An efficient synthesis of 4-alkenyl/alkynyl-6-methyl-2-pyrones via Pd-catalysed coupling on 4-bromo-6-methyl-2-pyrone

Article abstract of DOI:10.1016/S0040-4039(02)02207-4

We herein report the efficient syntheses of biologically active 4-alkenyl- and 4-alkynyl-6-methyl-2-pyrones using Pd-catalysed coupling procedures. A palladium on carbon/triphenylphosphine combination is shown to be the most effective catalyst for Sonogas

Full text of DOI:10.1016/S0040-4039(02)02207-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8853–8857
An efficient synthesis of 4-alkenyl/alkynyl-6-methyl-2-pyrones via
Pd-catalysed coupling on 4-bromo-6-methyl-2-pyrone
Lester R. Marrison,a Julia M. Dickinson,a Razwan Ahmeda and Ian J. S. Fairlamba,b,
*
aDepartment of Chemistry and Materials, John Dalton Building, the Manchester Metropolitan University, Chester Street,
Manchester M1 5GD, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 28 August 2002; revised 23 September 2002; accepted 4 October 2002
Abstract—We herein report the efficient syntheses of biologically active 4-alkenyl- and 4-alkynyl-6-methyl-2-pyrones using
Pd-catalysed coupling procedures. A palladium on carbon/triphenylphosphine combination is shown to be the most effective
catalyst for Sonogashira cross-coupling of several terminal acetylenes with 4-bromo-6-methyl-2-pyrone in yields of up to 95%.
© 2002 Elsevier Science Ltd. All rights reserved.
The 2-pyrone moiety is found in a large number of
naturally-occurring biologically active compounds.1 It
finds a wide variety of applications in organic synthesis
as a cyclobutane precursor,2 a diene component in
Diels–Alder reactions,3 and as a precursor to other
heterocyclic systems.4 Despite their synthetic utility, the
synthesis and construction of substituted 2-pyrones is
fraught with difficulties, often requiring a multi-step
synthesis via an acyclic precursor. Methods for the
introduction of substituents within the preformed
pyrone ring via electrophilic or nucleophilic substitu-
tion are cumbersome. These reactions generally lead to
ring-opening and rearrangements and the pyrone ring is
impossible to regenerate. Indeed, few direct substitu-
tions onto the 2-pyrone ring have been reported.5 There
has been notable recent interest in the synthesis of
3-alkynyl-5-bromo-2-pyrones.6 Our interest in this area
stems from the associated antimicrobial, human ovar-
ium carcinoma (A2780) and human chronic myeloge-
nous leukaemia (K562) inhibitory properties of
4-alkenyl/alkynyl-substituted-6-methyl-2-pyrones (Fig.
1).7
To the best of our knowledge there is only one report
on the oxidative addition of Pd(0)-based catalysts to the
C4-position of appropriately halogenated pyrones.8
Indeed, there is every reason to suspect that the C4-car-
bon centre is very reactive towards oxidative addition
Figure 1. Biologically active 2-pyrones.
The promising anti-cancer and anti-leukaemia activities
prompted us to devise efficient synthetic routes to these
compounds using a variety of Pd-catalysed coupling
procedures (Scheme 1).
Scheme 1. Synthesis of 4-alkenyl and 4-alkynyl pyrones.
Reagents and conditions: (i) PBr3, DMF, 70°C; (ii) [Pd] cat.,
CuI, Et3N, RCꢀCH; (iii) [Pd] cat., RCHꢁCHM (E), Solv.; (iv)
Pd/C, H2, quinoline, benzene.
Keywords: pyrones; palladium; organometallic couplings.
* Corresponding author. Tel.: +44-(0)-1904-434091; fax: +44-(0)-
1904-432516; e-mail: ijsf1@york.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02207-4

