Oxidative esterification of primary alcohols with TEMPO/CaCl2/Oxone under hydrous conditions

Article abstract of DOI:10.1016/j.tetlet.2016.05.066

Symmetric esters are important compounds in the chemical industry, which creates demand for simple and efficient synthetic routes. Oxidative esterification is a promising method to achieve these aims. Here, we show that TEMPO/CaCl₂/Oxone forms a convenient catalytic system for the synthesis of the aforementioned symmetric esters from primary alcohols in a biphasic dichloromethane-water solvent mixture. The substrate scope of the reaction method is complementary to those previously published and the terminal oxidant appears to play an important role. In addition, the method is shown to oxidize thiols preferentially over alcohol functional groups to give disulfide-bridged compounds.

Full text of DOI:10.1016/j.tetlet.2016.05.066

Accepted Manuscript
Oxidative esterification of primary alcohols with TEMPO/CaCl /Oxone under
2
hydrous conditions
Sven Hackbusch, Andreas H. Franz
PII:
S0040-4039(16)30600-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.066
TETL 47685
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 April 2016
16 May 2016
17 May 2016
Please cite this article as: Hackbusch, S., Franz, A.H., Oxidative esterification of primary alcohols with TEMPO/
CaCl /Oxone under hydrous conditions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
2
016.05.066
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1
Tetrahedron Letters
Oxidative esterification of primary alcohols with TEMPO/CaCl /Oxone under
2
hydrous conditions
a
a,
Sven Hackbusch and Andreas H. Franz 
a
Department of Chemistry, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Symmetric esters are important compounds in the chemical industry, which creates demand for
simple and efficient synthetic routes. Oxidative esterification is a promising method to achieve
Received in revised form
Accepted
Available online
2
these aims. Here, we show that TEMPO/CaCl /Oxone form a convenient catalytic system for the
synthesis of the aforementioned symmetric esters from primary alcohols in a biphasic
dichloromethane-water solvent mixture. The substrate scope of the reaction method is
complementary to those previously published and the terminal oxidant appears to play an
important role. In addition, the method is shown to oxidize thiols preferentially over alcohol
functional groups to give disulfide-bridged compounds.
Keywords:
TEMPO
metal-free oxidation
oxidative esterification
symmetrical esters
2
009 Elsevier Ltd. All rights reserved.
a 94% yield, however intermolecular ester formation was not
reported. This finding encouraged us to adapt the method to form
symmetrical esters from primary alcohols.
1
. Introduction
Symmetric esters have found broad application in the
chemical industry, from flavor and fragrance industries to
pharmaceutical and cosmetic preparations. Oxidative
esterification has been reported as a convenient pathway to both
2
. Results and Discussion
To our surprise, replication of literature procedures with
1-5
symmetric esters, as well as asymmetric esters. Both metal-
benzyl alcohol in anhydrous solvents failed and showed no
consumption of starting material after 1h by GC/MS.
Conversely, however, the addition of a small amount of water
lead to complete disappearance of the alcohol and formation of
benzaldehyde, as observed by GC/MS after stirring at rt
overnight.
13
containing as well as metal-free reagents and catalysts have been
1,6-9
developed for this type of reaction.
The use of primary
alcohols as starting material is potentially the most efficient way
to form symmetrical esters, omitting the necessity for aldehyde or
carboxylic acid intermediates. The mechanism of the reaction can
be presented as a three step-two oxidation process (see Figure 1).
The alcohol is first oxidized to the corresponding aldehyde,
forms a hemiacetal with another alcohol and the hemiacetal is
This observation proved repeatable in the case of 1-hexanol,
with 0% conversion of the alcohol in the absence of water even
after 24 h. (Table 1, Entry 1). However, in the presence of water
the alcohol was converted into hexanal and hexylhexanoate.
Subsequently, we screened a number of reaction conditions to
optimize the method for the oxidative esterification of 1-hexanol
5
,8,10,11
finally oxidized to the symmetric ester.
derivatives, such as 2,2,6,6-tetramethyl-1-piperidinyloxy
TEMPO) and other stable derivatives have found use in this
ester-forming methodology due to the generally mild conditions
Nitroxyl radical
(
3
,5,10,12
employed.
However, drawbacks exist in the published
(Table 1). In all reactions, aldehyde was found as a side product,
methods, such as the requirement of anhydrous conditions in one
with little to no amounts of hexanoic acid. These observations are
in agreement with the stepwise mechanism of the oxidative
esterification, as suggested by others (see Figure 1).
5,10
case and the use of stoichiometric amounts in another. More
recently, a TEMPO-catalyzed oxidation using Oxone® and
calcium chloride giving aromatic aldehydes from a variety of
5,8,10,11
13
benzylic alcohols was reported. Interestingly, the same reaction
conditions also produced γ-butyrolactone from 1,5-pentadiol with
—
——

