23OC(O)CH3, GC/MS (m/z; EI): 226 (Mþ), 167 (MþeC2H3O2),
43 (C2H3Oþ).
4. (a) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk. SSSR 1967, 176, 97e100;
(b) Scriven, E. F. V.. Chem. Soc. Rev.. 1983, 129e161; (c) Vedejs, E.; Diver, S. T. J.
Am. Chem. Soc. 1993, 115, 3358e3359.
5. Bonduelle, C.; Martín-Vaca, B.; Cossío, F. P.; Bourissou, D. Chem.dEur. J. 2008, 14,
5304e5312.
4.7.8. (h)33 Ester 8 (cyclododecyl isobutyrate): colorless liquid. 1H
NMR (500 MHz, CDCl3)
d
5.01 (m, H, OCHe), 2.51 (sept, H, J¼6.8 Hz,

3476
N. Lu et al. / Tetrahedron 72 (2016) 3468e3476
6. Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99e102.
7. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989e1993.
8. Hcfle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17,
569e583.
21. Lu, N.; Chang, W.-H.; Tu, W.-H.; Li, C.-K. Chem. Comm. 2011, 7227e7229.
22. Wang, Z.-L.; Li, M.-X.; Wei, L.-H.; Wang, J.-P. Acta Crystallogr. E 2006, 62,
o2274eo2275.
23. Sudhakar, P.; Kumar, S. V.; Vishweshwar, P.; Babu, J. M.; Vyas, K. CrystEngComm
2008, 10, 996e1002.
€
9. With DMAP Citrate, the dermal toxicity is reduced to such an extent that it
(12 g/100 mL) only produces local irritation: also see Ref. 8.
10. Price, K. E.; Mason, B. P.; Bogdan, A. R.; Broadwater, S. J.; Steinbacher, J. L.;
McQuade, D. T. J. Am. Chem. Soc. 2006, 128, 10376e10377.
11. (a) Bergbreiter, D. E.; Tian, J.; Hongfa, C. Chem. Rev. 2009, 109, 530e582;
(b) Rubinsztajn, S.; Zeldin, M.; Fife, W. K. Macromolecules 1991, 24,
2682e2688.
24. Wang, Z.-L.; Li, M.-X.; Wei, L.-H.; Wang, J.-P. Acta Crystallogr. E 2006, 62,
o2171e2172.
25. (a) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc. Perkin Trans. 2
2001, 651e699; (b) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem.,
Int. Ed. 2003, 42, 1210e1250.
26. (a) Sakakura, A.; Kawajiri, K.; Ohkubo, T.; Kosugi, Y.; Ishihara, K. J. Am. Chem.
Soc. 2007, 129, 14775e14779; (b) Sammakia, T.; Hurley, T. B. J. Org. Chem. 1999,
64, 4652e4664.
27. Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.dEur. J. 2005,
11, 4751e4757.
28. Fischer, C. B.; Xu, S.; Zipse, H. Chem.dEur. J. 2006, 12, 5779e5784.
29. Bosco, J. W. J.; Saikia, A. K. Chem. Commun. 2004, 1116e1117.
30. Klomp, D.; Djanashvili, K.; Cianfanelli Svennum, N.; Chantapariyavat, N.; Wong,
C.-S.; Vilela, F.; Maschmeyer, T.; Peters, J. A.; Hanefeld, U. Org. Biomol. Chem.
2005, 3, 483e489.
12. Chen, H.-T.; Huh, S.; Wiench, J. W.; Pruski, M.; Lin, V. S.-Y. J. Am. Chen. Soc. 2005,
127, 13305e13311.
ꢁ
ꢁ
13. Dalaigh, C. O.; Corr, S. A.; Gun’ko, Y.; Connon, S. J. Angew. Chem., Int. Ed. 2007, 46,
4329e4332.
14. Gleeson, O.; Tekoriute, R.; Gun’ko, Y. K.; Connon, S. J. Chem.dEur. J. 2009, 15,
5669e5673.
15. Vuluga, D.; Legros, J.; Crosse, B.; Bonnet-Delpon, D. Chem.dEur. J. 2010, 16,
1776e1779.
16. Zhang, W. Chem. Rev. 2009, 109, 749e795.
31. Takahashi, K.; Shibagaki, M.; Matsushita, H. Bull. Chem. Soc. Jpn. 1989, 62,
2353e2361.
17. Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc. 2001, 123, 11490e11491.
18. Dinh, L. V.; Gladysz, J. A. Angew. Chem., Int. Ed. 2005, 44, 4095e4097.
19. Lu, N.; Tu, W. H.; Shing, J. S.; Wen, Y. S.; Liu, L. K. J. Mol. Struct. 2010, 980,
101e107.
32. Bosco, J. W. J.; Raju, B. R.; Saikia, A. K. Synth. Commun. 2004, 34, 2849e2855.
ꢁ
ꢁ
33. Aubert, C.; Begue, J. P.; Biellmann, J. F. Tetrahedron 1986, 42, 5581e5590.
34. Chakraborti, A. K.; Shivani, J. J. Org. Chem. 2006, 71, 5785e5788.
20. Banerjee, R.; Saha, B. K.; Desiraju, G. R. CrystEngComm 2006, 8, 680e685.