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L. R. Marrison et al. / Tetrahedron Letters 43 (2002) 8853–8857
9–12, Table 1). Switching to the more stable Pd(0)
complex, Pd2dba3·CHCl3, gave the coupled products in
much better yields (entries 13–16, Table 1). But to our
delight we found that use of a Pd/C and PPh3 combina-
tion could be used with great success.
and we thus initially screened a variety of conditions
for Sonogashira alkynylations of 4-bromo-6-methyl-2-
pyrone (available in 79% yield using PBr3 in DMF at
70°C) with various terminal alkynes to provide a series
of 4-alkynyl-6-methyl-2-pyrones (3a–d) (Table 1).9
Using the Pd/C and PPh3 catalyst combination we
explored the synthesis of a range of alkynyl coupled
products (3e–m) (Table 2).
Initial investigations employing the standard catalyst
for Sonogashira reactions; bis(triphenylphosphine)-pal-
ladium(II) chloride (PPh3)2PdCl2 proved unsuccessful in
a variety of solvents (entries 1–4, Table 1). The poor
catalytic activity was surprising, as the analogous Sono-
gashira coupling of pyrones at the 3- and 5-positions
are facile using this catalyst, particularly where DMF is
employed as the reaction solvent.6 Switching the solvent
to DMF failed to improve our yields. We next focussed
attention on the Pd(OAc)2/PPh3 pro-catalytic system to
generate formally a [Pd(0)(PPh3)2] species in situ
(entries 5–8, Table 1) which gave the coupled products
in satisfactory yields. Employment of the air and light
sensitive Pd(PPh3)4 resulted in similar yields (entries
To the best of our knowledge this is the first time that
the true scope of the Pd/C and PPh3 catalyst system has
been shown to have such a dramatic effect for any
Pd-catalysed cross-coupling reaction. Note that only 2
mol% of Pd is used under these conditions.
From inspection of Table 2 (entries 1 and 2) it can be
seen that simple aliphatic alkynes couple in good yields,
compare also entries 19 and 20, Table 1. The low yields
observed for propargyl alcohol and p-aminophenyl-
acetylene (entries 3 and 5, Table 2) may be attributed to
the presence of easily removable protons and subse-
quent inhibition of the catalyst. However, having said
that, Cho and co-workers6b were able to couple the
latter alkyne with 3,5-dibromo-2-pyrone using DMF as
a solvent and thus H-bonding may have a deleterious
effect on the catalyst activity in CH3CN. For entry 5
(Table 2) there is also the possibility of competing
pyridone and oligomer formation. Protection of both
the alcohol as its tetrahydropyranyl ether and the
amine as the acetamide (entries 4 and 6, Table 2,
respectively) saw a dramatic increase in the yields. The
unreactivity of propargyl acetate should be noted.
Some intriguing examples are entries 7 and 8 (Table 2).
Both the nitro and acetyl groups are electron-withdraw-
ing but give significantly different yields. A comparison
of other Pd(0) catalysts was made to see whether the
effect was independent of the choice of catalyst (Table
3).
Table 1. Sonogashira couplingsa
Entry
Catalyst system
R
Yield (%)
1
2
3
Pd(PPh3)2Cl2/CuI/Et3Nb
Pd(PPh3)2Cl2/CuI/Et3Nb
Pd(PPh3)2Cl2/CuI/
Et3N/THFb
(CH3)3Si
Ph
Ph
0
Trace
12
4
Pd(PPh3)2Cl2/CuI/
Ph
Trace
Et3N/DMFb
5
6
7
8
Pd(OAc)2/PPh3/CuI/Et3Nb (CH3)3Si
Pd(OAc)2/PPh3/CuI/Et3Nb Ph
50
43
48
27
47
32
52
53
69
Pd(OAc)2/PPh3/CuI/Et3Nb CH3(CH2)3
Pd(OAc)2/PPh3/CuI/Et3Nb CH3(CH2)5
The most efficient catalyst was found to be Pd(PPh3)4
where >99% conversion of the coupled product for
9
Pd(PPh3)4/CuI/Et3Nc
Pd(PPh3)4/CuI/Et3Nc
Pd(PPh3)4/CuI/Et3Nc
Pd(PPh3)4/CuI/Et3Nc
(CH3)3Si
Ph
CH3(CH2)3
CH3(CH2)5
1
10
11
12
13
p-nitrophenylacetylene was observed by H NMR. The
large change in yields of one electron-withdrawing
group with another is observed for each catalyst and
therefore the yields are independent of choice of cata-
lyst. It is believed that the acetate is coordinating to Pd
and thereby deactivating the catalyst. This may also
explain why propargyl acetate was likewise inactive.
Pd2dba3·CHCl3/PPh3/CuI/ (CH3)3Si
Et3Nd
14
15
16
Pd2dba3·CHCl3/PPh3/CuI/ Ph
73
62
56
Et3Nd
Pd2dba3·CHCl3/PPh3/CuI/ CH3(CH2)3
Et3Nd
Deprotection of 4-TMS-ethynyl-6-methyl-2-pyrone 3a
to generate 4-ethynyl-6-methyl-2-pyrone 6 was per-
formed with a view to coupling our alkyne unit with a
large variety of alkenyl and aryl halides (Scheme 2).
Pd2dba3·CHCl3/PPh3/CuI/ CH3(CH2)5
Et3Nd
17
18
19
20
Pd–C/PPh3/CuI/Et3Ne
Pd–C/PPh3/CuI/Et3Ne
Pd–C/PPh3/CuI/Et3Ne
Pd–C/PPh3/CuI/Et3Ne
(CH3)3Si
Ph
CH3(CH2)3
CH3(CH2)5
82
74
77
73
Standard silyl cleavage using methanolic KOH and 1 M
solutions of tetrabutylammonium fluoride (TBAF) at
room temperature resulted in spontaneous decomposi-
tion of the 2-pyrone unit. For TBAF the reaction could
be conducted at −78°C for 2 h to give the deprotected
alkyne 6 in 80% yield. Unfortunately we have so far
been unable to couple this pyrone with aryl halides
under a variety of standard conditions (Et3N as base
a All coupling reactions were conducted at reflux with dry Et3N and
dry CH3CN (2.5:1.5), CuI (4 mol%) under N2 for 3 h. CH3CN was
used unless stated.
b 6 mol% [Pd] catalyst, 18 mol% PPh3.
c 6 mol% [Pd] catalyst.
d 2.5 mol% [Pd] catalyst, 15 mol% PPh3.
e 10% Pd/C (20 wt%), PPh3 (25 wt%).

