The synthesis of substituted phenols from pyranone precursors

Article abstract of DOI:10.1016/j.tet.2009.07.083

The syntheses of various substituted phenols from pyranone precursors, namely 4H-pyran-4-one, 3-(benzyloxy)-2-methyl-4H-pyran-4-one (benzyl-maltol), 2,6-dimethyl-4H-pyran-4-one and diethyl 4-oxo-4H-pyran-2,6-dicarboxylate (diethyl chelidonate) are presented. A variety of pronucleophiles were used in combination with tert-butanol as solvent and potassium tert-butoxide as base, using conventional heating methods and microwave conditions.

Full text of DOI:10.1016/j.tet.2009.07.083

Tetrahedron 65 (2009) 8165–8170
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The synthesis of substituted phenols from pyranone precursors
,
Laura J. Marshall a, Karl M. Cable b, Nigel P. Botting a
*
a School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK
b GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 April 2009
Received in revised form 6 July 2009
Accepted 28 July 2009
Available online 6 August 2009
The syntheses of various substituted phenols from pyranone precursors, namely 4H-pyran-4-one,
3-(benzyloxy)-2-methyl-4H-pyran-4-one (benzyl-maltol), 2,6-dimethyl-4H-pyran-4-one and diethyl
4-oxo-4H-pyran-2,6-dicarboxylate (diethyl chelidonate) are presented. A variety of pronucleophiles were
used in combination with tert-butanol as solvent and potassium tert-butoxide as base, using conven-
tional heating methods and microwave conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Phenol
Pyranone
Maltol
2,6-Dimethylpyranone
Chelidonic acid
Pronucleophile
Isotopes
1. Introduction
NO2
OHC
OHC
CH3
aq. NaOH
+
NO2
O
Many natural products such as polyketides, coumarins and fla-
vonoids contain mono-phenolic or polyphenolic moieties.1 New
methodology for the preparation of phenols is therefore potentially
valuable in natural product synthesis. Traditional methods for the
preparation of phenols2 include hydrolysis of diazonium salts,
Baeyer–Villiger oxidation, displacement of aromatic halides and
oxidation of aryl boronates. More recent methods include the cat-
alytic C–H activation/borylation/oxidation procedure developed by
Maleczka and Smith3 and palladium-catalysed C–O bond
formation.4
An alternative strategy involves the construction of the benzene
nucleus from acyclic, non-aromatic precursors with the sub-
stituents already in place.5 This offers a way of overcoming the
problems associated with direct introduction of ring substituents,
which often leads to isomeric mixtures. The reaction of an acetone
derivative 1 with nitromalondialdehyde 2 to provide p-nitrophenol
3 is an important reaction of this type (Scheme 1).6 Its significance
is increased by the fact that replacement of acetone by methyl alkyl
ketones, or homologous dialkyl ketones, gives rise to 1,2,4-tri- or
1,2,4,6-tetra-substituted derivatives.7
CH2R
R
R = H, 65%
OH
R = Et, 70%
2
1
R = COOH, 90%
3
Scheme 1. Synthesis of p-nitrophenol derivatives from acetone derivatives and
nitromalondialdehyde.6
Another strategy is the synthesis of benzene derivatives from
heterocyclic precursors, which undergo either a rearrangement or
an extrusion process. Oxygen-containing heterocycles such as
pyrylium salts are particularly susceptible to nucleophilic attack
and serve as useful precursors to polysubstituted aromatic com-
pounds. The advantage of this approach is that substituents present
in the heterocycle are incorporated into the aromatic product in
a regiospecific manner. Scheme 2 shows the reaction of a pyrylium
salt 4 with nitromethane 58 or acetylacetone 69 to give an aromatic
R2
R2
R2
O
O
H3C NO2
R3
R1
R3
R1
R3
O
+
R1
5
6
COCH3
NO2
4
8
7
R1=R2=R3=Ph
70%
R1=R2=R3=CH3
72%
* Corresponding author. Tel.: þ44 1334 463856; fax: þ44 1334 3080.
E-mail address: npb@st-andrews.ac.uk (N.P. Botting).
Scheme 2. Synthesis of polysubstituted aromatic compounds from pyrylium salts.8,9
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.083

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L.J. Marshall et al. / Tetrahedron 65 (2009) 8165–8170
nitro compound 7 or ketone 8, respectively. After addition of the
nucleophile, ring opening occurs followed by ring closure and
elimination of water to give the product.
