Mechanochemically Initiated Achmatowicz Rearrangement

Article abstract of DOI:10.1080/00397911.2014.963624

The Achmatowicz rearrangement converts furfuryl alcohols, obtainable from renewable carbohydrates, into 6-hydroxy-2H-pyrane-3(6H)-ones, which are versatile intermediates for organic synthesis. We describe here the first examples of a solvent-free mechanochemical Achmatowicz rearrangement. Furfuryl alcohols were prepared from furfurals using mechanochemically initiated reductions and Reformatsky reactions. Mechanochemical reaction conditions for the Achmatowicz rearrangement of the obtained furfuryl alcohols were optimized and applied to a series of derivatives, yielding the corresponding rearrangement products in yields of 39 to 95%. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.963624

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Mechanochemically Initiated
Achmatowicz Rearrangement
a
a
a
Carolin Falenczyk , Benjamin Pölloth , Petra Hilgers & Burkhard
a
König
a
Institute of Organic Chemistry, University of Regensburg,
Regensburg, Germany
Accepted author version posted online: 14 Oct 2014.Published
online: 13 Dec 2014.
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To cite this article: Carolin Falenczyk, Benjamin Pölloth, Petra Hilgers & Burkhard König
2014): Mechanochemically Initiated Achmatowicz Rearrangement, Synthetic Communications:
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Synthetic Communications , 0: 1–7, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2014.963624
MECHANOCHEMICALLY INITIATED ACHMATOWICZ
REARRANGEMENT
Carolin Falenczyk, Benjamin Pölloth, Petra Hilgers, and
Burkhard König
Institute of Organic Chemistry, University of Regensburg, Regensburg,
Germany
GRAPHICAL ABSTRACT
Abstract The Achmatowicz rearrangement converts furfuryl alcohols, obtainable from
renewable carbohydrates, into 6-hydroxy-2H-pyrane-3(6H)-ones, which are versatile
intermediates for organic synthesis. We describe here the first examples of a solvent-free
mechanochemical Achmatowicz rearrangement. Furfuryl alcohols were prepared from
furfurals using mechanochemically initiated reductions and Reformatsky reactions.
Mechanochemical reaction conditions for the Achmatowicz rearrangement of the
obtained furfuryl alcohols were optimized and applied to a series of derivatives, yielding
the corresponding rearrangement products in yields of 39 to 95%.
Keywords Achmatowicz rearrangement; ball mill; furfural; mechanochemistry;
solvent-free
INTRODUCTION
Compounds derived from carbohydrates are a sustainable alternative to
oil-based chemicals and their use in chemical synthesis becomes more important with
depleting fossil carbon resources. In particular, the synthesis of furans from carbo-
hydrates is well established and a long-known route. Furfural (1a) is readily obtained
Received September 4, 2014.
Address correspondence to Burkhard König, Institute of Organic Chemistry, University of
Regensburg, Regensburg 93040, Germany. E-mail: burkhard.koenig@chemie.uni-regensburg.de
1

2
C. FALENCZYK ET AL.
Figure 1. Carbohydrate-based chemicals furfural (1a) and HMF (1b) and the Achmatowicz rearrangement.
1]
[
from hemicellulose by acid catalysis and the dehydration of fructose over solid acid
[
2]
catalysts gives 5-hydroxymethylfurfural (HMF, 1b). However, a broader synthetic
applicability of the heteroarenes as starting materials is limited by their stability.
An elegant way to introduce functionality and increase their chemical reactivity is
the Achmatowicz rearrangement, leading to 6-hydroxy-2H-pyrane-3(6H)-ones
[
3]
(
Fig. 1). These pyranones are valuable synthetic intermediates, which have been
[
4]
[5]
used in the synthesis of antimicrobials, monosaccharides and their analogs,
natural products, and several drugs.
[
6]
Several methods have been developed for the Achmatowicz rearrangement,
allowing a one-step procedure from a furfural alcohol derivative to the correspond-
ing 6-hydroxy-2H-pyrane-3(6H)-one. The Achmatowicz rearrangement requires
[
6a]
a stoichiometric oxidant like N-bromosuccinimide (NBS)
or m-chloroperoxy-
[
4]
benzoic acid (mCPBA), which are the most commonly used oxidizing reagents,
but also catalysts such as vanadyl acetylacetonate (VO(acac) ) or titanium tetra
2
(
isopropoxide) (Ti(Oi-Pr) ) in combination with tert-butylhydroperoxide are suitable
4
[
7]
[8]
[9]
oxidizing agents. Enzymatic or singlet oxygen -mediated oxidations have also
been reported. The Achmatowicz reaction in solution is well established. Alternative
solvent-free reaction conditions could be mechanochemically performed in a ball
mill. Mechanochemistry is so far only rarely applied in organic synthesis, but offers
particular advantages if reactants are insoluble, their solubility is incompatible, or
[10]
solvents should be entirely avoided.
Herein, we describe the first mechanochemical Achmatowicz reaction of fur-
furyl alcohols to 6-hydroxy-2H-pyrane-3(6H)-ones. The furfuryl starting materials
are derived from carbohydrate precursors and were also obtained from ball milling
under solvent-free reaction conditions.
RESULTS AND DISCUSSION
Mechanochemical Synthesis of Starting Materials
Furfural (1a) and its derivatives were used to obtain starting materials for the
Achmatowicz rearrangement under solvent-free mechanochemical reaction con-
ditions. Naimi-Jamal et al. already demonstrated the reduction of 1a to furfuryl alco-
[
11]
hol (2a) through ball milling with sodium borohydride.
Common reduction
[
12]
[12,13]
[12,13]
strategies such as Grignard,
Reformatsky,
or Luche reactions
were

