N-PEGylated Thiazolium Salt: A Green and Reusable Homogenous Organocatalyst for the Synthesis of Benzoins and Acyloins

Article abstract of DOI:10.1007/s10562-020-03417-3

N-PEGylated-thiazolium salt is used as efficient catalyst for the benzoin condensation. The catalyst was synthesized by reaction of activated polyethylene glycol 10,000 (PEG-10000) with 4-methyl-5-thiazoleethanol (sulfurol). Reaction mixture undergoes temperature-assisted phase transition and catalyst separated by simple filtration. After reaction course, catalyst can be recycled and reused without any apparent loss of activity which makes this process cost effective and hence ecofriendly. Synthesized benzoins and acyloins by this method have been characterized on the basis of melting point and ¹H-NMR spectral studies. Graphic Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-020-03417-3

Catalysis Letters
https://doi.org/10.1007/s10562-020-03417-3
N‑PEGylated Thiazolium Salt: A Green and Reusable Homogenous
Organocatalyst for the Synthesis of Benzoins and Acyloins
Ali Javaheri Haghighi1 · Javad Mokhtari1 · Khashayar Karimian2
Received: 12 March 2020 / Accepted: 4 October 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
N-PEGylated-thiazolium salt is used as efcient catalyst for the benzoin condensation. The catalyst was synthesized by
reaction of activated polyethylene glycol 10,000 (PEG-10000) with 4-methyl-5-thiazoleethanol (sulfurol). Reaction mixture
undergoes temperature-assisted phase transition and catalyst separated by simple fltration. After reaction course, catalyst can
be recycled and reused without any apparent loss of activity which makes this process cost efective and hence ecofriendly.
1
Synthesized benzoins and acyloins by this method have been characterized on the basis of melting point and H-NMR
spectral studies.
Graphic Abstract
Keywords N-PEGylated thiazolium salt · Benzoin condensation · Acyloins · Homogenous catalysis · Pegylation · Sulfurol
1 Introduction
The benzoin reaction is one of the oldest reactions in organic
chemistry, found serendipitously by Liebig and Wohler in
Electronic supplementary material The online version of this
1832 [l]. They discovered that the cyanide anion can catalyze
article (https://doi.org/10.1007/s10562-020-03417-3) contains
the union of two molecules of aromatic aldehydes to aford
supplementary material, which is available to authorized users.
α-hydroxy ketones [1]. More than a century later, Onium
* Javad Mokhtari
salts have been known to catalyze the benzoin reaction by
Ukai et al. who discovered catalytic activity of 3-ethylthiazo-
lium bromide [2]. This may be regarded as an early example
of organocatalysis using an azolium salt. Breslow, in 1958,
investigated the catalyst role of thiazolium salt for the self-
condensation of benzadehyde to benzoin and proposed a
mechanism, which generally admitted [3, 4]. He depicted
the catalytically active species as a thiazolium zwitterion
(the resonance structure of an NHC) and proposed that the
reaction proceeds via an enaminol intermediate. However,
j.mokhtari@srbiau.ac.ir
* Khashayar Karimian
kkarimain@arast.com
Ali Javaheri Haghighi
javaherichem@gmail.com
1
Departments of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
2
Institute of Biochemistry and Biophysics, University
of Tehran, P.O. Box: 13145-1384, Tehran, Iran
Vol.:(0123456789)
1 3

A. J. Haghighi et al.
in the recent years, many researchers have challenged this
mechanism with evidence [5–7]. Almost three decades later
Bertrand et al. used the N-heterocyclic carbene (NHC) as
catalytically active species in the benzoin reaction with a
stable phosphinocarbene [8]. Stetter’s in 1976 used N-ben-
zyl sulfurol chloride for benzoin condensation and may be
regarded as the frst report of an NHC-catalysed benzoin
reaction on a synthetically useful scale [9].
PEG in the low temperature and as a result, easily separation
of catalyst from the reaction mixture (Scheme 1).
2 Experimental Section
PEG was obtained from Kimiagaran Emrouz Ltd., Iran.
Thiamine Mononitrate or Vitamin B1 for the synthesis of
4-methyl-5-thiazoleethanol was obtained from Nokam Phar-
maceutical Co., Iran. Aldehydes and solvents were obtained
from commercially available sources such as Sigma–Aldrich
and Merck without any purifcation. 1H-NMR spectra were
measured (CDCl3) with a Bruker DRX-500 AVANCE spec-
trometer at 500.13. Melting points were measured on an
Electrothermal 9100 apparatus.
