A solvent-free catalytic protocol for the Achmatowicz rearrangement

Article abstract of DOI:10.1039/c8gc03030h

Reported here is the development of an environmentally friendly catalytic (KBr/oxone) and solvent-free protocol for the Achmatowicz rearrangement (AchR). Different from all previous methods is that the use of chromatographic alumina (Al₂O₃) allows AchR to proceed smoothly in the absence of any organic solvent and therefore considerably facilitates the subsequent workup and purification with minimal environmental impacts. Importantly, this protocol allows for scaling up (from milligram to gram), recycling of the Al₂O₃, and integrating with other reactions in a one-pot sequential manner.

Full text of DOI:10.1039/c8gc03030h

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A solvent-free catalytic protocol for the
Achmatowicz rearrangement†
Cite this: Green Chem., 2019, 21, 64
a,b
Guodong Zhaoa and Rongbiao Tong
*
Received 26th September 2018,
Accepted 17th November 2018
DOI: 10.1039/c8gc03030h
rsc.li/greenchem
Reported here is the development of an environmentally THF/H2O (4/1) solution was identified as the most effective
friendly catalytic (KBr/oxone) and solvent-free protocol for the solvent system, partially due to the optimal solubility of both
Achmatowicz rearrangement (AchR). Different from all previous organic substrates (furfuryl alcohols) and inorganic reagents
methods is that the use of chromatographic alumina (Al2O3) allows used (oxone and KBr). From the point of view of green chem-
AchR to proceed smoothly in the absence of any organic solvent istry, the THF/H2O solvent system is still not ideal and pre-
and therefore considerably facilitates the subsequent workup and cludes subsequent transformations such as O-acetylation and
purification with minimal environmental impacts. Importantly, this O-Boc protection, in a one-pot manner. Herein, we report our
protocol allows for scaling up (from milligram to gram), recycling recent efforts that led to the development of a solvent-free cata-
of the Al2O3, and integrating with other reactions in a one-pot lytic protocol for the AchR (Fig. 1). This new protocol rep-
sequential manner.
resents the first example of a solvent-free catalytic AchR with
broad substrate scope, and importantly enables us for the first
time to further functionalize the AchR products in a one-pot
sequential manner, which tremendously reduces the use of
organic solvents in the liquid–liquid extraction workup and
purification.
The Achmatowicz rearrangement (AchR) is the choice reaction
for the synthesis of versatile dihydropyranone acetals,1–5 key
synthetic precursors for functionalized tetrahydropyrans, dihy-
dropyranones, oxidopyrylium, δ-lactones, and pyranoses.6–15
Therefore, the AchR continues to attract much attention from
the synthetic and medicinal communities and to find wide
applications in the total synthesis of natural products, includ-
ing >17 natural products from our lab.16–25 The increasing
importance of the AchR has led to the development of many
new efficient methods by identifying new oxidants,26–41 and
two oxidants, namely N-bromosuccinimide (NBS)42 and
m-chloroperoxybenzoic acid (m-CPBA),43 were found to be
among the most efficient ones. However, the use of these stoi-
chiometric oxidants produces quantitative amounts of the
organic byproduct of m-chlorobenzoic acid or succinimide,
which usually requires immediate column chromatography for
purification. To address this problem associated with the
environmental concern from the organic byproducts, we pre-
viously developed a green catalytic protocol44 for the AchR by
the identification of 5 mol% KBr as the catalyst and oxone as
the stoichiometric terminal oxidant. In this new protocol, a
The development of a solvent-free45 process for organic
reactions is a green chemistry approach because organic sol-
vents are ecologically harmful and the largest contributors to
the magnitude of the E factor.46 The additional advantages of
solvent-free conditions include low cost and reduced reaction
time.47,48 In particular, catalytic processes under solvent-free
conditions greatly reduce the environmental impact and econ-
omic cost.49 Nevertheless, there are relatively few processes
using catalysis under solvent-free conditions. This paucity is
not unexpected because catalyst efficiency is usually very sensi-
tive to the solvent properties and concentration.50 In this
context, we sought a solid reaction medium that could support
our solid catalyst (KBr) and oxidant (oxone) for the reaction
with liquid substrates (furfuryl alcohols). A literature search
aDepartment of Chemistry, The Hong Kong University of Science and Technology,
Clearwater Bay, Kowloon, Hong Kong, China. E-mail: rtong@ust.hk;
Fax: +(852)23581594; Tel: +(852) 23587357
bHKUST Shenzhen Research Institute, Shenzhen 518057, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03030h
Fig. 1 Our new solvent-free catalytic protocol for the Achmatowicz
rearrangement (AchR).
