4-hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

Article abstract of DOI:10.3762/bjoc.10.116

Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products.

Full text of DOI:10.3762/bjoc.10.116

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic
coupling partners in Mitsunobu reactions
and oxa-Michael additions
Michael J. Burns, Thomas O. Ronson, Richard J. K. Taylor
and Ian J. S. Fairlamb*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1159–1165.
Department of Chemistry, University of York, Heslington, York,
YO10 5DD, U.K.
doi:10.3762/bjoc.10.116
Received: 18 January 2014
Accepted: 15 April 2014
Published: 20 May 2014
Email:
Ian J. S. Fairlamb* - ian.fairlamb@york.ac.uk
* Corresponding author
Associate Editor: B. Stoltz
Keywords:
© 2014 Burns et al; licensee Beilstein-Institut.
License and terms: see end of document.
heterocycles; Mitsunobu reaction; oxa-Michael addition; 2-pyrone;
vinyl ethers
Abstract
Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them
as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields
on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct
complex 2-pyronyl ethers, which are found embedded in a number of natural products.
Introduction
The 2-pyrone motif is a prevalent structural feature of many similar compounds from the same family have been shown to
complex natural products and biologically active compounds exhibit phospholipase A2 (PLA2) inhibitory activity [6]. Whilst
[1,2]. Various functionalised 2-pyrones have been identified as the chemistry of 2-pyrones is generally well-developed [7], effi-
promising candidates for the treatment of illnesses ranging from cient routes to these types of complex structural units are
Alzheimer’s disease [3] to cancer [4]. An important sub-class of elusive, and the total synthesis of these and similar natural prod-
pyrones are the 4-hydroxy-2-pyrones, which are sometimes ucts remains a challenge [8].
found embedded into larger natural products as pyronyl ethers,
such as in the phacelocarpus 2-pyrones 1 and 2 (Figure 1). Simple 2-pyrones such as 4-hydroxy-6-methyl-2-pyrone
These compounds are secondary metabolites isolated from the (triacetic acid lactone, 3a, Figure 1) are readily and cheaply
Australian marine red alga Phacelocarpus labillardieri [5]; available, making them seemingly ideal building blocks for the
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We recently published an example of the Mitsunobu reaction
using the compound 4-hydroxy-6-methyl-2-pyrone (3a) [14].
To the best of our ability, we could find only limited precedent
for this procedure being used previously in this way [15-17]. In
our case, we were able to further modify the resulting pyronyl
ether forming a trisubstituted enol ether, which then underwent
a Suzuki–Miyaura cross-coupling or direct arylation-type reac-
tion. As part of our extensive studies on reactions involving
2-pyrone derivatives, we report herein a significant expansion
of the Mitsunobu protocol to a variety of different coupling
partners, along with an alternative route to the formation of
2-pyronyl enol ethers using an oxa-Michael addition to propio-
Figure 1: The phacelocarpus 2-pyrones 1 and 2.
synthesis of such complex pyrone-containing molecules. As late esters. Both procedures are mild, tolerate a wide range of
heterocyclic aromatic enols, they have a high acidity and dense functionality, and afford good to excellent yields of products in
functionality which leads to a diverse reactivity profile. This the majority of cases.
means that 4-hydroxy-2-pyrones are also useful precursors to a
Results and Discussion
number of other structural units and versatile intermediates in
organic synthesis.
Mitsunobu reactions
Using the standard conditions of stirring diisopropyl azodicar-
Despite, or perhaps because of, this varied reactivity, O-func- boxylate (DIAD) and triphenylphosphine in dichloromethane at
tionalisation reactions of 4-hydroxy-2-pyrones, to afford room temperature for 18 hours, we tested the substrate scope of
2-pyronyl ethers (e.g., Scheme 1), remain almost entirely the reaction (Table 1). In addition to the silyl-protected alcohol
limited to reactions with methylating agents or simple alkyl or reported previously [14] (Table 1, entry 3), we found that a
acyl halides. These often require heating with a base such as variety of useful functionality on the alcohol was well-tolerated,
K2CO3 or DBU, and the available functionality is therefore including a terminal alkene (Table 1, entry 2), a tosylate leaving
limited to esters or simple primary alkyl groups [9-11]. Even in group (Table 1, entry 4), and a halide (Table 1, entry 5). Some-
simple cases the yields obtained are variable as the 2-pyrone what more exotic functional groups such as a phosphonate ester
unit is prone to degradation under harsh conditions, repre- (Table 1, entry 6) or a dimethyl acetal (Table 1, entry 7) were
senting an interesting synthetic chemistry challenge to address. still tolerated in the reaction, albeit in more modest yields. A
The ability to install more complex functionality on the hydroxy variety of alkylated 2-pyrones 3b–e were synthesised according
group of 6-alkyl-4-hydroxy-2-pyrones would be of consider- to the method of Hsung and co-workers [18], in order to further
able synthetic value.
