A simple procedure for the esterification of alcohols with sodium carboxylate salts using 1-tosylimidazole (TsIm)

Article abstract of DOI:10.1016/j.tetlet.2007.12.068

An efficient and selective method for esterification of alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, alcohols are refluxed with a mixture of RCO₂Na (R: alkyl and aryl), TsIm, and triethylamine in the presence of catalytic amounts of tetra-n-butylammonium iodide (TBAI) in DMF to afford the corresponding esters in good yields. This methodology is highly efficient for various structurally diverse alcohols with selectivity for ROH: 1° > 2° > 3°.

Full text of DOI:10.1016/j.tetlet.2007.12.068

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1115–1120
A simple procedure for the esterification of alcohols with
sodium carboxylate salts using 1-tosylimidazole (TsIm)
a,
b
b
*
Mohammad Navid Soltani Rad , Somayeh Behrouz , Mohammad Ali Faghihi ,
Ali Khalafi-Nezhad a
a Department of Chemistry, Faculty of Basic Sciences, Shiraz University of Technology, Shiraz 71555-313, Iran
b Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Received 7 November 2007; revised 5 December 2007; accepted 12 December 2007
Abstract
An efficient and selective method for esterification of alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this
method, alcohols are refluxed with a mixture of RCO2Na (R: alkyl and aryl), TsIm, and triethylamine in the presence of catalytic
amounts of tetra-n-butylammonium iodide (TBAI) in DMF to afford the corresponding esters in good yields. This methodology is highly
efficient for various structurally diverse alcohols with selectivity for ROH: 1° > 2° > 3°.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Esterification; Alcohol; Carboxylic salts; Triethylamine (TEA); N-(p-Toluenesulfonyl)imidazole (TsIm); Tetrabutylammonium iodide (TBAI)
Esterification is an important reaction due to the wide
utility of esters in organic and bioorganic synthesis.1 Esteri-
fication is extensively employed for the protection and
further manipulation of the carboxylic acid functional
group as well as the synthesis of natural products. There
are numerous general methods for accessing carboxylic
esters.1,2 Among these, the direct esterification reaction of
carboxylic acids with alcohols in the presence of a large
number of different reagents and various conditions was
established.1,2 Moreover, the esterification of carboxylic
acids or their salts with carbon electrophiles such as alkyl
halides,3 sulfonates,3b,4 epoxides,5 aziridines,6 diazo com-
pounds,7 quaternary ammonium salts,8 oxonium ions,9
acetals,10 trialkyl phosphates,11 trialkyl phosphites,12 methyl-
trialkoxy phosphonium tetrafluoborate salts,13 t-butyl
ethers,14 ditosylamines,15 strained cycloalkanes,16 and mul-
tiple bonds17 is a well-known procedure. The reaction of
carboxylic salts with carbon electrophiles is usually pre-
ferred because of easier handling, higher nucleophilicity,
simpler work-up, and cleaner reaction in comparison with
carboxylic acids. In view of the wide diversity of alcohols
with respect to alkyl halides, the reaction of carboxylic salts
with alcohols would seem to be a suitable and attractive
strategy, and indeed there are a few reports that have exem-
plified the esterification of alcohols via carboxylic salts
including Mitsunobu conditions18 using sodium19 or zinc20
carboxylate/Ph3P/diethyl azodicarboxylate (DEAD) or
diisopropyl azodicarboxylate (DIAD) and potassium car-
boxylate/Ph3P/CCl4.21 The aforementioned methods have
several drawbacks such as non-generality for various types
of alcohols and carboxylic acids, the use of expensive
DEAD or DIAD, low yields, long reaction times, tedious
work-up as well as cumbersome separation from the gener-
ated Ph3P@O, and unreacted Ph3P. Hence, there is still a
need to develop practical and convenient methods for the
esterification of alcohols with carboxylate salts. Recently,
we reported 1-tosylimidazole (TsIm) as a highly efficient,
cheap and stable reagent for the one-pot conversion of
alcohols to alkyl azides22a and nitriles.22b In continuation
of our interest in the application of TsIm in organic
*
Corresponding author. Tel.: +98 711 7261392; fax: +98 711 7354523.
E-mail addresses: soltani@sutech.ac.ir, nsoltanirad@gmail.com (M. N.
Soltani Rad).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.068