It is known that pyran-4-ones can serve as useful precursors for
phenols, where the pyranone carbonyl ultimately becomes the
phenolic hydroxyl group. This method was used by Steglich and co-
workers for the synthesis of isotopically labelled phenols.10 Scheme
3 shows the synthesis of ethyl 4-hydroxy[1-13C]benzoate 9a from
4H-pyran-4-one 10 using diethyl [2-13C]malonate 11a as the source
of isotopic label (Scheme 3).
diethyl malonate 11. The acetyl group was selectively removed in
refluxing aqueous acid. There was no evidence for the formation of
4-hydroxyacetophenone by loss of the ester group. Although only
carried out on unlabelled substrates thus far, this selectivity will be
of use when considering the synthesis of 13C-labelled compounds
as shown in Scheme 4. Use of diethyl [1,3-13C2]malonate 11b would
ultimately result in loss of half of the isotopically labelled carbon
during acid reflux. However if ethyl [1-13C]acetoacetate 12a was
used, all of the isotopic label would be retained.
13
13
13
EtO2C CO2Et
EtO2C COCH3
O
CO2Et
a
a
13C
O
a,b
13CH2(CO2Et)2
+
O
O
C
O
O
13C 13
13C
O
b
O
10
O
b
11a
EtO
CH3
O
OEt
EtO
OH
9a
11b
12a
10
Scheme 3. Reagents and conditions: (a) tBuOH, KOtBu, reflux; (b) 1 M HCl, reflux, 80%.10
13CO2Et
13CO2Et
This reaction does not appear to have been studied since the
time of Steglich’s publications.10,11 We envisaged that the scope of
this reaction could be extended to include the use of other pyran-4-
one substrates and nucleophiles. This would allow the preparation
of a range of para-substituted phenols from simple heterocyclic
precursors.
OH
OH
9b
9b
Scheme 4. Proposed reagents and conditions: (a) tBuOH, KOtBu, reflux; (b) 1 M HCl, reflux.
An important potential application of this methodology is in the
preparation of isotopically labelled compounds. The number of
commercially available [13C]-labelled benzene derivatives is rela-
tively small. They are often only available in uniformly ring-labelled
form and tend to be expensive. New methods for the construction
of benzene derivatives with regioselective placement of isotopes
within the ring are therefore potentially useful. Compounds mul-
tiply labelled with stable isotopes are valuable as internal standards
in LC–MS13,14 and GC–MS15 analysis.
In this paper, we report an improved method for the synthesis of
para-substituted phenols from 4H-pyran-4-one 10 and a variety of
carbon nucleophiles. The results of experiments with other pyran-
4-ones are also presented. Both conventional and microwave
heating were employed and results compared. This approach has
already been used by Botting and co-workers for the preparation of
[1,3,5-13C]gallic acid.12
The results of experiments with other pronucleophiles are
shown in Scheme 5. The pyranone reacted more slowly with
nitromethane 5 and acetylacetone 6 and longer reaction times were
required. After heating for 20 h at reflux, reaction with nitro-
methane 5 gave 4-nitrophenol 13 in 80% yield. Similarly reaction
with acetylacetone 6 gave 4-hydroxyacetophenone 14 in 95% yield.
Reaction of the pyranone with ethyl cyanoacetate was particularly
slow. However 4-hydroxybenzonitrile 15 was obtained in 78% yield
after heating at reflux for 27 h in the presence of 3 equiv of base and
1.6 equiv of ethyl cyanoacetate.
R
O
a, b
O
OH
10
9: R=CO2Et, 67%
13: R=NO2, 80%
14: R=COCH3, 57%
15: R=CN, 86%
2. Results and discussion
Table 1 shows the pronucleophiles studied and their respective
pKa values compared to tert-butanol.
Scheme 5. Reagents and conditions: (a) tBuOH, KOtBu, pronucleophile, reflux; (b) 1 M
Previous work had shown that ethyl 4-hydroxy[1-13C]benzoate
9a was obtained in 85% yield by heating 4H-pyran-4-one 10
(1.6 equiv) and diethyl [2-13C]malonate 11a (1.0 equiv) with po-
tassium tert-butoxide (1.3 equiv) in tert-butanol at reflux (Scheme
3).10,11 After varying the number of equivalents of pyranone, pro-
nucleophile and base, we found the optimum conditions to be
1.7 equiv of pyranone, 1 equiv of diethyl malonate and 1.3 equiv of
base with a reflux time of 3 h, followed by a further hour at reflux
after addition of acid. Ethyl 4-hydroxybenzoate 9 was obtained in
94% crude yield and did not require further purification.
Interestingly, the same product was obtained in 65% yield when the
reaction was carried out using ethyl acetoacetate 12 in place of
HCl, reflux.
Encouraged by these results we wished to extend the scope of
this methodology to other pyran-4-ones. Maltol 16 is one of the
few commercially available substituted pyran-4-ones. Use of
substituted pyran-4-one substrates would facilitate the synthesis
of polysubstituted phenols with a substitution pattern derived
from the pyranone starting material. In the case of maltol, the
synthesis of polyphenols such as catechols could be achieved. In
order to prevent unwanted side reactions, the 3-hydroxy group
was first protected as the benzyl ether 17. Scheme 6 outlines the
reactions carried out using this pyranone. Initially, the reaction of
17 with diethyl malonate 11 resulted in poor conversion to 18.