explore the scope of the Mitsunobu process. This involves a
one-pot silyl-protection of the hydroxy group of 6-methyl-4-
hydroxy-2-pyrone 3a with HMDS, followed by lithiation and
alkylation (Scheme 2).
Scheme 1: Generalised O-functionalisation of 6-alkyl-4-hydroxy-2-
pyrones 3.
The Mitsunobu reaction is a well-established, widely used and
invaluable tool for synthetic chemists [12]. It is usually
employed to couple an acidic nucleophile with a primary or sec-
ondary alcohol, and as a mild reaction it tolerates a range of
Scheme 2: Synthesis of alkylated 2-pyrones 3b–e.
functionality in both coupling partners, allowing it to be used on These more structurally complex systems also underwent
complex and sensitive substrates. Given the high acidity of Mitsunobu reaction with various alcohols in good to excellent
hydroxypyrones such as 3 (Scheme 1; R1 = H, pKa = 4.94 [13]), yields (Table 1, entries 8–12). Compounds 4i–l could find
they would appear to be ideal coupling partners in the further utility in the synthesis of phacelocarpus 2-pyrones in the
Mitsunobu reaction.
future.
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Table 1: Synthesis of 2-pyronyl ethers 4a–l.
Entry
1
Alcohol
Pyrone
Product
Yield (%)a
70
5a
5b
3a
3a
3a
3a
3a
4a
4b
4c
4d
4e
2
3
4
5
54
98
99
82
5c
5d
5e
6
30
5f
3a
4f
7
8
23
81
5g
5b
3a
3b
4g
4h
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Table 1: Synthesis of 2-pyronyl ethers 4a–l. (continued)
9
75
5b
3c
4i
10
50
5b
3d
4j
11
52
5h
3d
4k
12
61
5i
4l
3d
aYield of product isolated following chromatography on silica gel.
Oxa-Michael additions
Table 2: Michael addition reaction optimisation.
Whilst the formation of pyronyl ethers is useful in itself, the
ability to introduce an unsaturated group onto the oxygen,
leading to a pyronyl enol ether, would have additional value.
This is a highly unusual motif found in some marine polyketide
natural products (such as compound 1, Figure 1). Conjugate
addition to α,β-ynones represents an intuitive and efficient route
to vinyl compounds, and is well-established with a plethora of
oxygen-based nucleophiles [19]. Addition of highly acidic
coupling partners can be challenging, however, due to the low
nucleophilicity of the conjugate base in which the electron
density is extensively delocalised. To the best of our ability we
could not find a single previous published example of a Michael
addition employing 4-hydroxy-2-pyrones.
Entry
Temperature (°C)
Time (h)
Yield (%)a
1
2
3
4
20
20
45
80b
2
48
63
82
67
16
16
0.5
aYield of product isolated following chromatography on silica gel.
bReaction performed under microwave irradiation.
Initial experiments reacting 4-hydroxy-2-pyrone 3a with methyl
propiolate (6a) in the presence of an amine base afforded only
moderate yields of product 7a (Table 2, entry 1). However,
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Beilstein J. Org. Chem. 2014, 10, 1159–1165.
raising the temperature of the reaction and increasing the reac- pentafluorophenyl propiolate resulted in a poor yield (Table 3,
tion time led to a significant increase in the conversion to prod- entry 9).
uct and an isolated yield of 82% (Table 2, entry 3). Further
heating under pressure with microwave irradiation led to a As an extension to this methodology, we explored the addition
decrease in yield.
