Transition-Metal-Free Poly(thiazolium) Iodide/1,8-Diazabicyclo[5.4.0]undec-7-ene/Phenazine-Catalyzed Esterification of Aldehydes with Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b01617

Poly(3,4-dimethyl-5-vinylthiazolium) iodide was used as a polymer precatalyst in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and phenazine for the oxidative esterification of aldehydes with alcohols. Selective functionalization of OH groups was achieved in the presence of NH₂ groups. The poly(thiazolium) iodide/DBU/phenazine system exhibited excellent catalytic activity and could be reused five times without loss of activity.

Full text of DOI:10.1021/acs.orglett.7b01617

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Poly(thiazolium) Iodide/1,8-
Diazabicyclo[5.4.0]undec-7-ene/Phenazine-Catalyzed Esterification
of Aldehydes with Alcohols
Supill Chun and Young Keun Chung*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Korea
S
* Supporting Information
ABSTRACT: Poly(3,4-dimethyl-5-vinylthiazolium) iodide
was used as a polymer precatalyst in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and phenazine for the
oxidative esterification of aldehydes with alcohols. Selective
functionalization of OH groups was achieved in the presence
of NH2 groups. The poly(thiazolium) iodide/DBU/phenazine
system exhibited excellent catalytic activity and could be
reused five times without loss of activity.
Scheme 1. Examples of Reusable Organic Oxidants and
sters are ubiquitous motifs in natural products and
pharmaceuticals. They are also used as building blocks
NHC-Catalyzed Esterification Reactions6d,7f,h
E
and protecting groups in the synthesis of many biologically
active compounds.1 Thus, the synthesis of esters has garnered
considerable attention, and many useful methods have been
established.2 Among them, the direct transformation of
aldehydes with alcohols to esters (oxidative esterification) is
attractive in terms of atom economy.3 Extensive efforts have
been put forth to identify efficient and practical methods for
oxidative esterification, and several viable methods have been
reported.4 Air was used as a clean oxidant in some transition-
metal-catalyzed oxidative esterification reactions.5 Nevertheless,
many reported methods involve harsh reaction conditions, have
limited substrate scopes, and require transition-metal catalysts
that are difficult to prepare. Such requirements restrict the
utility of these methods. Thus, metal-free catalysts have
garnered considerable interest.
Recently, N-heterocyclic carbene (NHC)-catalyzed redox
esterification of aldehydes with alcohols has emerged as a
powerful strategy for the formation of esters.6 Examples of
metal-free NHC-catalyzed7 and NHC transition-metal-cataly-
zed5a,b,8 esterifications have been reported. However, the use of
stoichiometric amounts of oxidants is required in NHC-
catalyzed reactions. Several years ago, Studer et al. had reported
an oxidative esterification using 1,3-dimethyltriazolium iodide
as a precatalyst in the presence of DBU and 3,3′,5,5′-tert-
butyldiphenoqinone. However, the catalytic system utilized an
expensive quinone as the oxidant although it was readily
recovered by oxidation in air (Scheme 1a).7f
(Scheme 1a).7h In 2013, Connon et al. reported an oxidative
esterification in the presence of a triazolium precatalyst and
excess base (DBU, 110 mol %) in air, albeit with limited
substrate scope (Scheme 1b).6d Despite these important
advances, significant challenges remain for the synthesis of
esters under atom-economic, eco-friendly, and mild reaction
conditions from readily available materials in the presence of a
reusable catalyst.9,10
In 2011, Zeitler et al. also reported an oxidative lactonization
using a thiazolium precatalyst with azobenzene as the oxidant,
but the oxidant recovery process required harsh conditions and
the reaction was only applicable to intramolecular esterification
Received: June 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We recently developed highly efficient, recyclable polymer-
based organocatalytic systems, such as poly(4-vinylimidazo-
lium) iodide11 and poly(3,4-dimethyl-5-vinylthiazolium) io-
dide.12 These polymeric catalysts were successfully recovered
and reused several times without any decrease in performance.
As such, we sought to expand the applications of the
poly(thiazolium)iodide/base/phenazine system in the ester-
ification of aldehydes with alcohols. Herein, we report a highly
efficient method for the oxidative esterification of aldehydes
with alcohols, which employs a polymer-based organocatalyst,
poly(3,4-dimethyl-5-vinylthiazolium) iodide, as the precatalyst
and phenazine as the reusable external oxidant (Scheme 1c). A
simple, efficient, ligand-free, transition-metal-free, high-yielding,
direct esterification of aldehydes and alcohols in the presence of
a reusable poly(thiazolium) precatalyst and DBU was thus
developed in this study. To the best of our knowledge, the
developed catalytic system facilitates one of the most general
and selective oxidative esterification reactions of aldehydes with
alcohols currently available.
acetone and DMF gave the corresponding esters in 15% and
78% yields, respectively (entries 7 and 8, respectively).
