Deep eutectic solvent-catalyzed Meyer-Schuster rearrangement of propargylic alcohols under mild and bench reaction conditions

Article abstract of DOI:10.1039/d0cc06584f

The Meyer-Schuster rearrangement of propargylic alcohols into α,β-unsaturated carbonyl compounds has been revisited by setting up an atom-economic process catalyzed by a deep eutectic solvent FeCl3·6H2O/glycerol. Isomerizations take place smoothly, at room temperature, under air and with short reaction times. The unique solubilizing properties of the eutectic mixture enabled the use of a substrate concentration up to 1.0 M with the medium being recycled up to ten runs without any loss of catalytic activity. This journal is

Full text of DOI:10.1039/d0cc06584f

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Deep eutectic solvent-catalyzed Meyer–Schuster
rearrangement of propargylic alcohols under mild
and bench reaction conditions†
Cite this:DOI: 10.1039/d0cc06584f
Received 1st October 2020,
Accepted 9th November 2020
Nicolas Rıos-Lombardıa,a Luciana Cicco,bc Kota Yamamoto,a
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c
Jose A. Hernandez-Fernandez,b Francisco Morıs,a Vito Capriati,
´
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a
Joaquın Garcıa-Alvarez *b and Javier Gonzalez-Sabın
*
DOI: 10.1039/d0cc06584f
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rsc.li/chemcomm
The Meyer–Schuster rearrangement of propargylic alcohols into solvents (DESs) are binary or ternary mixtures comprising at
a,b-unsaturated carbonyl compounds has been revisited by setting least one hydrogen bond acceptor (HBA) and at least one
up an atom-economic process catalyzed by a deep eutectic solvent hydrogen bond donor (HBD) with a melting point much lower
FeCl3Á6H2O/glycerol. Isomerizations take place smoothly, at room than that of either of the individual components and that of an
temperature, under air and with short reaction times. The unique ideal liquid mixture. DESs whose components come from renew-
solubilizing properties of the eutectic mixture enabled the use of a able sources have emerged as green solvents due to their low
substrate concentration up to 1.0 M with the medium being toxicity and volatility and have been progressively replacing
recycled up to ten runs without any loss of catalytic activity.
toxic and volatile organic compounds (VOCs) in many fields
such as catalysis, main-group chemistry, electrochemistry, solar
The last decades have witnessed extraordinary advances in technology, and food and pharmaceutical formulations.4 DESs
synthetic organic chemistry. Today, extensive compound showing Lewis type or Brønsted type acidity as well as other types
libraries are prepared by using combinatorial chemistry–robotics of catalytic influence in various reactions have been found to
and even the most complex natural products can be synthesized display key roles in several cornerstone organic transformations
in a laboratory. However, the environmental concerns imposed such as oxidations, aldol or pericyclic reactions as well as
by society today are forcing chemists to reshape the long- condensation and multi-component reactions.5 Among all the
established paradigms, while concepts such as biorenewable DESs, there is growing interest in those containing metallic salts
resources, sustainability or circular economy are being rapidly acting as either HBDs or HBAs because of their inherent catalytic
implemented in the chemical industry.1 Thus, besides the high properties. For example, a DES consisting of FeCl3Á6H2O and
yield and selectivity, a new synthetic process preferably must: mono-ethylene glycol (MEG) (2: 1) was shown to enable the
(i) be safe for both human beings and the environment, (ii) take conversion of cellulose into gluconic acid via sequential acidic
place under mild reaction conditions, (iii) be catalytic, and (iv) be hydrolysis and further oxidation of the transiently formed
performed using inexpensive and sustainable solvents. As a glucose.6
matter of fact, solvents account for about 80–90% of the total
mass used in any organic reaction, and 80–85% of the waste ment is the atom economical chemical transformation of
produced.2
propargyl alcohols into a,b-unsaturated carbonyl compounds.