However the yield was improved to 73% by use of 3 equiv of base,
1.6 equiv of pronucleophile and a reaction time of 47 h. The re-
action of 17 with nitromethane 5 and acetylacetone 6 resulted in
low yields of 19 and 20 under all conditions studied. After pro-
longed heating (>40 h) in the presence of 2.3 equiv of base and
1.6 equiv of pronucleophile, phenols 19 and 20 were isolated in 20%
and 10% yield, respectively. However, reaction with ethyl cyanoa-
cetate was more successful, with 21 being obtained in 93% yield
under conditions identical to those used for the preparation of 18.
Table 1
Pronucleophiles and pKa values relative to tert-butanol
Pronucleophile
pKa value
Acetylacetone
Ethyl cyanoacetate
Nitromethane
Ethyl acetoacetate
Diethyl malonate
tBuOH
9
9
10
11
13
18

L.J. Marshall et al. / Tetrahedron 65 (2009) 8165–8170
8167
R
Ethyl 4-hydroxy-2,6-dimethylbenzoate 23 was obtained in 18%
yield after heating at reflux for 44 h in the presence of 3 equiv of
base and 1.6 equiv of diethyl malonate 11. Under similar conditions
24 was obtained from ethyl cyanoacetate in 57% yield. These yields
were much lower than those obtained with unsubstituted 4H-
pyan-4-one 10. These results support the hypothesis that the pyr-
anone starting material 22 was being consumed by the pathway
described above. Reactions of 22 with nitromethane 5 and acetyl-
acetone 6 gave complex mixtures of products, with none of the
desired phenols being observed.
O
O
b, c
a
BnO
HO
BnO
O
17
O
16
OH
18: R=CO2Et, 99%
19: R=NO2, 53%
20: R=COCH3, 86%
21: R=CN, 99%
Scheme 6. Reagents and conditions: (a) Benzyl bromide, aq NaOH, MeOH, reflux, 20 h,
98%; (b) tBuOH, KOtBu, pronucleophile, reflux; (c) 1 M HCl, reflux.
Finally, we investigated the reactivity of an electron poor 2,6-
disubstituted pyranone. Chelidonic acid 25 was converted into
diethyl ester 26 as shown in Scheme 9. In this case, the reactions
of 26 with diethyl malonate 11 and ethyl cyanoacetate gave
complex mixtures of products, with none of the desired phenols
being observed. However it was found that the reaction with
nitromethane 5 could be carried out under milder conditions
than those used for pyanones 17 and 22. Phenol 27 was obtained
in 46% yield after heating at reflux for 24 h in the presence of
3 equiv of base and 1.1 equiv of nitromethane 5. Reducing the
amount of base to 1.1 equiv did not affect the yield significantly.
The reaction of 26 with acetylacetone 6 under the same condi-
tions gave only traces of the desired phenol 28 under conven-
tional heating methods.
Benzyl-maltol 17 is relatively electron rich compared to 4H-py-
ran-4-one 10 due to the presence of the oxygen at the 3-position.
This may offer a possible explanation for the poor reactivity of 17
with some nucleophiles. However there was also evidence that the
pyranone starting material was being converted into other products
by a competing pathway. It is known that pyranones with alkyl
groups in the 2- and 6-positions, such as 2,6-dimethyl-4H-pyran-4-
one 22, can be deprotonated.16,17 Side-chain deprotonation followed
by reaction with electrophiles has been exploited in the synthesis of
more complex pyranones, such as those shown in Scheme 7. Alter-
native protecting groups for the 3-hydroxy group were also exam-
ined, including Boc and acetate, however, in these cases complex
mixtures of products were obtained due to increased side reactions
and cleavage of protecting groups during the acid hydrolysis step.
R
HO2C
O
CO2H
EtO2C
O
CO2Et
EtO2C
CO2Et
a
b, c
O
O
O
O
O
a, b
a, c
OH
O
25
O
26
OH
O
27: R=NO2, 48%
22
28: R=COCH3, 35%
Scheme 7. Reagents and conditions: (a) LDA, THF, ꢀ78 ꢁC; (b) CH3CHO (47%);
(c) BrCH2CH]C(CH3)2 (yield not given).16,17
Scheme 9. Reagents and conditions: (a) EtOH, conc. HCl, reflux, 24 h, 99%; (b) tBuOH,
KOtBu, pronucleophile, reflux; (c) 1 M HCl, reflux.