Increasing the amount of phenol led to no noticeable change
in the yield (entry 10). However, when 1.2 equiv of the
aldehyde was used, the best yield (93%) was observed (entry
11). When the amount of oxidant (phenazine) was decreased
to 0.6 equiv, the desired product was obtained in 53% yield
(entry 12). No reaction was observed in the absence of a
catalyst or phenazine. When a monomer (3,4-dimethyl-5-
vinylthiazolium iodide) was used as the precatalyst instead of
the polymer precatalyst, the product was isolated in 78% yield
(entry 13). The optimum reaction conditions were as follows: 7
mol % of precatalyst, 14 mol % of DBU, 1.2 equiv of phenazine,
1.0 mL of DMSO at 40 °C for 18 h.
With the optimized reaction conditions in hand, we
investigated the activity of the catalyst in the reaction of
phenol with a variety of aryl aldehydes (Scheme 2).
Scheme 2. Esterification Reactions of Phenol with Aromatic
a
As a model reaction, we initially examined the reaction of
benzaldehyde with phenol (a weak nucleophile) in the presence
of the thiazolium polymer precatalyst (5 mol %), phenazine
(1.2 equiv), and DBU (10 mol %) in DMSO at room
temperature for 18 h (Table 1). The initial reaction conditions
Aldehydes
Table 1. Screening of Esterification Reaction of
a
Benzaldehyde with Phenol
c
catalyst
(mol %)
temp
(°C)
yield
(%)
b
entry
oxidant
solvent
1
2
3
4
5
6
7
8
9
phenazine
phenazine
phenazine
phenazine
azobenzene
benzoquinone
phenazine
phenazine
phenazine
phenazine
phenazine
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
acetone
DMF
5
7
25
25
25
40
40
40
40
40
60
40
40
40
40
70
77
75
88
85
8
10
7
7
7
7
15
78
85
83
93
53
78
7
DMSO
DMSO
DMSO
DMSO
DMSO
7
d
10
7
e
11
7
f
12
phenazine
7
a
g
Conditions: aldehyde (0.6 mmol), phenol (0.5 mmol), cat. (7 mol
13
phenazine
7
%), DBU (14 mol %), phenazine (0.6 mmol), DMSO (1 mL).
Isolated yield. 60 °C.
a
Conditions: benzaldehyde (0.5 mmol), phenol (0.6 mmol), DBU (2
equiv of catalyst), oxidant (0.6 mmol), 18 h, catalyst = poly(3,4-
b
c
b
c
dimethyl-5-vinylthiazolium) iodide. 1 mL used. Isolated yield.
d
e
Phenol (1 mmol) used. Benzaldehyde (0.6 mmol), phenol (0.5
f
g
Benzaldehydes having alkyl, ether, nitrile, or halogen group(s)
and 2-naphthaldehyde were converted into the corresponding
phenyl esters in good to excellent yields (3a−j, 69−94%).
Benzaldehydes having electron-donating (3-OMe, 3l) and
electron-withdrawing (3-Br, 3k) groups could be transformed
into esters. Notably, 3,4,5-trimethoxy-substituted benzaldehyde
(3m, 78%) and furan-2-carbaldehyde (3n, 71%) were good
substrates. However, 4-nitrobenzaldehyde turned out to be a
poor substrate (3o, 26%).
Next, the esterification of benzaldehyde with various types of
alcohols was investigated (Scheme 3). Neither alcohol
oxidation nor aldol condensation was observed under the
reaction conditions. Various phenols containing alkyl, alkene,
mmol) used. 0.3 mmol used. 3,4-Dimethyl-5-vinylthiazolium iodide
used as a catalyst.
were adopted from a previous study.12a After the reaction, the
expected ester was isolated in 70% yield (entry 1). The amount
of catalyst influenced the yield of the reaction (entries 1−3).
The yield of the reaction was slightly dependent on the reaction
temperature (the yield at 25 °C (entry 2) and 40 °C (entry 4)
were 77% and 88%, respectively). The use of oxidants such as
phenazine, azobenzene, and benzoquinone afforded the
corresponding esters in 88%, 85%, and 8% yields, respectively
(entries 4−6). Changing the reaction solvent from DMSO to
B
DOI: 10.1021/acs.orglett.7b01617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Esterification of Aromatic Aldehydes with Various
Alcohols
Scheme 4. Ester Bond Formation with Aliphatic Aldehydes
and Alcohols
a
a
a
Conditions: aldehyde (2.2 mmol), alcohol (0.5 mmol), cat. (11 mol
%), DBU (21 mol %), phenazine (0.6 mmol), 24 h, 60 °C, DMSO (1
b
c
d
mL). Isolated yield. 30 h, 80 °C. Aldehyde (0.6 mmol), alcohol (0.5
mmol), cat. (7 mol %), DBU (14 mol %), 18 h, 40 °C.
Relatively higher yields were observed for secondary aldehydes
(5d and 5e: 96 and 86%) as compared to primary aldehydes
(5a−5c: 69−77%).