First described in 1922,7 the Meyer Schuster (MS) rearrange-
In this context, the use of non-conventional media has It usually requires harsh conditions with strong acids as
brought new perspectives in many research fields.3 Deep eutectic catalysts, thereby competing with the Rupe reaction if the
propargylic alcohol has C–H bonds at the b-position.8 Indepen-
´
´
dent studies by the Cadierno and Garcıa-Alvarez groups have
shown that this rearrangement can take place with excellent
selectivity and result in neat water when mediated by Lewis acid
catalysts (e.g., In- and Ag(I)-based catalysts) (Scheme 1). It
required, however, temperatures up to 160 1C even with the
use of microwave irradiation.9 Milder conditions have been
a
´
EntreChem SL, Vivero Ciencias de la Salud. Santo Domingo de Guzman,
Oviedo, 33011, Spain. E-mail: jgsabin@entrechem.com
b
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Departamento de Quımica Organica e Inorganica, (IUQOEM),
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Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA),
´
Facultad de Quımica, Universidad de Oviedo, Oviedo, E-33071, Spain.
E-mail: garciajoaquin@uniovi.es
c
`
Dipartimento di Farmacia-Scienze del Farmaco, Universita di Bari ‘‘Aldo Moro’’,
used successfully with
a
Re(I)-based catalyst in neat
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, Bari I-70125, Italy
[BMIM][PF6] as ionic liquid (IL), at 80 1C and under a nitrogen
atmosphere, although the scope was restricted to terminal
† Electronic supplementary information (ESI) available: Experimental proce-
dures, 1H and 13C NMR spectra, HPLC analyses. See DOI: 10.1039/d0cc06584f
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We envisaged that the high concentration of catalytic species
within metallic LADESs containing Zn, Fe, Mn or Cu could
offset a lower reactivity. Isomerization of 1,1-diphenyl-2-
propyn-1-ol (1a) into 3,3-diphenylpropenal (1b) was selected
as a model reaction. The mild and bench-type reaction condi-
tions involved RT, under air, and 250 mM as substrate loading.
Preliminary screening revealed that only those DESs having
metallic salt as the HBA actively catalyzed the rearran-
gement (Table 1, entries 5,6). The mixtures FeCl3Á6H2O/Gly
(3 : 1 mol molÀ1) and FeCl3Á6H2O/MEG (2 : 1 mol molÀ1
)
emerged as optimal as they converted 1a into 1b in 10 min
only (Table 1, entries 6 and 7). When alternatively using ZnCl2/
Gly (2 : 1 mol molÀ1), the conversion reached 70% after 24 h
only (Table 1, entry 5). In all the other cases tested, even longer
reaction times (up to 24 h) did not lead to any measurable
conversion. A possible explanation might reside in the fact that
FeCl3 is the strongest Lewis acid of the series,13 being on the
same ground of reactivity of InCl3, which is a traditional
catalyst for MS rearrangements.9 Quite interestingly, the null
conversion displayed by the counterpart choline chloride
Scheme 1 Meyer–Schuster rearrangement of propargylic alcohols in
aqueous media or alternative non-conventional solvents.
(ChCl)-based DES, namely ChCl/FeCl3 (1 : 2 mol molÀ1
)
(Table 1, entry 2), revealed the critical role played by FeCl3 as
an HBA to ensure a successful outcome. How important is the
synergistic use of the two DES components and, thus, the
peculiar three-dimensional structure of the so-formed DES?
To answer this question, a solution of 1a in Gly was treated with
10 mol% of FeCl3Á6H2O. After 24 h at RT, HPLC analysis
revealed the presence of exclusively the starting material and
by-products (Table 1, entry 10). Even upon increasing the
concentration of FeCl3Á6H2O up to 40 mol%, a very low con-
version was detected (Table 1, entry 11). To gain more insights
into the influence of the nature of the solvent, the reaction was
run into three prototypical eutectic mixtures, namely ChCl/Gly
(1 : 2 mol molÀ1), ChCl/MEG (1 : 2 mol molÀ1) and ChCl/H2O
(1 : 2 mol molÀ1) using 10 mol% of FeCl3Á6H2O, as well as in
toluene and water. The reaction profile in toluene revealed low
conversion and the formation of some unidentified products
(Table 1, entry 16), whereas in the three DESs and water only
the starting material was recovered (Table 1, entries 12–15). We
conclude that the reaction is not or poorly affected by iron-
based catalysts as such. This is in agreement with the few
reports on Fe-catalyzed MS isomerizations.14 At the same time,
the poor solubility of FeCl3 in those eutectic mixtures at RT, as
well as of 1a in water, poses critical pitfalls to approaching a
manufacturing setting. The results compiled in Table 1 indicate
the importance of the nanostructure of the DES on the reactivity
of FeCl3Á6H2O/Gly (3 : 1 mol molÀ1), which enhanced the catalytic
activity of iron species and displayed high-solubilization power.