In our experiments the addition of more base improved con-
version to phenolic products in some cases, but also resulted in the
generation of unwanted side-products. Deprotonation of the
methyl groups followed by reaction with other species in the re-
action mixture may account for this. In order to investigate the
effects of alkyl substituents on the reaction with pronucleophiles
some reactions with 2,6-dimethyl-4H-pyran-4-one 22 were ex-
amined, as shown in Scheme 8.
Following studies using conventional heating, microwave irra-
diation was examined as a way of accelerating these reactions. It
was anticipated that shorter reaction times would suppress the
formation of unwanted side-products and lead to higher yields of
the desired phenolic compounds. A wide range of conditions were
studied in order to optimise each reaction where the desired
product was observed under conventional heating methods. The
results are summarised in Table 2.
As expected, microwave irradiation greatly accelerated the re-
actions with most giving optimum results after 30 min. Microwave
experiments with 4H-pyran-4-one 10 gave yields similar to those
obtained by conventional heating. The main advantage was the
shorter reaction time. However substantial improvements in yield
were observed with pyanones 17 and 22 when microwave heating
was employed. Microwave irradiation did not improve yields sig-
nificantly in reactions with diethyl chelidonate 26.
R
O
a, b
O
OH
22
23: R=CO2Et, 81%
24: R=CN, 47%
Scheme 8. Reagents and conditions: (a) tBuOH, KOtBu, pronucleophile, reflux; (b) 1 M
HCl, reflux.
Table 2
Reaction conditions and results for microwave-assisted reactions, including comparison with yields obtained using conventional heating methods
Product
Pyranone
Pyranone (eq)
Pronucleophile (eq)
KOtBu (eq)
Time (min)
Temp (ꢁC)
Microwave yield (%)
Conventional yielda (%)
9
10
10
10
10
17
17
17
17
22
22
26
26
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.1
1.1
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.1
1.1
2.0
3.0
2.3
2.0
2.3
2.3
2.0
2.0
2.3
2.3
30
15
30
30
30
30
30
30
30
30
30
30
120
120
150
150
120
120
150
120
150
120
120
120
67
80
57
86
99
53
86
99
81
47
48
35
94
80
95
78
73
20
10
93
18
57
46
2
13
14
15
18
19
20
21
23
24
27
28
a
Using conditions previously discussed and given in Section 4.2.

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L.J. Marshall et al. / Tetrahedron 65 (2009) 8165–8170
Interestingly, we observed that the optimum quantities of re-
solution was then heated under reflux for a further 1 h. The solvent
was removed at reduced pressure, and water (40 mL) was added to
the residue. The aqueous phase was extracted with diethyl ether or
ethyl acetate (3ꢂ30 mL). The combined organic phase was washed
with water (2ꢂ30 mL), brine (30 mL), dried (MgSO4), and solvent
removed at reduced pressure to give the product.
actants and base used in the microwave-assisted reactions were not
always the same as those required under conventional heating. In
experiments with benzyl-maltol 17, 2–2.3 equivalents of base gave
the cleanest reaction profiles. Addition of more base caused the
formation of side products. The same observation was found in
experiments with 2,6-dimethyl-4H-pyran-4-one 22. 2 equiv of base
were optimum under microwave conditions, whereas 3 equiv were
detrimental to the reaction, presumably for reasons described
earlier. In several cases microwave heating at 150 ꢁC enhanced
yields in reactions, which gave poor yields by conventional heating.
4.2.1.1. Ethyl 4-hydroxybenzoate (9). Using the general procedure
with 4H-pyran-4-one 10 (1 g, 10.4 mmol), diethyl malonate 11 (1 g,
6.2 mmol) or ethyl acetoacetate 12 (1.17 g, 9 mmol), KOtBu (8.2 mL,
8.2 mmol), and 3 h reflux time. Extractions were with diethyl ether.
Product 9 was recovered as an orange solid (0.96 g, 94% from
diethyl malonate, or 0.64 g, 65% from ethyl acetoacetate). Mp 111–
111.5 ꢁC (lit18 112–115 ꢁC); dH (400 MHz, CDCl3) 1.39 (3H, t, J¼7.0 Hz,
CH3), 4.36 (2H, q, J¼7.0 Hz, CH2), 6.90 (2H, d, J¼8.0 Hz, H-3 and 5),
7.97 (2H, d, J¼8.0 Hz, H-2 and 6); dC (100 MHz, CDCl3) 14.3 (CH3),
61.0 (CH2), 115.2 (CH-3,5), 122.5 (C-1), 131.9 (CH-2,6), 160.3 (C-4),
167.1 (C]O).
3. Conclusion
In summary, we have explored the scope of the base-catalysed
reaction of pyran-4-ones with a range of carbon nucleophiles for
the synthesis of phenols. Under conventional heating, the most
successful results were obtained with 4H-pyran-4-one 10 and
3-(benzyloxy)-2-methyl-4H-pyran-4-one (benzyl-maltol) 17. Lim-
ited success was achieved with 2,6-dimethyl-4H-pyran-4-one 22
and diethyl chelidonate 26. The use of microwave irradiation ac-
celerated the reactions with most being complete within 30 min.