Since the frst thiazolium salt catalyzed benzoin con-
densation [2] a continuous research for a new and efcient
thiazolium salts catalyst for the benzoin condensation has
been carried out. To name a few, this includes the use of
3-ethylbenzothiazolium bromide [10], 3-mesyl cyclohep-
tathiazolium perchlorate [11], N-ethylsulfurol bromide
[12], 3-(2,6-diisopropylphenyl)thiazolium perchlorate [13]
and etc. However, all of these reports have signifcant draw-
backs such as separation and recyclability of the catalyst,
low isolated yields and long reaction time. Difculties asso-
ciated with the recovery of the catalyst from the reaction
mixture have prevented the application of thiazolium salts
to the benzoin condensation on a preparative scale. In fact, a
few research article in application of the polymer-supported
thiazolium salt and recovery of the catalyst in the benzoin
condensation have been made [14–18]. Our group in 1984
used chloromethylated-polystyrene copolymer-bound thia-
zolium salt as efcient catalyst in the benzoin condensation
[17]. This and the amazing number of diverse chemical
transformation catalyzed by thiazolium salt [4] and using
of PEGylated resolving agent for the resolution of racemic
mixtures by our group [19] encouraged us to evaluate the
prospects of N-PEGylated thiazolium salt as catalyst in the
benzoin condensation due to phase transition property of
2.1 Activation of PEG‑10000
The process of Bückmann et al. [20] was used with minor
modifcation. PEG (10,000) (5 g, 0.5 mmol) was dissolved
in 150 ml of toluene, followed by the distillation of 50 ml
of the solvent to remove traces of moisture. After cooling to
35 °C, freshly distilled anhydrous triethylamine (0.375 ml,
2.7 mmol) was added. Freshly phosphorus tribromide
(0.15 ml, 2.1 mmol), dissolved in 10 ml of dry toluene, and
was then added dropwise over 1 h at 35 °C under a dry nitro-
gen atmosphere with continuous stirring. The mixture was
refuxed for 1 h and triethylammonium chloride was removed
by passing the hot solution through a bed of Celite. The solu-
tion was treated with 0.5 g of decolorizing carbon at 50 °C and
fltrated over Celite. The fltrate was stored at 4 °C overnight,
afording activated PEG, which was fltered at 4 °C. The solid
Scheme 1 Synthesis of benzo-
ins and acyloins catalyzed by of
N-PEGylated thiazolium salt
1 3

N-PEGylated Thiazolium Salt: A Green and Reusable Homogenous Organocatalyst for the Synthesis…
product was further purifed by dissolving in 0.5 L of absolute
ethanol at 60 °C and treating with 0.25 g of decolorizing car-
bon, followed by fltration over Celite. The ethanolic fltrate
was stored overnight at 4 °C to recrystallize the product. The
solid material was separated by fltration and washed with
cold ethanol and then ether. After drying in a vacuum desic-
cator 4.9 g of a pale yellow product was obtained (97%).
was cooled to 0–5 °C, the resulting precipitate was fltered
and washed by cold toluene (5 ml). Then, the fltrate was
evaporated under reduced pressure and oily product was
purifed by column chromatography (silica gel, n-hexane/
EtOAc) to aford benzoin and acyloin 5a–h. structure of all
1
product was characterized by melting point and H-NMR
spectra (See supporting information).
2.2 Preparation of N‑PEGylated Thiazolium
Bromide
3 Result and Discussion
4-methyl-5-thiazoleethanol (sulfurol) (0.6 g, 4 mmol) and
activated PEG (10,000) (20 g, 2 mmol) was dissolved in
200 ml of acetonitrile. Thereafter, the resulting pale yel-
low solution was stirred at refux for 24 h. The solvent was
evaporated under reduced pressure and toluene was added to
oily crude product. The reaction mixture was then cooled to
0–5 °C to crystallize the product. The solid material was sep-
arated by fltration and washed with cold toluene and then
ether. After drying in a vacuum desiccator 18 g of a pale
yellow product was obtained (88%). The product was char-
acterized 1H-NMR spectra. 1H-NMR (500 MHz, CDCl3): δ
1.87 (bs, 1H, OH), 3.04 (t, J=6.5 Hz, 2H, CH2), 3.66 (bs, n
CH2), 3.86 (t, J=6.5 Hz, 2H, CH2), 8.62 (bs, CH).