In order to extend the utility of the developed system, the
chemical selectivity was examined by studying the reaction of 4-
aminophenol with benzaldehyde (Scheme 5, eq 1). An ester
Scheme 5. Chemoselective Esterification of Benzaldehyde
over Amidation
a
Conditions: aldehyde (0.6 mmol), alcohol (0.5 mmol), cat. (7 mol
%), DBU (14 mol %), phenazine (0.6 mmol), DMSO (1 mL).
b
c
d
Isolated yield. 60 °C. Cat. (11 mol %), DBU (21 mol %), 38 h, 80
°C.
halogen, nitrile, or nitro group(s) afforded high to excellent
yields of the corresponding esters (4a−j). Sterically shielded
phenol or phenol bearing a nitro group provided lower yields at
40 °C (4f, 48%; 4j, 29%). In both cases, elevated temperatures
(60 °C) were required to drive the reaction to obtain higher
yields of 63%. Aliphatic alcohols, such as 3-phenylprop-2-en-1-
ol, n-octanol, propargyl alcohol, and (4-chlorophenyl)methanol,
also worked well for this reaction. Interestingly, double and
triple bonds were tolerated in the oxidative esterification (4k
and 4m). In the reaction of benzaldehyde with methanol, the
expected ester was produced in a high yield. However, during
the purification, some of the ester evaporated. Thus, 1,1′-
biphenyl-4-carbaldehyde was used instead of benzaldehyde in
the reaction with methanol, and the expected product (4o) was
isolated in 92% yield. A secondary alcohol, cyclohexanol, was
also a good substrate (4p, 60%). However, a tertiary alcohol,
tert-butyl alcohol, was unreactive under the reaction conditions.
Heteroaromatic aldehydes containing furan or thiophene
moieties were good substrates for the esterification with
aliphatic alcohols (4q and 4r). However, in the case of
indole-3-carboxaldehyde, an N-methylated ester, 4s, was
isolated in 25% yield.
was isolated as a major product, and a trace amount of an amide
was formed (eq 1). Thus, this method is useful for the selective
functionalization of OH groups in the presence of NH2 groups.
To determine the selectivity between nucleophiles, a
competition experiment between octanol and octylamine with
benzaldehyde was carried out (eq 2). The ester (67%) was
formed in preference to the amide. A similar experiment with
cyclohexanol and piperidine showed a 9:1 preference for the
ester (overall yield: 40%) (eq 3).
A possible mechanism for the poly(thiazolium)/base/
phenazine-catalyzed esterification reaction based on the widely
accepted mechanism is depicted in Figure 1.4b The benzylic
alcohol intermediate is generated upon reaction of the carbene
with the aldehyde. Finally, nucleophilic substitution by the
alcohol takes place to give the desired esters.
Reactions between aliphatic aldehydes and aliphatic alcohols
were also examined (Scheme 4). Aliphatic aldehydes, including
primary, secondary, and cyclic aldehydes were good substrates
and afforded high yields (69−96%) of the corresponding esters.
In order to recycle the catalytic system, the catalyst was
recovered by addition of hydroiodic acid.12a Moreover, we also
C
DOI: 10.1021/acs.orglett.7b01617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government
(2014R1A5A1011165 and 2007-0093864). S.C. is a recipient
of a BK21 Plus Fellowship.
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recovered phenazine from the reaction mixture to overcome
the potential drawback of its stoichiometric use. To our delight,
separation of the reduced dihydrophenazine from the product
in organic solvents under air afforded the reoxidized, active
oxidant phenazine (96−99% in each cycle) (see the Supporting
Information). Thus, the recovered catalytic system could be
successfully reused without considerable decrease in perform-
ance over five cycles (each time, 81−91% yield) (see the SI).
In conclusion, we have developed a novel poly(thiazolium)
iodide/DBU-catalyzed oxidative esterification of aldehydes with
alcohols. The catalytic system showed high activity with a
variety of aromatic and aliphatic aldehydes and alcohols. The
methodology described herein has several advantages, including
being a metal-free catalytic system, and the recovery and
reusability of the organic precatalyst and phenazine oxidant.
The polymer precatalyst exhibited higher catalytic activity than
the monomeric analog and could be reused five times without a
considerable decrease in activity. Thus, the precatalyst has great
potential, and further investigations of the applicability of the
polymer-based thiazolium system in other reactions are in
progress in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01617.
(10) Suzuki, K.; Yamaguchi, T.; Matsushita, K.; Iitsuka, C.; Miura, J.;
Akaogi, T.; Ishida, H. ACS Catal. 2013, 3, 1845.
Experimental procedures, characterization data, and
reuse procedures of poly(3,4-dimethyl-5-vinylthiazolium)
iodide and phenazine in the reaction of esterification
(PDF)
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(b) Seo, U. R.; Chung, Y. K. RSC Adv. 2014, 4, 32371.
(12) (a) Chung, J. Y.; Seo, U. R.; Chun, S.; Chung, Y. K.
ChemCatChem 2016, 8, 318. (b) Chun, S.; Chung, J. Y.; Chung, Y. K.
ChemCatChem 2016, 8, 2476.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ykchung@snu.ac.kr.
ORCID
Young Keun Chung: 0000-0002-2837-5176
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b01617
Org. Lett. XXXX, XXX, XXX−XXX