Heteropolyacid ionic liquid heterogeneously catalyzed synthesis of isochromansviaoxa-Pictet-Spengler cyclization in dimethyl carbonate

Article abstract of DOI:10.1039/d1ra01004b

A recyclable and efficient heterogeneous, green catalyst based on the synthesis of Keggin-type polyoxometalate (H₃PMo₁₂O₄₀) and vitamin B1 analogue 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium (HEMT),i.e., [HEMTH]H₂[PMo₁₂O₄₀] was prepared. Oxa-Pictet-Spengler cyclization of arylethanols and aldehydes were catalyzed to afford various substituted isochromans in moderate conditions with excellent yields using dimethyl carbonate (DMC) as a green solvent. Furthermore, this protocol was applicable in a gram-scale reaction, and the catalyst could be recycled eight times without significant loss of activity.

Full text of DOI:10.1039/d1ra01004b

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Heteropolyacid ionic liquid heterogeneously
catalyzed synthesis of isochromans via oxa-Pictet–
Spengler cyclization in dimethyl carbonate†
Cite this: RSC Adv., 2021, 11, 10610
a
a
b
a
Guoping Yang,a Ke Li,
Kai Zeng,a Yijin Li,
*
Tao Yu and Yufeng Liu
*
A recyclable and efficient heterogeneous, green catalyst based on the synthesis of Keggin-type
polyoxometalate (H3PMo12O40) and vitamin B1 analogue 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-
ium (HEMT), i.e., [HEMTH]H2[PMo12O40] was prepared. Oxa-Pictet–Spengler cyclization of arylethanols
and aldehydes were catalyzed to afford various substituted isochromans in moderate conditions with
excellent yields using dimethyl carbonate (DMC) as a green solvent. Furthermore, this protocol was
applicable in a gram-scale reaction, and the catalyst could be recycled eight times without significant
loss of activity.
Received 6th February 2021
Accepted 2nd March 2021
DOI: 10.1039/d1ra01004b
rsc.li/rsc-advances
counter-cation precursor.28 Various polysubstituted olens were
synthesized by the dehydration of alcohols with alcohols (or
Introduction
alkenes) in a green solvent dimethyl carbonate (DMC) catalyzed by
[HMTH]2H2[SiW12O40]. We are making attempts to further develop
this catalytic system for more valuable reactions, for example, the
synthesis of isochromans from arylethanols and aldehydes via oxa-
Pictet–Spengler cyclization (Scheme 1a).
Isochroman is a prominent structure motif and is the core
structure of numerous bioactive natural products, such as 6-
methoxy-1,1,3,7-tetramethylisochroman-8-ol (DMHI), glucoside
Green chemistry has been widely advocated for the reasons of
economic development, environmental degradation, resource
consumption and so on. In particular, green catalytic chemistry
has received widespread attention. As part of our interest in the
eld of polyoxometalates (POMs) and green chemistry, POMs
have played vital roles in organic synthesis as acid–base cata-
lysts for the past few decades.1–7 Among those, the application of
noncorrosive, inexpensive, and readily available Keggin-type
heteropolyacids (HPAs) for organic transformations including
condensation, cycloaddition and coupling reactions has been
extensively studied.8–14 However, HPAs are generally homoge-
neous catalysts in most of the reported systems. Since homo-
geneous catalysts are difficult to recycle, there is an urgent need
to develop a recyclable heterogeneous catalytic system based on
HPAs from the perspective of environmental sustainability.15–21
Ionic liquids (ILs) have drawn considerable attention among
various heterogeneous designs of HPAs due to their non-volatility,
high thermal stability, and excellent catalytic activity. In the past
few decades, the counter-cation precursors of some typical HPAs-
based ionic liquids have been designed as pyridine, 1-methyl
imidazole, and 1-methyl-2-pyrrolidinone, etc.22–27 Our group is
committed to developing HPA-based ionic liquids for green
synthesis. In the previous work, our group synthesized [HMTH]2-
H2[SiW12O40] using H4SiW12O40 and the analogue compound 5-(2-
hydroxyethyl)-4-methylthiazole (HMT) of vitamin B1 as the
aEast China University of Technology, Jiangxi Province Key Laboratory of Synthetic
Chemistry, Nanchang 330013, People's Republic of China. E-mail: yiu@ecut.edu.cn
bEast China University of Technology, School of Nuclear Science and Engineering,
Nanchang, 330013, China. E-mail: tyu@ecut.edu.cn
Scheme 1 (a) Precursors for HPA-based ionic liquids; (b) representa-
tive examples of isochromans with biological activities; (c) synthesis of
substituted isochromans via oxa-Pictet–Spengler cyclization (this
work).