MECHANOCHEMICAL ACHMATOWICZ REARRANGEMENT
3
Table 1 Synthesis of furfuryl alcohol derivatives through ball milling
a
Entry
Reactant A
Reactant B
A/B
Product
Yield (%)
b
1
1:3
38
2
NaBH
4
4
1:10
1:10
Traces
c
3
NaBH
72 /64
a
Yields were not optimized.
w%: Zn:NH Cl:1a = 10:4:1.
4
b
c
The reaction was performed with additional choline chloride.
previously also investigated under solvent-free conditions. Following these methods
we performed the reduction on selected furfuryl derivatives through ball milling,
yielding substituted furfuryl alcohol derivatives, which served as precursors for the
Achmatowicz rearrangement (Table 1). All reactions were performed in a planetary
ball mill containing 10 agate milling balls (8–10 mm) with a drive of 425 rpm and
a reaction time of 60 min.
The Reformatsky reaction (Table 1, entry 1) in the ball mill uses zinc as the
[14]
reduction agent. The sodium borohydride reduction of 5-hydroxymethylfurfural
HMF) (1b) (Table 1, entry 2) and ketone 1c (Table 1, entry 3) through ball milling
afforded the corresponding alcohol 2e in good yield, but compound 2d was only
(
[
15]
obtained in traces and synthesized according to literature. The addition of choline
chloride as an additive was investigated in the conversion of ketone 1c (Table 1, entry
3
) and gave a slightly improved yield of 72%. Furfuryl alcohol (2a) and DL-1-(2-
furyl) ethanol (2b) are commercially available as starting materials for the
Achmatowicz rearrangement.
Mechanochemical Achmatowicz Rearrangement
The reaction conditions (Table 2) such as oxidant, solid support, and ball mill
parameters for the Achmatowicz rearrangement were optimized using furfuryl
alcohol (2a). All reactions were performed in a planetary ball mill containing 10
agate milling balls (8–10 mm) with 425 rpm.
Although NBS is one of the most common oxidizing agents for the
Achmatowicz reaction, 3a was not obtained (Table 2, entries 1–4). The same result
was observed for the use of manganese oxide (MnO ) (Table 2, entry 5) or potassium
2
permanganate (KMnO ) (Table 2, entry 6). Variation of the starting material to 2b,
4
the addition of water, or the change of the solid support did not yield the expected

4
C. FALENCZYK ET AL.
a
Table 2 Mechanochemical Achmatowicz reaction of 2a with different oxidants
Entry
[O]
Time (min)
Solid support
2a/[O]
Yield (%)
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
30
30
30
60
60
60
30
30
Al
Al
2
O
O
3
1:1
1:2
1:1
1:1
1:1
1:2
1:1
1:1
—
—
—
—
—
—
45
47
2
3
Quartz sand
Quartz sand
Quartz sand
Quartz sand
MnO
2
KMnO
mCPBA
mCPBA
4
Al O
2 3
Quartz sand
a
2a / solid support = 1:10.
Achmatowicz product. However, the use of mCPBA resulted in the desired product
a (Table 2, entries 7 and 8). The reaction was performed in the presence of acidic α
aluminium oxide (α-Al O ) or quartz sand. The solid supports showed no significant
3
-
2
3
difference in yield (45% and 47%) under similar reaction conditions. Quartz sand
proved to be advantageous in the workup, as it is removed by filtration. The
Table 3 Variation of reaction time and ratio of 2a and mCPBA
Entry
2a/mCPBA
Time (min)
Yield (%)
1
2
3
4
5
6
7
1:1
1:1
1:1
1:1
1:2
1:2
1:2
7
39
53
47
45
64
92
95
15
30
60
7
15
30
Table 4 Comparison of different reported Achmatowicz rearrangement methods with ball milling
conditions
Entry
Method
Reagent
Yield (%)
1
2
3
4
5
6
mCPBA (ball mill)
mCPBA (solvent free, no ball mill)
2a
2a
2a
2a
2a
2b
95
80
48
88
73
63
[
4]
mCPBA (first publication)
[16]
mCPBA (solvent: CH
Cl
2 2
)
[
3]
[
2
Br /MeOH
NBS/MeOH
6a]