When 4H-pyran-4-one 10 was used, there was little difference
between the yields obtained using microwave and conventional
heating. However substantial improvements in yield were ob-
served with other pyran-4-ones when microwave heating was
employed.
4.2.1.2. 4-Nitrophenol (13). Using the general procedure with 4H-
pyran-4-one 10 (1 g, 10.4 mmol), nitromethane 5 (0.7 g, 11.5 mmol),
KOtBu (11.5 mL, 11.5 mmol), and 5 h reflux time. Extractions were
with diethyl ether. Product 13 was recovered as an off-white solid
(1.16 g, 80%). Mp 109–110 ꢁC (lit19 110–115 ꢁC); dH (400 MHz,
DMSO-d6) 6.90 (2H, d, J¼9.2 Hz, H-2 and 6), 8.10 (2H, d, J¼9.2 Hz,
H-3 and 5), 8.26 (1H, s, OH); dC (100 MHz, DMSO-d6) 115.9 (CH-2,6),
131.1 (CH-3,5), 139.1 (C-4), 164.7 (C-1).
This chemistry also has potential application for the regiospe-
cific placement of carbon isotopes into benzene derivatives.
4.2.1.3. 4-Hydroxyacetophenone (14). Using the general procedure
with 4H-pyran-4-one 10 (0.95 g, 9.88 mmol), acetylacetone
6 (2.69 g, 19.76 mmol), KOtBu (19.8 mL, 19.8 mmol), and 20 h reflux
time. Extractions were with diethyl ether. Product 14 was recovered
as a yellow solid (1.29 g, 95%). Mp 105–105.5 ꢁC (lit19 106–108 ꢁC);
dH (400 MHz, CDCl3) 2.60 (3H, s, CH3), 6.97 (2H, d, J¼9.0 Hz, H-3 and
5), 7.92 (2H, d, J¼9.0 Hz, H-2 and 6), 8.17 (1H, s, OH); dC (100 MHz,
CDCl3) 26.3 (CH3), 115.6 (CH-3,5), 129.4 (C-1), 131.2 (CH-2,6), 161.5
(C-4), 198.8 (C]O).
4. Experimental
4.1. General information
NMR spectra were recorded on a Varian Gemini 2000 (1H
300 MHz, 13C 75.45 MHz) or a Bruker Avance 400 (1H 400 MHz, 13
C
100 MHz) spectrometer. 13C NMR spectra were recorded using the
PENDANT or DEPTQ sequence and internal deuterium lock.
Chemical shifts (
d
) in ppm are given relative to Me4Si, coupling
4.2.1.4. 4-Hydroxybenzonitrile (15). Using the general procedure
with 4H-pyran-4-one 10 (0.96 g, 10.0 mmol), ethyl cyanoacetate
(2.13 g, 16.0 mmol), KOtBu (30 mL, 30.0 mmol), and 27 h reflux
time. Extractions were with ethyl acetate. Product 15 was recovered
as a red solid (0.926 g, 78%). Mp 109–109.5 ꢁC (lit20 109–110 ꢁC); dH
(400 MHz, DMSO-d6) 6.90 (2H, d, J¼8.7 Hz, H-3 and 5), 7.64 (2H, d,
J¼8.7 Hz, H-2 and 6), 10.62 (1H, s, OH); dC (100 MHz, DMSO-d6)
101.0 (C-1), 116.4 (CH-3,5), 119.5 (CN), 134.2 (CH-2,6), 161.6 (C-4);
HRMS (CI): MHþ, found 120.0449, C7H6NO requires 120.0450.
constants (J) are given in Hz. IR spectra were recorded on a Perkin–
Elmer series 1420 FT IR spectrophotometer. The samples were
prepared as Nujol mulls or thin films between sodium chloride
discs and recorded in cmꢀ1. Low resolution and high resolution
electrospray mass spectra were recorded on a Micromass LC-T
(time-of-flight). Melting points were recorded on an Electrother-
mal melting point apparatus and are uncorrected. Analytical TLC
was carried out on Merck 5785 Kieselgel 60F254 fluorescent plates.
The components were observed under ultraviolet light (254 nm).
All chemicals were used as delivered from Sigma–Aldrich unless
otherwise indicated. tert-Butanol was dried by stirring with 3 Å
molecular sieves overnight, followed by filtration. All microwave-
assisted reactions were carried out on a Biotage Initiator-60, using
a single mode resonator, with dynamic field tuning at a maximum
power of 300 W at 2.45 GHz. All quoted yields are for crude isolated
products, without any further purification. Portions of these ma-
terials were purified by Mass Directed Auto Prep (MDAP) when
necessary to allow full characterisation of the product.