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra01004b
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B and aspergillus pseudodeectus (Scheme 1b), which are Accordingly, [HEMTH]2H[PMo12O40] (ILs-4) and [HEMTH]3[-
valuable biologically and pharmaceutically active organic PMo12O40] (ILs-5) were prepared using 2 mmol and 3 mmol of
molecules.29–31 Due to the importance of isochromans, the HEMT and H3PMo12O40 (1 mmol), respectively (IR characterization
synthesis of isochromans have undoubtedly received consider- is shown in Fig. S1†). All of the ionic liquids were used as catalysts
able attention, and the synthetic methods of isochromans have in the condensation reaction. It is clear that ILs-2 exhibits better
achieved greatly development.32,33 There are two important catalytic activity than other ionic liquids as shown in Fig. 1D.
methods for the synthesis of isochromans, including the cyclo-
Then, we studied the inuence of reaction temperature, time
dehydration of homophthalyl alcohols and the cyclization of and catalyst loading on the reaction. As shown inꢀFig. 2, the
phenylethanol which is called oxa-Pictet–Spengler reaction.34,35 conversion of the substrate could reach 99% at 30 C, but the
The catalysts are used in the latter are usually Fe(OTf)2, Bi(OTf)3, selectivity is relatively low. When the temperature was risen, the
SnCl4 and other expensive Lewis acid, or HCl, TfOH and other yield of the desired product 3a could be obtained 85% at 70 ꢀC
corrosive Bronsted acid (TfOH ¼ triuoromethanesulfonic (Fig. 2A). As can be seen from Fig. 2B, with the increase of the
acid).33,36–40 And the solvents are toluene, benzene, dioxane and reaction time, the yield of the desired product 3a gradually
so on.41–45 These methods show disadvantages such as long increased to 91% in 20 min. To further improve the yield of
reaction times, high temperature, and unrecyclable catalysts. desired product 3a, the catalyst loading in the reaction was
Therefore, it is urgent to develop a green and efficient catalytic
system for the synthesis of isochromans.
Based on our previous research on the application of HPAs-
based ionic liquids in various reactions, we envisioned that the
application of inexpensive, noncorrosive, acidic HPAs-based
ionic liquids could be a green, practical and efficient strategy
for the synthesis of isochromans via oxa-Pictet–Spengler reaction.
Herein, we report a practical protocol to synthesize isochromans
under the mild conditions catalysized by [HEMTH]H2[PMo12O40]
(Scheme 1c). This catalyst could be easily recycled at least 8 times
without signicantly reducing activity or selectivity.
Results and discussion
To optimize the optimal reaction conditions, we carried out our
study by the reaction of 2-(3,4-dimethoxyphenyl)ethan-1-ol 1a
and benzaldehyde 2a in dichloroethane (DCE) at 50 ꢀC for
10 min using different HPAs (3 mol%), i.e., H3PMo12O40,
H3PW12O40, H4SiW12O40 as catalyst (Fig. 1A). First, the catalytic
effects of HPAs was investigated. As shown in Fig. 1B,
H3PMo12O40 was the best catalyst for the reaction and the yield
of product 3a was 80%. 54% and 43% yields of 3a was obtained
in the cases of H3PW12O40 and H4SiW12O40 as catalysts. No yield
of 3a was observed when the reaction was performed in the
absence of catalyst. Among those HPAs, H3PMo12O40 shows the
weakest acidity but the soest heteropoly anion. Subsequently,
H3PMo12O40 was applied as optimal catalyst to screen the
solvent. Some common solvents were examined, and the effect
of some green solvents on the reaction has been mainly studied
including propylene carbonate (PC), ethylene carbonate (EC),
cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC),
H2O. As shown in Fig. 1C, no yield was observed when the
reaction was conducted in H2O. The reaction in PC and EC
delivered 3a in 54% and 35% yield, respectively. While 3a can be
obtained with good yields in DMC and CPME. In particular, 3a
could be obtained in 89% yield when DMC was used as solvent
(see ESI† for details). Subsequently, [HMTH]H2[PMo12O40] (ILs-1), Fig. 1 (A) Oxa-Pictet–Spengler reaction of 1a and 2a; (B) conversation
and yield profile for the examination of HPAs catalysts (DCE as solvent,
Table S1†); (C) conversation and yield profile for the optimization of the
reaction solvents (H3PMo12O40 as catalyst, Table S2†); (D) conversation
and yield profile for the examination of HPAs-based ionic liquids (DMC
[HEMTH]H2[PMo12O40] (ILs-2), and [HBMTH]H2[PMo12O40] (ILs-3)
were prepared using 5-(2-hydroxyethyl)-4-methylthiazole (HMT), 3-
ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium (HEMT), 3-benzyl-5-
(2-hydroxyethyl)-4-methylthiazol-3-ium (HBMT) and H3PMo12O40
as solvent, Table S3†) (yields were determined by GC using biphenyl as
as the raw materials by a procedure similar to the literature.28 an internal standard).