By capitalizing on these results, we then evaluated the scope
of the reaction by treating several propargylic carbinols with
FeCl3Á6H2O/Gly at RT and under air (Table 2). Aryl-containing
propargylic alcohols 2a–7a bearing either electron-donating or
electron-withdrawing groups (Table 2, entries 2–7) underwent a
smooth MS rearrangement, thereby providing unsaturated
aldehydes 2b–7b in 85–92% yields. On the other hand, aliphatic
alcohols 8a–10a, bearing a C–H bond at the b-position, required
alkynes.10 Herein, we unveil the unique catalytic properties of
the eutectic mixture FeCl3Á6H2O/glycerol (Gly) (3 : 1 mol molÀ1
)
to promote smooth MS rearrangements, working at room
temperature (RT, 25 1C) and under air.
From the extensive list of Lewis acidic DESs (LADESs)
available,11 we selected 8 mixtures bearing metal halides as
HBDs or HBAs (Table 1). The MS rearrangement has been
traditionally monopolized by using noble metal-containing
complexes based on Au, Ag or Ru working in toxic VOCs.12
Table 1 MS rearrangement of 1,1-diphenyl-2-propyn-1-ol (1a) catalyzed
by metallic LADES or solvents at RT and under aira
Entry LADES or solventb
Catalyst (% mol) Time (min) cc (%)
d
1
2
3
4
5
6
7
8
ChCl/ZnCl2 (1 : 2)
ChCl/FeCl3Á6H2O (1 : 2)
ChCl/MnCl2Á4H2O (1 : 2)
ChCl/CuCl2Á2H2O (1 : 2)
ZnCl2/Gly (2 : 1)
FeCl3Á6H2O/Gly (3 : 1)
FeCl3Á6H2O/MEG (2 : 1)
MnCl2/Gly (2 : 1)
CuCl2Á2H2O/Gly (2 : 1)
Gly
—
—
—
—
—
—
—
—
240
240
240
240
240
10
—
—
—
—
d
d
d
20e
499
499
10
d
240
240
240
240
240
240
240
240
240
—
d
9
—
—
d
10
11
12
13
14
15
16
FeCl3 (10)
FeCl3 (40)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
—
Gly
10
d
ChCl/Gly (1 : 2)
ChCl/MEG (1 : 2)
ChCl/H2O (1 : 2)
H2O
—
d
—
d
—
d
—
Toluene
15
a
Reactions performed under air, at RT using 0.2 mmol of 1a (250 mM).
b
c
d
The ratio is in molar ratio. Conversion measured by HPLC. Null
e
conversion after 24 h. 70% conversion after 24 h.
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Table 2 FeCl3Á6H2O/Gly (3 : 1 mol molÀ1)-catalyzed isomerization of
propargylic alcohols under air and mild reaction conditionsa
T
Time
cc
Yieldd
Entry Substrate
1b
(1C) (min) Product
(%) (%)
RT
RT
RT
10
10
10
499 85
Fig. 1 Work-up and recycling procedures for the MS rearrangement in
FeCl3Á6H2O/Gly (3 : 1 mol molÀ1) using different solvents.
2
3
499 86e
499 85
performance within 10 min reaction time (Table 2, entry 1).