Corresponding author. Tel.: +1-209-946-2189; fax: +1-209-946-2607; e-mail: afranz@pacific.edu

2
Tetrahedron
Table 1. Optimization of reaction conditions for the oxidative esterification of 1-hexanol.
a
Product ratio
Oxone®
a
Entry
H
2
O (mL)
CaCl
2
·2H
2
O (mmol)
t/h
Conv./%
GC Yield
(mmol)
2
a
3a
-
side products
1
2
3
4
5
6
7
8
9
0.0
1.0
0.5
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.5
1.5
2.0
2.0
1.5
1.5
1.1
1.3
24
2.5
2.5
2.5
2.5
2.5
5
0
44
65
82
80
87
>99
90
>97
96
35
91
97
62
82
-
-
0
0
90
91
89
86
89
83
88
78
77
31
88
88
<10
9
10
9
39
59
73
69
77
82
79
77
74
11
80
85
<6
7
b
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
1.5
0.5
0.5
0.5
0
11
14
11
14
12
10
23
4
0
0
0
3
2.5
5
0
12
0
1
1
1
1
1
1
0
1
2
3
4
5
5
5
65
0
c
5
12
12
6
4
5
4
0
d
e
1.5
>84
39
d
f
0.5
1.3
52
a
b
c
determined by GC/MS; a control reaction with anhydrous CaCl
2
gave the same result; no increase in conversion detected after 6h; mCPBA instead of
e
f
2 2
Oxone®; overlap with 3-chlorobenzoic acid; TBAB instead of CaCl ·2H O
Initially, we screened the amount of water needed for the
reaction to proceeded optimally and found that a 1:20 ratio of
water to dichloromethane gave the best combination of
conversion and selectivity after 2.5 h (Entries 2-5). The water
appeared to associate with Oxone® primarily and resulted in no
apparent phase separation in dichloromethane. Next, we varied
the amount of the terminal oxidant Oxone® and found that
higher amounts gave faster conversion of the starting material
When reducing the amount of chloride in the reaction, we
observed decreased selectivity for ester formation (Entry 10),
while higher than 0.5 equivalents of CaCl · 2 H O decreased
2 2
conversion and lead to chlorinated side products (Entry 11). This
can likely be attributed to a higher concentration of hypochlorite
13
in the mixture, which is an intermediate in the catalytic cycle.
In fine-tuning the amount of Oxone® used in the reaction, 1.1
equivalents of Oxone® were found to give incomplete
conversion of the alcohol, even after 6 h (entry 12). Meanwhile,
1.3 equivalents of Oxone® were found to give near complete
conversion after 4 h with near optimal selectivity, leading to an
overall GC/MS yield of 85 % for the reaction (Entry 13).
(Entries 5-9), but that this was accompanied by a decrease in
selectivity when the reactions were allowed to proceed for longer
times (Entries 7, 9). The decrease in selectivity could be
attributed to the formation of ester byproducts. We later found
that the formation of these side products could be suppressed
partially by setting up the reactions in the dark, which indicated
that the side product formation may occur in a radical-type
fashion (data shown in Supplementary Material).
Interestingly, when replacing Oxone® with mCPBA, a drastic
increase in carboxylic acid yield was observed at the expense of
hexanoate ester (Entry 14). Likewise, the use of tetra-n-butyl
ammonium bromide (TBAB) lowered the selectivity for ester-
formation and overoxidation to hexanoic acid was detected
(Entry 15). Taken together, this clearly illustrates the importance
of the appropriate choice of oxidant and halide donor to avoid
overoxidation of the aldehyde intermediate prior to formation of
the hemiacetal intermediate (compare Figure 1, side reaction I).
A variety of different solvents was also screened, however only
acetonitrile and chloroform gave similar but inferior yield
compared to dichloromethane, as observed by GC/MS (data
included in SI).
Next, we examined the substrate scope of the reaction (see
1
4
Figure 1. Accepted mechanism for the oxidative esterification of
Table 2). Using the optimized reaction conditions, the isolated
primary alcohols using TEMPO/CaCl
reactions I and II.
2
/Oxone® and potential side
yield for hexyl hexanoate 2a was improved over that previously
5,8,10,11
estimated by GC/MS
(Table 2, Entry 1). Other aliphatic
alcohols, including those with branched and ring-structures,