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studied. It can be found that the yield of the product 3a grad- products over 92% (92–96%) 92% (92–96%) (3b–3i, 3o). While
ually increased to 95% with the increase of the catalyst loading arylaldehydes with electron-donating groups, such as –CH3,
up to 4 mol% (Fig. 2C). Finally, the optimal condition for the –OCH3, –OCH2CH3, –CH(CH3)2, could provide isolated yield of
oxa-Pictet–Spengler reaction of 2-(3,4-dimethoxyphenyl)ethan- the corresponding isochroman products in up to 95% (91–95%)
1-ol 1a and benzaldehyde 2a was established when 4 mol% (3j–3n, 3p). The reaction was carried out using ortho-, meta-, and
[HEMTH]H2[PMo12O40] was used as catalyst in DMC at 70 ꢀC for para-substituted aromatic aldehydes as reaction substrate. As
20 min.
shown in Table 1, affected by steric hindrance, the yields of the
With the optimized reaction conditions in hand, we exam- desired products obtained from para-aldehydes was higher than
ined the scope of the method and found that it proceeded well that of meta-aldehydes, while the yields from meta-aldehydes
with various substituted aldehydes. This reaction system was was higher than the desired product obtained from ortho-alde-
not only suitable for aromatic aldehydes, but also for aliphatic hydes (3c > 3d > 3e, 3g > 3h > 3i, 3j > 3k > 3l). Particularly,
aldehydes (Table 1). As can be seen from the table, 2-(3,4- aliphatic aldehydes were proved to be also equally applicable to
dimethoxyphenyl)ethan-1-ol reacted with arylaldehydes bearing this catalytic system and afford isochromans in high isolated
electron-withdrawing groups, such as –F, –Cl, –Br, –NO2, –CN, yields (3r–3u), including butyraldehyde, pentanal, hexaldehyde
could afford isolated yield of the corresponding isochroman and phenylacetaldehyde. Meanwhile, phenethyl alcohol was
applied to test the reaction activity under the optimal catalytic
conditions, it could be found that in case of non-activated
phenethyl alcohol which had no activating substituents on
phenyl ring, the reaction did not occur as obviously as expected.
As long as there was an activated functional group on the
benzene ring, the reaction could proceed well. For example, 2-
(3-methoxyphenyl)ethan-1-ol reacted with benzaldehyde under
optimal reaction conditions and 94% of the corresponding
desired product 3q was obtained.
Table
1
[HEMTH]H2[PMo12O40]-catalyzed
oxa-Pictet–Spengler
reaction of arylethanols and aldehydes to access substituted
isochromansa
Fig.
2 (A) Investigation of the reaction temperature ([HEMTH]
H2PMo12O40 as catalyst, DMC as solvent, 10 min, Table S4†); (B)
optimization of the reaction time (70 ꢀC, Table S5†); (C) examination of
the loading of [HEMTH]H2[PMo12O40] (DMC as solvent, 70 ꢀC, 20 min,
Table S6†) (yields were determined by GC using biphenyl as an internal
standard).
a
Reaction conditions:
1 (0.6 mmol), 2 (0.66 mmol), [HEMTH]
H2[PMo12O40] (4 mol%), DMC (3 mL), isolated yields.