of hydroxypyrones to both an allene and an internal alkyne to
furnish a trisubstituted enol ether. Addition of 4-hydroxy-6-
Following reaction optimisation, we applied these conditions to methyl-2-pyrone (3a) to the terminal allene 8 under the opti-
a number of different propiolate esters and alkylated 4-hydroxy- mised conditions proceeded smoothly to give the trans-trisub-
2-pyrones (Table 3). Surprisingly, the tolerance of the reaction stituted enol ether 9 in 52% yield (Scheme 3). However,
to different ester groups proved rather limited. The switch from numerous attempts to apply these conditions to an internal
methyl propiolate to tert-butyl propiolate (6b) led to a slight alkyne failed to furnish any desired product, presumably due to
drop in yield (Table 3, entry 2), but moving to pentafluoro- the steric influence of the additional methyl group. However,
phenyl propiolate (6c) reduced the yield to a modest 27% after an exhaustive screening of conditions (see Supporting
(Table 3, entry 3). An attempt with N-methoxy-N-methyl- Information File 1 for full details), we found that the addition of
propiolamide (6d) led to no product formation (Table 3, entry copper(I) iodide to the reaction mediated the addition of pyrone
4), and significant recovery of starting material. Changes in the 3a to ethyl 2-butynoate (10). The reaction was performed with a
C-6 substituent on the pyrone were tolerated much better, with sub-stoichiometric quantity of DBU (whilst primarily func-
yields from good to excellent for a range of pyrones with tioning as a base, the DBU was also suspected to be acting
methyl propiolate (Table 3, entries 5–8). A further attempt with partially as a co-solvent as the solubility of the 3a was found to
Table 3: Synthesis of pyronyl vinyl ethers 7.
Entry
1
Electrophile
Pyrone
Product
Yield (%)a
82
6a
6b
3a
3a
7a
7b
2
3
61
27
3a
3a
6c
6d
7c
7d
4
0
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Table 3: Synthesis of pyronyl vinyl ethers 7. (continued)
5
64
6a
3d
3b
3e
7e
6
68
6a
7f
7
86
6a
7g
8
82
6a
3c
7h
9
37
6c
3c
7i
aYield of product isolated following chromatography on silica gel.
Scheme 3: Michael addition of 3a to allene 8 and internal alkyne 10.
be greatest at 0.66 equivalents) in THF under microwave irradi- Conclusion
ation (Scheme 3), and afforded the desired product in moderate In conclusion, 4-hydroxy-6-alkyl-2-pyrones are effective
yield after just 0.5 h (longer reaction times led to degradation of coupling partners in Mitsunobu reactions and oxa-Michael addi-
the product). Extension of the chain to an ethyl group (i.e., tions. The reactions have been shown to tolerate a range of
using ethyl 2-pentynoate) served to further reduce the reactivity different functional groups by virtue of the mild conditions
towards addition and no product was formed even under the employed, affording the desired products in moderate to excel-
optimised conditions.
lent yields in the majority of cases. This protocol offers a prac-
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Experimental
General procedure 1: Mitsunobu reaction with 4-hydroxy-2-
pyrones: To a stirred solution of the pyrone (1 equiv), tri-
phenylphosphine (1.5 equiv) and alcohol (1.5 equiv), in
dichloromethane (4 mL mmol−1) under nitrogen either at 0 °C
or ambient temperature, was carefully added DIAD (1.5 equiv)
over 10–30 min (depending on scale), so as to avoid the genera-
tion of excess heat (<5 °C internal temperature increase). The
solution was then stirred at rt (typically 18–25 ºC) for 16 hours,
and the solvent removed in vacuo. Byproduct phosphine oxide
was removed from the crude residue by dissolving the product
in ether (2 mL mmol−1), and vacuum filtration to remove the
solid oxide. The ether was then removed in vacuo and the
residue purified via flash column chromatography to afford the
desired product.
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4-hydroxy-2-pyrones: The pyrone (1 equiv), triethylamine
(1 equiv) and propiolate ester (2 equiv) were stirred in CH2Cl2
(2 mL mmol−1) at 45 °C for 16 h. The solvent was then
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Detailed experimental procedures, characterisation data for
compounds 3b–e, 4a–l, 5d, 7a–i and 9 and 1H NMR
spectra for novel compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-116-S1.pdf]
License and Terms
This is an Open Access article under the terms of the
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Acknowledgements
T.O.R. is funded by an EPSRC DTA PhD studentship. We are
grateful to Merck-Schering for CASE top-up funding (Drs.
Zoran Rankovic and Mark York). EPSRC grant EP/D078776/1
(PhD studentship for M.J.B.) part-funded this research. I.J.S.F.
thanks the Royal Society for previous support (University
Research Fellow).
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
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