The present work is the result of endowment of known thia-
zolium salt catalyst with physico-chemical properties of poly-
ethylene glycol (PEG). We used polyethylene glycol (PEG) to
N-PEGylate the thiazole for two reasons. First, PEG dissolves
in aqueous and most organic solvents, providing a soluble cata-
lyst in a variety of solvent systems. Second, PEG is endowed
with unique physico-chemical properties allowing it to undergo
temperature-dependent as well as ionic strength-dependent
phase transition from a soluble chemical entity to a semisolid
or a solid. Therefore, in organic reaction medium the soluble
N-PEGylated thiazolium salt catalyst precipitates by cooling
the reaction mixture (Scheme 1). With the above assumption,
we have synthesized the catalyst three and investigated their
catalytic activity in the benzoin and acyloin condensation.
For the synthesis of catalyst, 4-methyl-5-(2′ -hydroxy-
ethyl)thiazole (2) was used as thiazole source which easily
obtained from the sulfte cleavage of thiamine [16]. Firstly,
Polyethylene glycol-10000 (PEG-10000) is activated using
phosphorus tribromide and then reaction of thiazole two
with activated PEG gives N-PEGylated thiazolium bromide
(3) (Scheme 2). The resulting catalyst is a new class of thia-
zolium salt which facilitates the benzoin condensation and
2.3 Catalytic Activity of N‑PEGylated Thiazolium
Salt in the Benzoin and Acyloin Condensation
To a mixture of PEGylated thiazolium bromide (0.25 g,
0.025 mmol) and Et3N (5 mg, 0.05 mmol) in toluene (5 ml)
and EtOH (2 ml), aldehyde (1 mmol) was added and the
resulting mixture was heated at refux for 12 h. After com-
pletion of the reaction (monitored by TLC) reaction mixture
Scheme 2 Synthesis of N-PEGylated thiazolium salt
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A. J. Haghighi et al.
Table 1 Optimization of reaction conditions
separation of the catalyst from the reaction mixture. Struc-
ture of the catalyst confrmed by 1H-NMR spectra (see sup-
porting information).
We commenced our investigation with the benzaldehyde
for the optimization of reaction condition. As shown in
Table 1, the yield proved invariant to the either base, but
nature of solvent greatly efects the yield of the reaction.
Diferent solvents such as EtOH, THF, toluene, CH2Cl2
and mixture of toluene/EtOH (3:1) were used. As shown
in Table 1, best result was obtained when mixture of tolu-
ene and ethanol were used (entries 19–21, 26 and 31). As
expected, the reaction in the abovementioned solvents and at
room temperature either did not lead to the formation of the
product or had a very low yield. But as shown in Table 1, the
yield increased with increasing temperature, and the desir-
able results were obtained in a mixture of toluene and etha-
nol (3:1). There are two possible reasons for this phenom-
enon; a. increasing the temperature (due to the high boiling
point of toluene) increases the reaction rate and b. solubility
of the catalyst increases due to the hydrogen bonds forma-
tion with ethanol. One of the most important advantages of
using toluene-ethanol mixture is that at high temperatures
the catalyst is completely soluble and the reaction mixture
is homogeneous, but with decreasing the temperature to
5 °C the catalyst becomes insoluble and easily separated
by fltration and more than 90% of the catalyst (by weight)
is recovered, while the product is soluble at this condition.
However, in other solvents (THF and CH2Cl2), both at high
and low temperatures, the catalyst is completely soluble,
and as a result, separating the catalyst is difcult and costly.
To explore the effect of different bases on reaction,
three bases including Et3N, N(iPr)2Et and DBU were used
(Table 1), but the results did not show signifcant change.
Therefore, triethylamine was used due to its availability.
Our results with changing amount of catalyst shown
that the catalytic loading no signifcant impact on the yield
(entries 20, 21). So, with optimization reaction condition in
hand (entry 19) we next turned to the question of substrate
scope, an issue that has limited the utility of the benzoin
condensation reaction in the past. We evaluated the perfor-
mance of catalyst 3 in benzoins and acyloins condensation
of substituted aromatic aldehydes with diferent electronic
and steric characters. As a shown in Table 2, the yield of the
reaction depends on the electron-donating or withdrawing
nature of the substituents. Aldehydes with electron-releasing
group (entries 2–5) aford good yields compared to with-
drawing group (entry 6).