A one-gram-scale isomerization of 1a (250 mM) proved to be
equally feasible, with 1b being isolated in a slightly higher yield
(88%). On the other hand, the intrinsic concentration of FeCl3
makes the recyclability of the DES mandatory to attain a
sustainable and catalytically-sound process. Thus, we devised
two possible reaction workups enabling the isolation of pro-
ducts. The first one consisted of an extraction step using an
organic solvent. As depicted in Fig. 1, the tested solvents were
classified into three groups: (i) miscible with DES, (ii) immis-
cible with DES but ineffective in the extraction, and (iii) immis-
cible with DES and effective in the extraction. The first
group comprising environmentally friendly candidates such
as cyclopentyl methyl ether (CPME), 2-methyl tetrahydrofuran
(2-Me-THF) or dimethyl isosorbide (DMI), was discarded for
obvious reasons. As for the second group, n-hexane and cyclo-
hexane led to two phases, but the target products could be
poorly extracted. Finally, some successful candidates were
identified, namely toluene, CH2Cl2, CHCl3 and cyrene, which
remained immiscible with DES. These solvents extracted the
product efficiently leaving the iron in the lower DES phase. In
terms of sustainability, cyrene, which is a bio-based solvent
obtained from cellulose,15 is highly recommended compared to
chlorinated derivatives. By using cyrene, the recyclability of the
catalytic system was assessed in the isomerization of 1a under
the conditions described in Table 2 (see the ESI†). As a result,
10 consecutive runs were successfully accomplished, each with
10 min reaction time (c 499%). Going further, the second
workup involved the challenge of avoiding any organic solvent.
Indeed, inspection of the crude reaction mixture revealed that
the MS rearrangement of internal propargylic alcohols like 11a
allowed the precipitation of a solid. The reaction mixture was
then diluted with water and the solid was filtered off, thus
providing pure 11b, whereas the DES was easily reconstituted
from the filtrate by evaporation of water. Following this proce-
4
RT
10
499 90
5
6
7
8
RT
RT
40
10
10
60
499 85
499 92
499 88
499 45f
40 480
40 480
9
499 60f
499 65f
10
40 480
11
12
13
RT
RT
RT
RT
30
30
30
30
499 92
499 90
499 75
499 92
14
a
Reactions performed under air, using 0.2 mmol of alcohol (250 mM).
Reaction performed at 1.0 M of 1a. Measured by HPLC. Isolated
b
c
d
e
f
yield after filtration through silica gel. E/Z ratio was 86 : 14. The yield
was affected by the volatility of the products.
a slight heating to 40 1C and at 8 h to be fully converted to dure, the DES could be reused for 10 consecutive cycles without
a,b-unsaturated methyl ketones 8b–10b as a result of Rupe using VOCs in any step (c 499%, see the ESI†).
rearrangement (Table 2, entries 8–10).8 Typically, Rupe-type
Finally, we investigated the utility of FeCl3Á6H2O/Gly to
rearrangements demand more drastic conditions than the MS promote some synthetic transformations involving catalytic
counterparts.9,10 Finally, internal propargylic alcohols 11a–14a FeCl3 in organic solvents (Scheme 2, see the ESI† for details).
were also isomerized to the corresponding enones 11b–14b First, the hydration of phenylacetylene (15) to afford acetophe-
(75–92% yields) at RT within 30 min reaction time (Table 2, none (16) was essayed at 300 mM in FeCl3Á6H2O/Gly. The
entries 11–14). Once the substrate scope was assessed, we process showed complete conversion after 18 h at 45 1C in
turned our attention to the greenness and applicability of the the absence of any co-catalyst/co-solvent,16 and the catalytic
process. We first tried to set out
a better volumetric system was recycled up to 4 runs (c 495%). It is worth
productivity. Pleasingly, by increasing the substrate (1a) mentioning that such reactions, when run in 1,4-dioxane and
loading from 250 mM to 1 M, we achieved a similar at 80 1C in the presence of 10% mol of FeCl3, required up to
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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Scheme 2 Reactions catalyzed by DES FeCl3Á6H2O/Gly (3 : 1 mol molÀ1).
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negligible yield.17 Some years ago, an efficient synthesis of
2-oxazolines and 2-oxazoles was reported to take place via a
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FeCl3 in chlorinated solvents.18 As a proof of concept, N-prop-2-
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into 5-methyl-2-phenyloxazole (18) at 40 1C within 4 h in FeCl3Á
6H2O/Gly, and the catalytic system was recycled up to 5 runs
(c 499%). Finally, we ascertained that the hydrolysis of several
methyl benzoate esters (19–22) could smoothly be accom-
plished within 14 h at 70 1C (90–499% conversion) in FeCl3Á
6H2O/Gly to afford the corresponding acids (23–26) in
85–95% yields (ESI†), whereas the traditional FeCl3-promoted
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115 1C in a sealed tube when using trichloroethylene as the
solvent.19 The Fe-based DES was stable at 70 1C, and thus it
could be efficiently recycled for 5 runs (see the ESI†).
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