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Scheme 3 The proposed mechanism for the oxa-Pictet–Spengler.
produce the corresponding product 3q in 90% yield at the same
reaction conditions as above (Scheme 2C).
Scheme 2 Gram-scale synthesis of substituted isochromans.
To test the reusability of the catalyst, the model reaction of 2-
(3,4-dimethoxyphenyl)ethan-1-ol 1a and benzaldehyde 2a was
carried out in the presence of 10 mol% of [HEMTH]H2[PMo12O40]
under the optimal reaction conditions. As shown in Fig. 3A, the
ionic liquid [HEMTH]H2[PMo12O40] could be recycled at least 8
times without signicant loss of activity. And aer 8 cycles of
reactions, XRD comparisons of the catalyst [HEMTH]H2[PMo12O40]
before and aer the reaction were performed, and it was found
that the catalyst did not change, which further conrmed that the
catalyst still has catalytic activity (Fig. 3B).
According to literatures,35,37,38 a possible reaction mechanism
was inferred as shown in Scheme 3. First, the aldehyde 2 was
activated by ILs-2 to form A, and then the activated aldehyde A was
attacked by two different positions of alcohol 1 to form B and C.
Then B underwent an intramolecular Friedel–Cras reaction and
closed the ring to form the desired product 3, while C underwent
an intramolecular dehydration to form the isochroman derivative.
Additionally, it had been found that the catalytic system was
easy to scale-up at gram-scale to synthesize the substituted
isochromans via the direct oxa-Pictet–Spengler reaction of ary-
lethanols and aldehydes, which is quite important in terms of
sustainability and practical application. As can be seen from
Scheme 2, the reaction of 1a (6 mmol, 1.09 g) and 2a (6.6 mmol,
0.70 g) generated the desired products 3a in 91% of isolated yield
catalyzed by [HEMTH]H2[PMo12O40] (4 mol%) in DMC at 70 ꢀC for
1 h (Scheme 2A). The gram-scale ring condensation reaction of 1a
and 2g generated the product 3g in yield of 93% under identical
conditions (Scheme 2B). Similarly, the reaction of 1b and 2a could
Conclusions
In conclusion, we successfully developed the [HEMTH]
H2PMo12O40/DMC green, recyclable and efficient heterogeneous
catalytic system for the synthesis of isochromans from aryletha-
nols and aldehydes via oxa-Pictet–Spengler cyclization in excellent
yields. Furthermore, the catalytic system has the advantages of
high yield, low catalyst loading, and short reaction time. It is worth
noting that the reaction could be scaled up and the heterogeneous
catalyst could be reused at least 8 times without signicant loss of
activity. Such ndings may pave the way for the development of
new green chemistry transformations.
Experimental
Typical procedure for direct oxa-Pictet–Spengler reaction of
arylethanols with aldehydes
To a 4 mL reaction vial, 2-(3,4-dimethoxyphenyl)ethan-1-ol (0.6
mmol), benzaldehyde (0.66 mmol), [HEMTH]H2[PMo12O40]
(4 mol%) and DMC (3 mL) were added. Then the reaction was
carried out in screw cap vials with a Teon seal at 70 ꢀC for desired
time. Aer cooling to room temperature, the mixture was further
puried by column chromatography (petroleum ether/EtOAc) to
afford the desired products (see the ESI† for details).
Fig. 3 (A) Recyclability of [HEMTH]H2PMo12O40 in oxa-Pictet–Spen-
gler reaction of 1a and 2a (yields were determined by GC using
biphenyl as an internal standard); (B) XRD characterization before and
after catalyst recycling.
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Disposal of catalyst in cyclic experiment
The reaction system was centrifuged, the supernatant was
removed, the precipitation part (catalyst) was washed ve times
with ethyl acetate, dried under vacuum at 50 ꢀC for 2 h, and then
put into the next cycle again.
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
Financial support from the Research Found of East China
University of Technology (no. DHBK2019265, DHBK2019267,
DHBK2019264), the Open Fund of the Jiangxi Province Key Labo-
ratory of Synthetic Chemistry (JXSC202008), Natural Science
Foundation of Jiangxi Province, China (20202BABL203004),
National Natural Science Foundation of China (21804019,
22001034) are gratefully acknowledged.
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