3
could be converted quickly and in moderate to good yields
Entries 2-5, 10). However, alcohols containing β-oxygen
c
1
1
1
2
k
l
24 h
24 h
NR
(
substitution failed to give good yields, as only traces of the
desired ester products 2f and 2h could be detected, while 2g was
isolated in low yield. In all three cases, the reactions did not give
full conversion after 24 h. As exemplified in Entry 7, using 2.0
equivalents of terminal oxidant, 2g could be isolated in 25%
yield at near full conversion of starting material, with the
aldehyde making up the majority of the product mixture.
Similarly, the β-ketone and β-ester containing alcohols 1k and 1l
did not give the desired esterification products. The low
reactivity for these compounds, which is in contrast to that found
by Abramovich et al. when using trichloroisocyanuronic acid as
the terminal oxidant under anhydrous conditions and pyridine as
a base additive, could be a result of the presence of water, which
might inhibit the hemiacetal formation (compare Figure 1, side
a
traces
1
1
3
4
m
n
o
24 h
3 h
NRc
a
traces
e
15
16
24 h
24 h
0%
d
5
p
0%
reaction II). However, it bears mentioning that in none of the
above cases, overoxidation to the carboxylic acid (either directly
or from the hydrate) was observed in appreciable amounts.
Unlike in other methods, the addition of pyridine to the reaction
mixture did not lead to improved yields in a test reaction with 2g,
g
1
7
q
6 h
n.d.
5,10
as isolated yield was virtually unchanged.
a
b
Table 2. Exploration of substrate scope
detected by DART-HRMS; with 2.0 eq Oxone® to achieve full onsumption
c
e
f
of ROH; NR = no reaction; chlorohydrin addition to double-bond; 10 ml
DCM; lactone product inseparable from polymerization side products via
g
column chromatography
The oxidative esterification of alcohols containing either an
alkene (2o) or alkyne (2p) functional group was unsuccessful,
due to the formation of chlorohydrin-addition products across the
double bond and other unidentified side products, respectively.
The β-cyano containing alcohol 1m was also unreactive under the
given conditions, while only trace amounts of product could be
observed with 2-fluoroethanol (1n). Lastly, the reaction
conditions were applied to 1,5-pentanediol (1q) to form the
corresponding lactone through intramolecular esterification,
however the formation of significant amounts of polymerization
side products (as detected by DART-MS, see SI), which were
inseparable via column chromatography, could not be suppressed
even at higher (0.1 mmol/mL) dilutions.
Isolated
Yield
92%
Entry
Compound
R
t / h
1
a
4 h
2
3
4
b
c
4 h
72%
29%
27%
24 h
24 h
When the established method was used for the transformation
of benzyl 2,3,4-tri-O-benzyl-β-D-glucopyranose, less than 50%
conversion was observed after 24 h and the desired 6,6’-linked
ester was not observed. The degradation of the starting material
by oxidative cleavage of the benzyl group (at either the 2, 3 or 4-
position) was identified as the major side reaction, which has
d
5
6
e
f
2.5 h
24 h
89%
3
been previously observed in a similar reaction. In addition,
a
traces of benzyl 2,3-O-benzyl-4,6-O-benzylidene-β-D-gluco-
pyranoside, due to oxidative C-O bond formation, could be
isolated as well.
traces
b
To gain additional knowledge about the selectivity of the
established method, competition experiments were performed: In
a reaction of equimolar amounts of 1-octanol and 2-octanol under
the established reaction (2:1.3 combined ratio of alcohols to
Oxone®), little to no selectivity was observed for the
consumption of primary over secondary alcohol (58:42 ratio as
determined by GC/MS) and only trace amounts of the mixed 2-
octanyl octanoate were observed in 1:6 ratio to the more
prevalent 1-octanyl octanoate. This is likely a result of competing
rates of hemiacetal formation, which should be higher for the
primary alcohol. In the reaction of benzyl alcohol or
benzaldehyde with hexanol, no significant amount of cross-
esterification was observed in either case, with the main products
being benzaldehyde and hexyl hexanoate, respectively.
7
8
g
24 h
24 h
9% (25% )
a
h
traces
c
9
i
24 h
NR
1
0
j
4 h
93%