1116
M. N. Soltani Rad et al. / Tetrahedron Letters 49 (2008) 1115–1120
Table 2
synthesis, herein, we report that 1°, 2°, and 3° alcohols can
be converted efficiently into their corresponding esters
using TsIm/RCO2Na in the presence of triethylamine
(TEA) and catalytic amounts of TBAI in DMF (Scheme 1).
The first step of this synthetic approach involved optimi-
zation of the reaction conditions. Initially, the effect of var-
ious solvents on the model reaction of 2-phenylethanol,
excess sodium benzoate (2.0 equiv) and freshly prepared
TsIm22a (1.2 equiv) in the presence of a catalytic amount
of TBAI was studied. The results are depicted in Table 1.
As the data in Table 1 indicates, DMF (entry 2) was the
most efficient solvent. Using anhydrous DMF, DMSO, and
HMPA (Table 1, entries 1, 3, and 6) afforded moderate
yields of the corresponding ester. The choice of the base
for activation of the alcohols for reaction with TsIm had
a great significance. In this case, we evaluated the potency
of several organic and inorganic bases on the model reac-
tion (Table 2). As the results in Table 2 indicate, TEA
(Table 2, entry 7) proved to be the most efficient base for
activation of 2-phenylethanol. Other bases afforded lower
yields of phenethyl benzoate.
We also studied the role of tetra-n-butylammonium salts
as phase transfer catalysts (PTC) on the model reaction
(Table 3). In the absence of PTC the reaction occurred
but only in moderate yield. However, using TBAI short-
ened the reaction time and an improved yield was obtained.
The use of an equimolar mixture of TBAI and TBAB
(Table 3, entry 7) gave no improvement in reaction. Other
PTCs (Table 3, entries 2–4 and 6) were not as effective as
TBAI (Table 3, entry 5). To determine whether iodide in
TBAI was responsible for catalysis of the reaction, we
Effect of various bases on the conversion of 2-phenylethanol into
phenethyl benzoate
Entry
Base
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
a
DBU
7
8
8
6
6
8
3
8
8
55
40
31
47
50
47
94
15
20
DABCO
DMAP
MgO
Cs2CO3
K2CO3
TEA
NaH
Al2O3
a
Basic alumina.
Isolated yield.
b
Table 3
Effect of various PTCs on the conversion of 2-phenylethanol into
phenethyl benzoate
Entry
PTC
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
a
None
TBAF
TBAC
TBAB
TBAI
(n-Bu)4NHSO4
TBAI/TBABc
7
9
9
6
3
9
7
40
47
52
60
94
43
70
a
Two equivalents of TEA were used.
Isolated yield.
(1:1) ratio.
b
c
examined other iodide sources including LiI, NaI, and KI
for the conversion of 2-phenylethanol into phenethyl ben-
zoate. Lower yields of 49%, 51%, and 60% were obtained.
The optimized amount of TsIm was found to be 1.2–
2.0 equiv per equivalent of alcohol. We also investigated
other TsIm analogues (Table 4).
As the data in Table 4 indicate, using TsIm (Table 4,
entry 3) increased the reaction rate and yield in comparison
with other sulfonyl analogues. Replacing the tolyl group in
TsIm with methyl, trifluoromethyl, and phenyl did not
afford satisfactory results (Table 4, entries 1, 2, and 4). Fur-
thermore, other azole analogues of TsIm were not as effec-
tive as imidazole (Table 4, entries 5 and 6). N-Tosyl
phthalimide (Table 4, entry 7) was inactive for the conver-
sion even after refluxing for 48 h.
Various sulfonyl chlorides were also examined instead of
TsIm (Table 5) but lower yields of esters were observed.
Using carboxylic acids instead of their sodium salts
afforded lower yields of the corresponding esters (Scheme
1).23 The generality and versatility of this method was dem-
onstrated by its application to a wide range of structurally
diverse alcohols and sodium carboxylate salts (Table 6). As
the results in Table 6 indicate, this method is suitable
for primary, secondary, and tertiary alcohols. Moreover,
this method is applicable for aromatic, N-protected
amino acids, and aliphatic sodium carboxylate salts. The
TsIm/TBAI/TEA
RCO2Na R' OH
+
RCO2R'
DMF, reflux, 3-7 h
R= alkyl and aryl
'
R= 1°, 2°and 3
°
alkyl
O
N
H
C
S
N
TsIm:
3
O
Scheme 1.
Table 1
Effect of various solvents on the conversion of 2-phenylethanol into
phenethyl benzoate
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
a
DMFa
DMF
DMSO
THF
MeCN
HMPA
Toluene
Acetone/H2Od
H2O
6
3
6
48
12
6
48
18
48
55
94
48
NRc
10
50
NR
Trace
NR
Anhydrous DMF.
b
c
Isolated yield.
No reaction.
(1:1) ratio.
d