64 | Green Chem., 2019, 21, 64–68
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and our initial experimental attempts led us to identify chro-
matographic neutral alumina (Al2O3, Merck KGaA,
70–230 mesh, and pH = 6.8–7.8) as the ideal medium.51,52
We first examined and optimized the AchR reaction of 1a
using Al2O3 as the reaction medium (Table 1). To our delight,
82.7% yield of the AchR product 2a was obtained in only
5 min when 1a suspended in Al2O3 was mixed and stirred with
KBr (10 mol%), oxone (1.5 equiv.), H2O (10 eq.) and NaHCO3
(6 eq.) at room temperature (entry 1). Control experiments
suggested that Al2O3 (entry 2), H2O (entry 3), KBr (entry 4) and
NaHCO3 (entry 5) were indispensable for good yields. Notably,
the reaction time was significantly reduced from 30 min (THF/
H2O/oxone/KBr) to 5 min (Al2O3/oxone/KBr). Further optimi-
zations (entries 6–12) allowed for the substantial reduction of
the quantity of oxone, Al2O3, NaHCO3 and H2O without com-
promising the high yield. The product 2a was isolated from
the reaction mixture by simple filtration with ethyl acetate and
the 1H-NMR spectrum of the concentrated filtrate (crude 2a)
was very clean (Fig. 2). Therefore, this new protocol could elim-
inate the liquid–liquid extraction (and drying) used in the
workup/purification of all prior methods.
Fig. 2 1H-NMR spectrum of the crude 2a.
Table 2 The substrate scope for the solvent-free AchRa
With the optimized conditions in hand, we set out to
examine the substrate scope (Table 2). Generally, a variety of
furfuryl alcohols could be employed for the AchR under these
solvent-free conditions, which demonstrated comparable
efficiency and generality to those solvent-mediated processes.
Furfuryl alcohol derivatives bearing ester (1j, 1o, and 1w),
alkene (1f–i), ketone (1m), Weinreb amide (1k), electron-rich
arenes (1x–ac), and sulfonamide (1n and 1p) at the 2- or 5-posi-
Table 1 Optimization of the AchR reaction of 1a under the solvent-free
conditions
b
Al2O3
(mg)
H2O
KBr
Oxone
(eq.)c
NaHCO3
(eq.)c
Yieldd
(2a, %)
Entrya
(eq.)c
(eq.)c
1
2
3
4
5
6
7
8
100
0
10
10
0
10
10
10
10
10
10
2
0.1
0.1
0.1
0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.5
1.5
1.5
1.5
1.5
1
0.6
1
1
6
6
6
6
0
6
6
6
6
6
6
1
82.7
20.7
0
a Reaction conditions: Furfuryl alcohol (0.2 mmol), KBr (0.1 eq.), oxone
(1.0 eq.), H2O (2.0 eq.), NaHCO3 (1.0 eq.), Al2O3 (120 mg), room tem-
perature, 5 min, and isolated yield. b Reaction conditions: Furyl alcohol
(0.2 mmol), KBr (0.4 eq.), oxone (2.0 eq.), H2O (8.0 eq.), NaHCO3
(2.0 eq.), Al2O3 (240 mg), room temperature, and 10 min.
100
100
100
100
100
30
20
30
30
30
31.9
50.7
81.4
55.9
82.3
56.7
84.3
78.4
91
9
10
11
12
1
1
1
1
2
tion of furan were excellent substrates for the AchR to provide
the corresponding dihydropyranone acetals in good to excel-
lent yields (72–97%). Notably, there were no potentially com-
peting side reactions, including arene bromination,53,54 alkene
dibromination,55 and alcohol oxidation,56 all of which have
been reported when the combination of oxone and stoichio-
a The reaction was carried out at room temperature: 1a (0.05 mmol)
suspended in Al2O3 was mixed and stirred vigorously with H2O, KBr
and NaHCO3 for 5 min. b Al2O3 was activated at 120 °C for 48 h. c The
equivalent of different materials to 1a. d Yield was determined by
1H-NMR of the crude reaction mixture using CH2Br2 as the internal
reference.
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metric alkali bromide was used. Heterocycles (1r–t) and the
widely used protecting groups like TIPS (1z), TBS (1ab and 1u),
Boc (1aa) and Bn (1v) were also well tolerated in our solvent-
free, catalytic AchR to afford the desired products in excellent
yields (81−96%).