MECHANOCHEMICAL ACHMATOWICZ REARRANGEMENT
5
variation of the reaction time and the ratio between 2a and the oxidant mCPBA
(Table 3) increased the product yield further to 95% in 30 min.
A yield of 92% is already obtained after 15 min (Table 3, entry 6). Long ball
milling times (Table 3, entry 4) may decrease the product yield due to thermal
decomposition of the product.
a
Table 5. Mechanochemically initiated Achmatowicz rearrangement with furfuryl alcohol derivatives
Entry
Reagent
Time (min)
Product
Yield (%)
1
30
95
2
3
4
15
30
71 [dr 2:1]
84 [dr 3:1]
b,c
d
e
30
63, 55, 45
5
105
—
—
a
Ratio of reagent / mCPBA = 1:2.
b
c
5:1 mixture of 3d and the corresponding hemiacetal 5.
w%: 2d / choline chloride = 1:1.
d
w%: 2d / choline chloride / quartz sand = 1:1:8.
w%: 2d / quartz sand = 1:10.
e

6
C. FALENCZYK ET AL.
Table 4 compares literature-reported methods for the Achmatowicz reaction
with our optimized mechanochemical conversion (Table 4, entry 1) of furfuryl
[
3,4,16]
alcohol 2a to 6-hydroxy-2H-pyrane-3(6H)-one (3a). The ball mill gives good yields
without using solvents or external cooling of the reaction mixture (Table 4, entries
3
–6). To illustrate the effect of continuous ball milling on the reaction progress,
the identical reaction mixture was ground and mixed, yielding 80% of product
Table 4, entry 2).
The reaction protocol for the Achmatowicz rearrangement in a ball mill was
(
then applied to several furfuryl alcohol derivatives (Table 5).
1
To investigate if the size of R (Table 5) influences the Achmatowicz rearrange-
ment, the furfuryl derivatives 2b and 2c were used under the optimized reaction
conditions. Both reactions afforded the expected product in good yields. Neither
the methyl group of 2b nor the more bulky ethyl ester group of 2c affect the forma-
tion of the Achmatowicz reaction (Table 5, entries 2 and 3). For 2b a reaction time of
1
5 min was sufficient (Table 5, entry 2). Furan-2,5-diyldimethanol (2d) was tested
as a solid starting material in the Achmatowicz reaction. This reaction gave the
expected product 3d in moderate yield in a 5:1 mixture with the corresponding
hemiacetal 5. The conditions for the solid starting material 2d were modified using
only choline chloride without quartz sand, which increased the yield from 45% (only
quartz sand), 55% (choline chloride and quartz sand), to 63%. The Achmatowicz
rearrangement for furfuryl alcohol 2e did not proceed in the ball mill. The
conversion of 2e by the Achmatowicz rearrangement has not been described by other
methods. A reason for this could be the complete loss of the aromaticity of the
benzofuran moiety of 2e.
CONCLUSION
In summary, we have described the first mechanochemically initiated
Achmatowicz rearrangement in a planetary ball mill using mCPBA as oxidant,
quartz sand as solid support, and choline chloride as additive. Using optimized
reaction conditions, furfuryl alcohol derivatives were converted to the corresponding
6
1
-hydroxy-2H-pyrane-3(6H)-ones with yields up to 95% and reaction times of only
5 to 30 min. The starting materials for the Achmatowicz reaction were likewise
obtained through ball milling: Mechanochemically initiated reductions or Refor-
matsky reactions of furfural (1a) and derivatives gave access to different substituted
furfuryl alcohol derivatives.
The mechanochemically initiated Achmatowicz rearrangement is an efficient
alternative procedure to reported methods in solution to obtain valuable inter-
mediates for organic synthesis from renewable bulk chemicals.
EXPERIMENTAL
[
17]
6
-Hydroxy-2H-pyran-3(6H)-one (3a)
The agate beaker was equipped with 10 agate milling balls, quartz sand (1.50 g),
a (87 µL, 1.0 mmol), and mCPBA (345 mg, 2.0 mmol) and milling was performed for
0 min. The reaction mixture was diluted with water (15 mL) and filtered. The water
2
3
was removed by lyophilisation, and 3a (108 mg, 95%) was thus obtained as yellow

MECHANOCHEMICAL ACHMATOWICZ REARRANGEMENT
7
1
solid. H NMR (400 MHz, CDCl ): d = 6.96 (dd, 1H, J = 3.1, 10.4 Hz, 5-H), 6.17 (d,
3
1
4
H, J = 10.4 Hz, 4-H), 5.64 (d, 1H, J = 3.1 Hz, 6-H), 4.58 (d, 1H, J = 16.9 Hz, 2-H),
.14 (d, 1H, J = 16.9 Hz, 2-H).
FUNDING
Financial support by the Fonds der chemischen Industrie is gratefully
acknowledged.
SUPPORTING INFORMATION
1
Full experimental data and H NMR data for compounds 2c,e and 3b,c,d can
be accessed on the publisher's website.
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