M. N. Soltani Rad et al. / Tetrahedron Letters 49 (2008) 1115–1120
1117
Table 4
Table 6
Comparison of TsIm reactivity with analogues on the conversion of
2-phenylethanol into phenethyl benzoate
Esterification of alcohols with sodium carboxylates using TsIm/TBAI/
TEA in refluxing DMF
Entry
Reagent
Time (h)
Yielda (%)
EntryRef.
Estera
Time
(h)
Yieldb
(%)
O
N
O
O
O
1
7
54
Me
S
N
13b,26,27
3
4
4
3
4
92
70
O
O
O
O
O
N
2
3
4
5
6
7
3
58
94
64
54
58
F3C
S
N
O
227b
O
N
S
N
O
33a,28
43b,29
529
51
O
S
N
7
N
O
O
O
O
S
N
94
N
10
10
O
O
O
NO2
O
S
N
N
65c
N
O
O
O
S
O
7
48
NRb
N
O
O
O
O
6
7
4
4
88
91
N
N
O
O
O
O
O
a
Isolated yield.
No reaction.
NO2
b
N
CH3
Table 5
Effect of various sulfonyl chlorides on the conversion of 2-phenylethanol
into phenethyl benzoate
8
9
5
7
64
68
Entry
Sulfonyl chloride
Time (h)
Yielda (%)
O
1
8
42
Me
S
Cl
N
O
N
O
O
2
3
8
8
8
48
50
37
F3C
S
Cl
O
O
( )
O
S
3
Cl
O
1018a
7
43
O
O
O
S
O
O
4
Cl
O
a
N
Isolated yield.
N
Cl
11
7
3
65
92
O
generality of the method was confirmed with respect to
allylic (Table 6, entries 15 and 22), propargylic (Table 6,
entry 16), benzylic (Table 6, entries 5, 9, 19, and 21),
aliphatic (Table 6, entries 1–3, 12–14, and 23), alicyclic
(Table 6, entries 8, 10, and 17) and other alcohols contain-
ing N-heterocycles (Table 6, entries 6, 7, 9, and 11).
O
1228a
O
(continued on next page)
Cl