4.2.1.5. 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (Bn-maltol) (17). To
a stirring solution of maltol 16 (6.55 g, 51.9 mmol) in MeOH (57 mL)
were added successively NaOH (2.28 g, 57.1 mmol) in water
(5.2 mL) followed by benzyl bromide (10.21 g, 59.7 mmol). The
mixture was heated at reflux for 20 h. The solvent was then re-
moved at reduced pressure to give a yellow oil, which was dis-
solved in DCM (50 mL) and washed with 5% aqueous NaOH solution
(50 mL) and water (50 mL). The organic fractions were combined,
dried (MgSO4) and the solvent was removed at reduced pressure to
give 17 as a pale yellow oil (10.96 g, 98%). Subsequent recrystalli-
sation from diethyl ether gave 17 as colourless needles (9.94 g,
89%). Mp 55.5–56 ꢁC (lit21 53–55 ꢁC); dH (300 MHz, CDCl3) 2.09 (3H,
s, CH3), 5.16 (2H, s, CH2), 6.37 (1H, d, J¼5.7 Hz, H-5), 7.25–7.36 (5H,
m, H-Ar), 7.60 (1H, d, J¼5.7 Hz, H-6); dC (75.45 MHz, CDCl3) 14.8
(CH3), 73.5 (CH2), 117.1 (CH-5), 128.3 (CH-12), 128.4 (CH-10,100),
129.0 (CH-11,110), 136.9 (C-9), 143.8 (C-3), 153.5 (CH-6), 159.8 (C-2),
175.1 (C]O); HRMS (CI): MHþ, found 217.0863, C13H13O3 requires
217.0865.
4.2. Experimental procedures
4.2.1. General procedure for reactions using conventional heating
methods. A solution of the pyranone and pronucleophile in dry
tBuOH (20 mL) was heated to reflux under argon. KOtBu (1 M so-
t
t
lution in BuOH) in a further volume of dry BuOH (30 mL) was
added drop-wise. The resulting mixture was heated under reflux
for the desired time after which 1 M HCl was added. The reaction

L.J. Marshall et al. / Tetrahedron 65 (2009) 8165–8170
8169
4.2.1.6. Ethyl 3-(benzyloxy)-4-hydroxy-2-methyl benzoate (18). Using
the general procedure with benzyl-maltol 17 (1 g, 4.6 mmol), diethyl
malonate 11 (1.18 g, 7.4 mmol), KOtBu (13.8 mL,13.8 mmol), and 47 h
reflux time. Extractions were with diethyl ether. Product 18 was
recovered as an orange oil (0.961 g, 73%). ymax/cmꢀ1 3400, 2981,1731,
1277; dH (400 MHz, CDCl3) 1.39 (3H, t, J¼7.2 Hz, CH3), 2.62 (3H, s,
CH3), 4.33 (2H, q, J¼7.2 Hz, CH2), 4.88 (2H, s, CH2), 6.81 (1H, d,
J¼8.6 Hz, H-6), 7.37–7.46 (5H, m, H-Ar), 7.72 (1H, d, J¼8.6 Hz, H-5); dC
(100 MHz, CDCl3) 14.2 (CH3), 14.3 (CH3), 60.5 (CH2), 75.9 (CH2–O),
112.4 (CH-5), 122.9 (CH-6), 128.3 (CH-10,100), 128.8 (CH-11,110), 134.4
(C-1),136.4 (CH-12), 144.6 (C-9), 152.4 (C-3), and 167.1 (C]O); HRMS
(CI): MHþ, found 287.1281, C17H19O4 requires 287.1283.
acetate. Product 24 was recovered from the organic phase as an
orange/red oil (0.449 g, 57%), and as an off-white solid after puri-
fication. Mp 176–176.5 ꢁC (lit23 177.5–177.7 ꢁC); ymax/cmꢀ1 3234,
2220, 1608, 1585, 1457, 1321, 1262, 1147, 845, 717, 705; dH (400 MHz,
CDCl3) 2.48 (6H, s, 2ꢂCH3), 6.69 (2H, s, H-3 and 5); dC (100 MHz,
CDCl3), 20.8 (CH3), 105.2 (C-1), 114.6 (CH-3,5), 117.7 (CN), 144.6 (C-
2,6), 158.8 (C-O); HRMS (CI): Mꢀ, found 146.0611, C9H8O6N requires
146.0606.