Entry Base
Catalyst
loading
(mol %)
Solvent
T (°C) Yielda (%)
1
2
3
4
5
Et3N
Et3N
Et3N
Et3N
Et3N
2.5
2.5
2.5
2.5
2.5
EtOH
THF
Toluene
CH2Cl2
rt
rt
rt
rt
5
-
5
-
Toluene/ EtOH rt
15
(2:1)
5
6
7
8
9
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
EtOH
THF
Toluene
CH2Cl2
rt
rt
rt
rt
Trace
-
5
-
10
Toluene/ EtOH rt
(2:1)
10
11
12
13
14
DBUb
DBU
DBU
DBU
DBU
2.5
2.5
2.5
2.5
2.5
EtOH
THF
Toluene
CH2Cl2
rt
rt
rt
rt
-
-
-
-
Toluene/ EtOH rt
10
(2:1)
15
16
17
18
19d
Et3N
Et3N
Et3N
Et3N
Et3N
2.5
2.5
2.5
2.5
2.5
EtOH
THF
Toluene
CH2Cl2
refux 41
refux 35
refux 54
refux 15
Toluene/ EtOH refux 80
(2:1)
20
21
Et3N
Et3N
5
Toluene/ EtOH refux 79
(2:1)
10
Toluene/ EtOH refux 80
(2:1)
22
23
24
25
26
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
N(iPr)2Et 2.5
EtOH
THF
Toluene
CH2Cl2
refux 35
refux 38
refux 52
refux 20
Toluene/ EtOH refux 76
(2:1)
27
28
29
30
31
DBUc
DBUc
DBU
DBU
DBU
2.5
2.5
2.5
2.5
2.5
EtOH
THF
Toluene
CH2Cl2
refux 44
refux 34
refux 53
refux 21
In the case of 4-nitrobenzaldehyde (Table 2, entry 6),
the imine α-carbanion (6, Scheme 3), the 4-nitro group
provides additional stability to imine α-carbanion by elec-
tron-withdrawing group contribution, rendering it a weaker
nucleophile for C–C bond formation with the second alde-
hyde [6, 21]. But in the case of electron-releasing group such
Toluene/ EtOH refux 75
(2:1)
aBased on quantitative TLC
b1,8- Diazabicyclo[5.4.0]undec-7-ene
cReaction conditions: Aldehyde (1 mmol), Base (2 mmol), Time: 12 h
d Optimization reaction condition
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N-PEGylated Thiazolium Salt: A Green and Reusable Homogenous Organocatalyst for the Synthesis…
Table 2 Evaluation of catalyst scope a
O
O
3
Catalyst (20 mol%)
R
R
H
R
Toluene/EtOH
OH
4a-h
5a-h
Entry
1
Aldehyde
Product
Yield
80
O
O
H
O
OH
4a
5a
2
3
4
79
82
78
O
H
OH
5b
4b
O
OMe
O
H
MeO
OH
MeO
4c
5c
O
Cl
O
H
Cl
OH
Cl
4d
5d
OH
5
6
79
H
O
O
O
O
O
4f
5f
Trace b
O
NO2
O
H
O2N
OH
O2N
4e
5e
1 3

A. J. Haghighi et al.
Table 2 (continued)
O
O
3
Catalyst (20 mol%)
R
R
H
R
Toluene/EtOH
OH
4a-h
5a-h
Entry
7
Aldehyde
Product
Yield
73
O
O
H
4g
OH
O
5g
8
74
O
H
OH
5h
4h
aReaction conditions: Aldehydes (1 mmol), catalyst (2.5 mol%), Et3N (5 mol%), Toluene (5 mL), EtOH (2 ml), 50 °C, Time: 2 h.b by TLC
Scheme 3 Formation of stable zwitterion in case of 4-nitrobenzaldehyde
Fig. 1 Reusability of the cata-
lyst for benzoin condensation of
benzaldehyde
Reusability of the catalyst
80
78
76
74
72
70
Run 1
Run 2
Run 3
Run 4
Run 5
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N-PEGylated Thiazolium Salt: A Green and Reusable Homogenous Organocatalyst for the Synthesis…
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temperature. The recovered catalyst was reused for benzoin
condensation of benzaldehyde. The result indicates that the
PEG-thiazolium salt catalyst can be used for several cycles
successfully with minimal loss of activity (Fig. 1).
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4 Conclusion
In conclusion, we have studied the simple and efective
method for the preparation of benzoins and acyloins by
N-PEGylated thiazolium salt as reusable catalyst. Regards
to the signifcant catalytic activity of the N-PEGylated thia-
zolium Salt, a range of aromatic and aliphatic aldehydes
with electron-releasing and electron with-drawing group
converted to the corresponding benzoin and acyloins rap-
idly with good to excellent yields. The major advantage of
this method is due to the simple recovery of the catalyst by
temperature-dependent phase transition of PEGylated thia-
zolium salt. Further studies on other useful application of
PEGylated catalysts and development of its catalytic scope
are in progress and would be presented in the future.
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Compliance with Ethical Standards
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Conflict of Interest The authors declare that they have no confict of
interest.
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