1118
M. N. Soltani Rad et al. / Tetrahedron Letters 49 (2008) 1115–1120
Table 6 (continued)
Furthermore, the benzoylation of cholesterol was possible
using this method (Table 6, entry 10).
EntryRef.
Estera
Time
(h)
Yieldb
(%)
The selectivity of this method was demonstrated via a
competitive reaction of a mixture consisting of 2-phenyl-
ethanol/1-phenylethanol/PhCO2Na/TsIm in the molar
ratio of (1:1:0.5:0.5) under the optimized conditions. The
results in Table 7 demonstrate the selectivity between pri-
mary and secondary alcohols. There was high selectivity
for esterification of the primary alcohol rather than the sec-
ondary analog. The same result was observed when a mix-
ture of 1-octanol and 2-octanol was investigated (Table 7).
Mechanistically, it is assumed that esterification of the
alcohol was achieved by a similar mechanism to that previ-
ously described for one-pot azidation22a and cyanidation22b
of alcohols using TsIm.
Thus, the alcohol is first converted into an alkyl tosylate
and subsequently via an SN2 type reaction, the nucleophile
(azide or cyanide) reacts with the alkyl tosylate to afford
the product. However, there are several facts that confirm
that the TsIm-mediated esterification reaction of the alco-
hol is not achieved merely via an SN2 type reaction: (a) Full
analysis of the reaction mixture revealed the presence of
mixed anhydrides of carboxylic and sulfonic acids24 besides
alkyl tosylate (from the reaction of alcohol and TsIm). (b)
Using our method for the conversion of optically pure
R-(+)-1-phenylethanol into its corresponding ester (Table
6, entry 5) was accompanied by a reduction in optical purity
(52% ee). This can be explained as a result of partial inver-
sion resulting from an SN2 type reaction of the carboxylate
anion and the alkyl tosylate and retention of configuration
from the reaction of mixed anhydrides and the alcohol at
the same time. (c) Using quantum mechanical calculations
including ab initio,25 6-31G or semi-empirical25 Austin
Model 1 (AM1) and Parameterized Model 3 (PM3)
endorse the formation of mixed anhydrides in comparison
with alkyl tosylates. Furthermore, frontier molecular orbi-
tal (FMO) theory25 calculations have indicated better inter-
action of the carboxylate anion HOMO with the LUMO of
Br
O
O
13
4
4
84
88
O
O
O
Br
14
O
O
1530a
3
4
92
90
Br
O
1630a
O2N
O
O
O
173b,30b
5
4
63
87
O
O
O2N
1831a
MeO
O
1931b
3
91
O
N
O
2031c
5
4
81
84
O
O
213c–e,21
O
O
O
22
5
5
80
61
O
Table 7
Competitive esterification of primary/secondary ROH with PhCO2Na
using TsIm
2332
O
Entry Alcohol mixture Ester
Time (h) Yielda (%)
O
Boc
N
O
2433
6
7
86
82
Ph
1
3
96
O
OH
Ph
O
O
Ph
O
Boc
O
4
HN
Ph
OH
Ph
O
Ph
O
2534
C6H13
2
4
97
OH
C6H13
O
O
Ph
a
1
All products were characterized by H and 13C NMR, IR, CHN, and
MS analysis.
3
b
Isolated yield.
Also obtained from optically pure R-(+)-1-phenylethanol, ½aꢀD +45 (c
C6H13 OH
C6H13
O
Ph
20
c
a
5, in MeOH) in 52% ee.
Isolated yield.

M. N. Soltani Rad et al. / Tetrahedron Letters 49 (2008) 1115–1120
1119
10. (a) Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1963, 2, 211–212; (b)
¨
TsIm in comparison with interaction of the alcohol conju-
gate base HOMO and the LUMO of TsIm.
Brechbuhler, H.; Buchi, H.; Hatz, E.; Schreiber, J.; Eschenmoser, A.
¨
¨
Angew. Chem., Int. Ed. Engl. 1963, 2, 212–213.
In conclusion, a convenient, efficient, and selective
method has been established for the esterification of alco-
hols using TsIm/RCO2Na/TEA/TBAI (cat.) in refluxing
DMF. This method has favorable generality and applica-
bility for various structurally diverse alcohols including pri-
mary, secondary, and tertiary alcohols with selectivity:
1° > 2° > 3°.
11. Harris, M. M.; Patel, P. K. Chem. Ind. 1973, 20, 1002.
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6784.
General procedure for esterification of alcohols with
sodium carboxylate using TsIm: To a double-necked round
bottom flask (100 mL) equipped with a condenser was
added
a
mixture of alcohol (0.01 mol), TsIm22a
(0.012 mol), TEA (0.015 mol), RCO2Na (0.02 mol) and a
catalytic amount of TBAI (0.1 g) in DMF (30 mL). The
mixture was refluxed, and in most cases, darkening
occurred. Reflux was continued until TLC monitoring indi-
cated no further improvement in the conversion (Table 6).
The solvent was evaporated under vacuum and the remain-
ing foam was dissolved in CHCl3 (100 mL) and subse-
quently washed with water (2 ꢁ 100 mL). The organic
layer was dried (Na2SO4) and evaporated. The crude prod-
uct was purified by column chromatography on silica gel
eluting with a mixture of n-hexane/EtOAc.35
23. Similar reaction conditions were employed for carboxylic acid except
that 3 equiv of TEA were employed.
24. Mazur, Y.; Karger, M. H. J. Org. Chem. 1971, 36, 528–531.
25. The ab initio (6-31G) quantum mechanic calculations were run using
GAUSSIAN 98 version 9.2 software. The semi-empirical Austin Model 1
(AM1) and Parameterized Model 3 (PM3) calculations were run on
MOPAC in CS Chem 3D Ultra 8(2004 Cambridge Soft) and
Hyperchem (Hypercube Inc., version 7). HOMO and LUMO were
indicated by Hyperchem (Hypercube Inc., version 7) software.
26. (a) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915–5925; (b) Ishihara,
K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127, 4168–
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Acknowledgments
We wish to thank the Shiraz University of Technology
and Shiraz University Research Councils for partial sup-
port of this work. We are also grateful to Ms. L. Mehboudi
for her assistance.
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3056; (b) Wakasugi, K.; Nakamura, A.; Tanabe, Y. Tetrahedron Lett.
2001, 42, 7427–7430.
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35. Selected data (Table 6, entries 7, 9 and 11). Benzoic acid 2-(2-methyl-
4-nitroimidazol-1-yl)ethyl ester (Table 6, entry 7): pale yellow crystals;
Rf (EtOAc/n-hexane) (2:1) 0.29; mp 137.4 °C; 1H NMR (CDCl3,
250 MHz): dppm 2.38 (s, 3H, Me), 4.26 (t, 2H, J = 5.3 Hz, NCH2),
4.53 (t, 2H, J = 5.3 Hz, OCH2), 7.32–7.47 (m, 3H, aryl); 7.76 (s, 1H,
C(5)–H, imidazole), 7.83–7.86 (m, 2H, aryl); 13C NMR (CDCl3,
62.5 MHz): dppm 13.08, 46.02, 62.69, 120.06, 128.66, 128.77, 129.50,
133.70, 145.14, 149.63, 165.87; IR (KBr) m cmꢂ1: 1710.9 (C@O); MS
(EI) [m/z (%)]: 275.09 (33.8); Anal. Calcd for C13H13N3O4: C, 56.72;
H, 4.76; N, 15.27. Found: C, 56.77; H, 4.80; N, 15.20. Benzoic acid
2-(benzimidazol-1-yl)-1-phenylethyl ester (Table 6, entry 9): bright
9. Raber, D. J.; Gariano, P.; Brod, A. O., Jr.; Gariano, A.; Guida, W.
C.; Guida, A. R.; Herbst, M. D. J. Org. Chem. 1979, 44, 1149–
1154.