4.2.1.12. Diethyl 4-oxo-4H-pyran-2,6-dicarboxylate (diethyl chelido-
nate) (26). To a solution of chelidonic acid 25 (10 g, 54.3 mmol) in
ethanol (500 mL) was added conc. HCl (50 mL). The reaction mix-
ture was heated at reflux for 24 h, after which time solvents were
removed at reduced pressure. The resulting residue was dissolved
in water (100 mL) and diethyl ether (100 mL). The aqueous layer
was extracted with diethyl ether (2ꢂ100 mL). The combined or-
ganic layers were washed with water (100 mL), brine (100 mL), and
dried (MgSO4). Solvents were removed at reduced pressure to give
26 as a light yellow solid (12.85 g, 99%). Mp 61–61.5 ꢁC (lit24 62 ꢁC);
dH (400 MHz, CDCl3) 1.42 (6H, t, J¼7.1 Hz, 2ꢂCH3), 4.46 (4H, q,
J¼7.1 Hz, 2ꢂCH2), 7.17 (2H, s, H-2 and 6).
4.2.1.7. 2-(Benzyloxy)-3-methyl-4-nitrophenol (19). Using the gen-
eral procedure with benzyl-maltol 17 (1 g, 4.6 mmol), nitrometh-
ane 5 (0.45 g, 7.4 mmol), KOtBu (10.6 mL, 10.6 mmol), and 44 h
reflux time. Extractions were with ethyl acetate. Product 19 was
recovered as an orange oil (0.238 g, 20%). ymax/cmꢀ1 2926, 1714,
1640, 1557; dH (400 MHz, CDCl3) 2.62 (3H, s, CH3), 4.93 (2H, s, CH2),
6.87 (1H, d, J¼9.1 Hz, H-6), 7.40–7.47 (5H, m, H-Ar), 7.86 (1H, d,
J¼9.1 Hz, H-5), 8.00 (1H, s, OH); dC (100 MHz, CDCl3) 13.8 (CH3),
76.5 (CH2), 112.8 (CH-5,6), 123.1 (CH-12), 128.3 (CH-10,100), 129.2
(CH-11,110); HRMS (CI): MHþ, found 260.0970, C14H14NO4 requires
260.0923.
4.2.1.13. Diethyl 2-nitro-5-hydroxyisophthalate (27). Using the
general procedure with diethyl chelidonate 26 (1 g, 4.2 mmol), ni-
tromethane 5 (0.29 g, 4.62 mmol), KOtBu (12.6 mL, 12.6 mmol),
24 h reflux time. Extractions were with diethyl ether. Product 27
4.2.1.8. 1-(3-(Benzyloxy)-4-hydroxy-2-methylphenyl)ethanone (20).
Using the general procedure with benzyl-maltol 17 (1 g,
4.6 mmol), acetylacetone 6 (1.01 g, 7.4 mmol), KOtBu (10.6 mL,
10.6 mmol), and 42 h reflux time. Extractions were with ethyl
acetate. Product 20 was recovered as an orange oil (0.118 g, 10%).
ymax/cmꢀ1 3032, 1719, 1648, 1255, 1187; dH (400 MHz, CDCl3) 2.01
(3H, s, CH3), 2.57 (3H, s, CH3), 4.88 (2H, s, CH2), 6.83 (1H, d,
J¼8.6 Hz, H-5), 7.39–7.45 (5H, m, H-Ar), 7.54 (1H, d, J¼8.6 Hz, H-6),
8.02 (1H, s, OH); dC (100 MHz, CDCl3) 14.4 (CH3), 29.3 (CH3), 75.9
(CH2), 112.1 (CH-5), 128.1 (CH-10,100), 129.0 (CH-11,110), 130.9 (CH-
6), 133.4 (C-1), 136.3 (CH-12), 145.1 (C-9), 152.3 (C-3), 200.0 (C]O);
HRMS (CI): MHþ, found 257.1176, C16H17O3 requires 257.1178.
was recovered as a yellow solid (0.548 g, 46%). Mp 84–84.5 ꢁC; ymax
/
cmꢀ1 3420, 2989, 2902, 1727, 1655, 1546, 1394, 1376, 1250, 1051,
1021, 1002, 823, 760; dH (300 MHz, CDCl3) 1.28 (6H, t, J¼7.1 Hz,
2ꢂCH3), 4.29 (4H, q, J¼7.1 Hz, 2ꢂCH2), 7.46 (2H, s, H-4 and 6); dC
(100 MHz, CDCl3), 13.6 (CH3), 63.1 (CH2), 120.6 (CH-4,6), 127.0 (C-
1,3), 142.5 (C-2), 157.3 (C]O), 163.6 (C-5); HRMS (CI): MHþ, found
284.0761, C12H14O7N requires 284.0770.
4.2.2. General procedure for microwave-assisted reactions. A vial
t
containing the pyranone, pronucleophile and KOtBu in dry BuOH
(7.5 mL) was treated with microwave irradiation for the desired
time at the required temperature, as indicated in Table 2. After this
time, 1 M HCl (7.5 mL) was added to the reaction mixture, and
microwave irradiation continued for a further 10 min at 120 ꢁC.