4
Tetrahedron
(
73.5 mg, 0.5 mmol) and TEMPO (1.6 mg, 0.01 mmol) in
dichloromethane (2 mL). The reaction was initiated by the
addition of 0.1 mL DI water. The reaction mixture was
stirred at RT for the indicated times or until TLC or
GC/MS showed consumption of the starting material and
then filtered. After evaporation of the solvent using a
rotavap, the crude reaction mixtures were separated via
column chromatography to yield the desired ester dimers.
Figure 2. Oxidation of β-mercaptoethanol using established reaction
conditions – product was not isolated.
Interestingly, the oxidation of 2-mercaptoethanol did not lead
to the symmetrical ester, but instead the disulfide-linked dimer
was detected by mass spectral techniques. As such, the oxidation
appears to be selective for thiols in the presence of alcohol
functional groups, due to their lower oxidation potential and this
might be useful in the formation of disulfide-bridged compounds.
Supplementary Material
Supplementary material containing experimental details, full
characterization as well as NMR + HRMS spectra of the isolated
compounds data, and other data mentioned above can be found
online at www.sciencedirect.com/science/journal/00404039.
In summary, we have established a convenient metal-free
oxidative esterification with TEMPO/CaCl /Oxone as the
2
oxidizer. The method gave satisfactory ester yields for a range of
primary alcohols. β-Substition was not well tolerated overall, as
substrates were either unreactive or required additional terminal
oxidant to lead to appreciable amounts of product formation.
However, the reaction does not require anhydrous conditions and
in fact water is required for the reaction to proceed. Additional
work to overcome the limitations of the presented method,
including the transformation of 6-unprotected monosaccharide
derivatives to 6,6’-linked ester disaccharides, by varying the
terminal oxidant and halide source is currently underway in our
laboratories.
Acknowledgments
Part of this work was presented in an oral presentation at the
st
2
51 ACS National Meeting & Exposition, San Diego, CA. The
authors thank Patrick Batoon and O. David Sparkman of the
Pacific Mass Spectrometry Facility.
References and notes
1
2
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Gaspa, S.; Porcheddu, A.; De Luca, L. Organic Letters
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General procedure for oxidative esterification of primary
alcohols: The respective alcohol (1.0 mmol) was added to
a suspension of Oxone® (400.0 mg, m., CaCl ∙ 2H O
2 2

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Oxidative esterification of primary alcohols with
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Oxidative esterification of primary alcohols with TEMPO/CaCl /Oxone
2
under hydrous conditions
a
a,
Sven Hackbusch and Andreas H. Franz 
a
Department of Chemistry, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA
HIGHLIGHTS



TEMPO/CaCl /Oxone as convenient catalytic system
2
Oxidative esterification of primary alcohols
Moderate to excellent yields under hydrous conditions

Corresponding author. Tel.: +1-209-946-2189; fax: +1-209-946-2607; e-mail: afranz@pacific.edu