1120
M. N. Soltani Rad et al. / Tetrahedron Letters 49 (2008) 1115–1120
yellow oil; Rf (EtOAc/n-hexane) (5:1) 0.56; 1H NMR (CDCl3,
ester (Table 6, entry 11): bright brown oil; Rf (EtOAc/n-hexane) (5:1)
0.36; 1H NMR (CDCl3, 250 MHz): dppm 3.71 (d, 2H, J = 4.7 Hz,
NCH2), 4.07 (d, 2H, J = 4.7 Hz, PhOCH2), 5.23 (m, 1H, OCH), 6.54–
6.95 (complex, 10H, C(4), C(5)–H imidazole, aryl), 7.32–7.35 (m, 1H,
aryl), 7.41 (s, 1H, C(2)–H imidazole); 13C NMR (CDCl3, 62.5 MHz):
dppm 46.72, 65.33, 71.49, 114.48, 120.09, 121.52, 126.78, 127.93,
129.10, 130.01, 130.40, 131.16, 131.30, 133.37, 137.65, 157.77, 164.30;
IR (liquid film) m cmꢂ1: 1726.2(C@O); MS (EI) [m/z (%)]: 356.09
(48.5); Anal. Calcd for C19H17ClN2O3: C, 63.96; H, 4.80; Cl, 9.94; N,
7.85. Found: C, 63.90; H, 4.83; Cl, 9.89; N, 7.88.
250 MHz): dppm 4.08 (dd, 1H, J = 4.5, 15.0 Hz, NCHaHb), 4.17 (dd,
1H, J = 6.3, 15.0 Hz, NCHaHb), 5.95 (t, 1H, J = 4.9 Hz, OCH), 6.82–
7.00 (complex, 12H, aryl), 7.37 (s, 1H, C(2)–H benzimidazole), 7.47–
7.59 (m, 2H, aryl); 13C NMR (CDCl3, 62.5 MHz): dppm 49.28, 74.25,
109.91, 119.99, 122.13, 122.93, 126.00, 128.17, 128.37, 128.68, 129.12,
129.49, 133.30, 133.91, 136.72, 143.18, 143.52, 165.04; IR (liquid film)
m cmꢂ1: 1720.4 (C@O); MS (EI) [m/z (%)]: 342.14 (36.4); Anal. Calcd
for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.21; H, 5.32;
N, 8.15. 2-Chlorobenzoic acid 2-(imidazol-1-yl)-1-phenoxymethylethyl