To demonstrate the additional value (environmental
benefit) of our solvent-free catalytic protocol over the corres-
ponding solvent-mediated process, we recycled the alumina
(Al2O3) six times without any noticeable decrease of the
efficiency for the gram-scale reaction (Table 3). It was noted,
Scheme 1 Solvent-free, one-pot, two-step reactions involving the
AchR.
however, that more water and
a longer reaction time
(25–35 min) were needed to achieve the high yield for the re-
cycling system. Remarkably, the recycling process was very
simple (Fig. 3): after the completion of the reaction, the reac-
tion mixture (solid) was transferred to a Buchner funnel (or a O-allylation, to examine such
a possibility (Scheme 1).
short chromatography column with cotton plug) for filtration Oxidation of the AchR product 2d to 5-hydroxy-2-pyrone 3 was
washed with ethyl acetate; the filter cake containing Al2O3 and successfully achieved in a one-pot, solvent-free manner by
inorganic salts (K2SO4, KBr, and an excess of oxone) could be using oxone/TEMPO (cat).60 Of note, KBr was used as the dual-
reused directly without further activation or purification. This role catalyst for both the AchR and subsequent oxidation. The
easy recycling operation largely benefited from the use of sequential reactions were performed as follows: treatment of
oxone and KBr, which did not produce organic byproducts. furfuryl alcohol 1d (0.2 mmol) suspended in Al2O3 (120 mg)
Additionally, these solvent-free conditions did not require with oxone (123 mg, 1.0 eq.), KBr (7.1 mg, 0.3 eq.), H2O
specialized equipment such as a ball mill/mixer used in (7.2 μL, 2.0 eq.), and NaHCO3 (16.8 mg, 1.0 eq.) and the reac-
mechanochemistry.57–59
tion mixture was stirred vigorously at room temperature for
To further exploit the synthetic advantages of our protocol 2 min, then to this reaction mixture were added oxone
over solvent-assisted methods, we were attracted to explore the (246 mg, 2.0 eq.) and catalytic TEMPO (6.25 mg, 0.2 eq.), the
possibility of solvent-free, one-pot, sequential reactions. We solid reaction mixture was stirred for 10 min, and then filtered
selected four important transformations of the AchR products, through a pad of silica gel with ethyl acetate to remove the
i.e., oxidation, O-acetylation, O-Boc protection, and solid byproduct and Al2O3, and concentrated in a vacuum, to
provide 3 in 84% overall yield. This is remarkable because we
have realized two solvent-free catalytic reactions in a one pot.
Table 3 Recycling use of Al2O3 (4.28 g) for the gram-scale AchR of 1d
Next, we derivatized 2d as acetate 4 and tert-butyl carbonate 5
in excellent yields (89% and 86% for two steps) by adding
Ac2O/DMAP and (Boc)2O/DMAP, respectively, to the reaction
vessel of the AchR. O-Acetylation and O-Boc protection are
among the most used direct transformations of the AchR pro-
ducts since they afford substrates for O-glycosylation,61,62
[5 + 2]-cycloaddition, and C-arylation. Surprisingly, these trans-
formations have been conventionally performed with the puri-
fied AchR products in a separate reaction vessel because the
stoichiometric byproduct from the oxidant (m-CPBA, NBS, tert-
BuOOH, Br2/MeOH, etc.) or aqueous reaction medium of the
AchR did not permit a one-pot anhydrous acetylation. The
final example of our sequential reactions was O-alkylation of
2d in 73% yield by adding Ag2O (92.7 mg, 2.0 eq.) and allyl
bromide (69 μL, 4.0 eq.) to the solvent-free AchR mixture.
Importantly, no aqueous workup was needed for all these two-
step, one-pot, solvent-free reactions and the products (3–6)
could be purified easily by transferring the solid reaction
mixture to the top of the silica gel in a chromatography
column eluting with hexane/ethyl acetate.
Entrya
H2O (eq.)
Time (min)
Yield (%)
1
2
3
4
5
6
3 eq.
6 eq.
6 eq.
6 eq.
9 eq.
9 eq.
10
10
15
20
25
35
92
91.6
91.2
91
90.9
90.2
a After filtration with ethyl acetate, the filtrate cake (Al2O3) was air-
flushed to dryness for re-use.
Nevertheless, we recognized that the one-pot, solvent-free
conditions could not be extended to the AchR–Kishi reduction
or AchR–Ferrier allylation. Since the Kishi reduction and
Ferrier-type allylation have been widely used for the synthesis
of tetrahydropyrans from the AchR products, we aimed to
Fig. 3 Workflow diagram of the gram-scale, solvent-free AchR with
recycling of Al2O3.
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found that an excess of BF3–Et2O (8.0 eq.) could effect the
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Conclusions
In summary, we have established a solvent-free catalytic proto-
col for the AchR, representing the greenest conditions to date.
The efficiency and utility of this new protocol was demon-
strated with (1) 29 examples, (2) six-times recycling of Al2O3 on
a gram scale, (3) the successful integration of oxidation,
O-acylation or O-allylation as a one-pot solvent-free reaction,
and (4) one-pot AchR/Kishi reduction and AchR–Ferrier allyl-
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previous methods include no solvent, no stoichiometric
organic byproduct generated from the oxidant, no liquid–
liquid extraction in the workup, and no column chromato-
graphy for purification. Furthermore, this new protocol is
operationally simple and does not require specialized equip-
ment (ball mill). It is expected that this new green protocol
will aid the application of the AchR in organic synthesis and
drug discovery.
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