Solvents were then removed at reduced pressure and water
(20 mL) was added. The aqueous phase was extracted with diethyl
ether (3ꢂ20 mL). The combined organic phase was washed with
water (2ꢂ20 mL), brine (20 mL), and dried (MgSO4). Solvents were
removed at reduced pressure to give the product. Characterisation
was as above, with the exception of diethyl 2-acetyl-5-hydroxy-
isophthalate 28 (see Section 4.2.2.1), which gave only trace
amounts using conventional heating methods and therefore was
not isolated or characterised at that point.
4.2.1.9. 3-(Benzyloxy)-4-hydroxy-2-methylbenzonitrile (21). Using
the general procedure with benzyl-maltol 17 (1 g, 4.6 mmol), ethyl
cyanoacetate (1.07 g, 7.4 mmol), KOtBu (13.8 mL, 13.8 mmol), and
47 h reflux time. Extractions were with ethyl acetate. Product 21
was recovered as an orange/red oil (1.13 g, 93%). ymax/cmꢀ1 2929,
2216, 1456, 1376; dH (400 MHz, CDCl3) 2.51 (3H, s, CH3), 4.92 (2H, s,
CH2), 6.84 (1H, d, J¼8.5 Hz, H-5), 7.33 (1H, d, J¼8.5 Hz, H-6) 7.39–
7.47 (5H, m, H-Ar); dC (100 MHz, CDCl3) 14.9 (CH3), 76.1 (CH2),
105.3 (C-1), 114.2 (CN), 118.2 (CH-5), 128.3 (CH-10,100), 129.1 (CH-
11,110), 130.1 (C-2), 131.6 (CH-6), 135.9 (CH-12), 144.5 (C-9), 153.3
(C-3); HRMS (CI): MHþ, found 240.1017, C15H14NO2 requires
240.1025.
4.2.2.1. Diethyl 2-acetyl-5-hydroxyisophthalate (28). Using the
general microwave-assisted procedure with diethyl chelidonate 26
and acetylacetone 6 under the conditions given in Table 2. Product
28 was recovered as a yellow solid (344 mg, 35%) mp 66–66.5 ꢁC;
ymax/cmꢀ1 3512, 2986, 1724, 1688, 1584, 1283, 1243, 1223, 1203,
1034, 1009, 799; dH (400 MHz, CDCl3) 1.37 (6H, t, J¼7.2 Hz, 2ꢂCH3),
2.64 (3H, s, CH3), 4.34 (4H, q, J¼7.2 Hz, 2ꢂCH2), 7.61 (2H, s, H-4 and
6); dC (100 MHz, CDCl3) 14.0 (CH3), 32.0 (CH3), 62.0 (CH2),121.2 (CH-
4,6), 129.7 (C-1,3), 131.6 (C-2), 155.7 (C]O), 165.0 (C–O); HRMS (CI):
Mꢀ, found 279.0875, C14H15O6 requires 279.0868.
4.2.1.10. Ethyl 4-hydroxy-2,6-dimethyl benzoate (23). Using the
general procedure with 2,6-dimethyl-4H-pyran-4-one 22 (1 g,
8.1 mmol), diethyl malonate 11 (2.1 g, 12.9 mmol), KOtBu (24.3 mL,
24.3 mmol), and 44 h reflux time. Extractions were with ethyl
acetate. Product 23 was recovered as an orange solid (0.283 g,
18%). Mp 65–65.5 ꢁC (lit22 62 ꢁC); dH (400 MHz, CDCl3) 1.38 (3H, t,
J¼7.1 Hz, CH3), 2.29 (6H, s, 2ꢂCH3), 4.37 (2H, q, J¼7.1 Hz, CH2),
8.50 (2H, s, H-3 and 5); dC (100 MHz, CDCl3) 14.3 (CH3), 20.1
(CH3), 60.8 (CH2), 114.5 (CH-3,5), 136.7 (C-2,6), 153.6 (C-4), 169.9
(C]O).
4.2.1.11. 4-Hydroxy-2,6-dimethylbenzonitrile (24). Using the gen-
eral procedure with 2,6-dimethyl-4H-pyran-4-one 22 (0.67 g,
5.4 mmol), ethyl cyanoacetate (1.15 g, 8.6 mmol), KOtBu (16.2 mL,
16.2 mmol), and 47 h reflux time. Extractions were with ethyl
Acknowledgements
Financial support by the BBSRC and GlaxoSmithKline is grate-
fully acknowledged.

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L.J. Marshall et al. / Tetrahedron 65 (2009) 8165–8170
12. Marshall, L. J.; Cable, K. M.; Botting, N. P. Org. Biomol. Chem. 2009, 7, 785–788.
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