L. R. Marrison et al. / Tetrahedron Letters 43 (2002) 8853–8857
Table 3. Effect of [Pd] catalyst on yields of 3k and 3la
8855
and either CH3CN, THF or DMF at reflux) using
Pd(OAc)2/PPh3 or Pd(PPh3)4 catalysts. We believe this
is due to the high reactivity of pyrone 6 with basic
solvents, in which immediate decomposition is
observed, even in solvents, such as diethyl ether and
ethanol at temperatures of −30°C. The pyrone is stable
in weakly acidic solvents such as chloroform and hex-
ane, respectively. For this reason it is important to note
that the isolation of this product must be done using
non-polar, neutral solvents.
Entry
1
Catalyst system
Alkyne (R)
p-NO2-Ph
p-NO2-Ph
Yieldb (%)
90 (98)
Pd(OAc)2/PPh3/CuI/
Et3N
Pd(PPh3)4/CuI/Et3N
Pd–C/PPh3/CuI/Et3N p-NO2-Ph
Pd(OAc)2/PPh3/CuI/
Et3N
2
3
4
95 (\99)
86 (94)
26
p-CH3CO-Ph
5
6
Pd(PPh3)4/CuI/Et3N
Pd–C/PPh3/CuI/Et3N p-CH3CO-Ph
p-CH3CO-Ph
35
35
a Conditions as for Table 1 and the respective catalyst systems.
Table 2. Further Sonogashira couplings using the Pd/C/
b Yields are based on pure isolated products. Yields in parenthesis are
by NMR.
PPh3 combinationa
Scheme 2. Reagents and conditions: (i) TBAF (1 M), THF,
−78°C; (ii) [Pd] cat., CuI, Et3N, CH3CN.
It was found that we could couple 2 to alkynylstan-
nanes 7 using a modified Stille procedure10 employing
(PPh3)2PdCl2 in THF/diisopropylamine (DIPA) (1:3
ratio) to give 4-phenylethynyl-6-methyl-2-pyrone 3b in
75% yield (Scheme 3). We were able to extend this to
other alkynes, where R=CH3(CH2)n, n=2, 3, 4 and 5,
3c–f) and good yields were observed (56–63%). Of
particular interest is the utility of these alkynylpyrones
as a dienophile in Diels–Alder reactions with electron-
deficient dienes.
Scheme 3. Reagents and conditions: (i) (PPh3)2PdCl2 (5
mol%), THF/DIPA; (ii) 300°C, benzophenone.
Scheme 4. Suzuki cross-coupling of 4-bromo-6-methyl-2-
pyrone 2. Reagents and conditions: (i) Pd(OAc)2 (6 mol%),
PPh3 (18 mol%), 9 or 10, benzene, D, 6 h.

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L. R. Marrison et al. / Tetrahedron Letters 43 (2002) 8853–8857
Table 4. Suzuki cross-coupling of alkenyl benzodioxaboroles and boronic acidsa
Entry
Alkene (R)
% Yield from benzodioxaboroles
% Yield from boronic acids
1
2
3
4
5
CH3(CH2)2 (11a)
CH3(CH2)3 (11b)
CH3(CH2)4 (11c)
CH3(CH2)5 (11d)
Ph (E) (11e)
35
32
41
32
31
58
66
60
56
27
a Conditions: Pd(OAc)2 (6 mol%), PPh3 (18 mol%), Na2CO3 (2 M), benzene, reflux, 6 h.
Compound 3b efficiently cyclises with 2,3,4,5-tetra-
phenylcyclopentadienone after a few minutes at 300°C
to give 4-(2%,3%,4%,5%,6%-pentaphenyl)phenyl-6-methyl-2-
pyrone 8 in excellent yield (>80%). These reactions are
currently being investigated further.
alkenylboronic acids was successful. The more stable
alkenylboronic acids proved more versatile and higher
yielding. The correct choice of base was essential for
such reactions, as strong bases tended to cause decom-
position of the starting material. Our complete evalua-
tion of other Pd-coupling procedures and important
biological results of these 4-alkenyl/alkynyl-6-methyl-2-
pyrones will be reported in full in due course.
Coupling of 2 with alkenylmetals: Many different types
of alkenyl metals (Al, Zn, B, Zr, Mg and Sn) may be
cross-coupled with aryl halides under Pd-catalysis. We
focussed our attention on the Suzuki coupling of ben-
zodioxaboroles 9 and boronic acids 10 with 2 (Scheme
4).
Acknowledgements
The bases generally used in Suzuki couplings are
NaOEt and NaOH, but these were far too strong for
the 2-pyrone unit to withstand due to the ease of basic
hydrolysis. Indeed, rapid pyrone decomposition is
observed in minutes. We found that using Na2CO3 (2
M), Pd(OAc)2 (6 mol%) and PPh3 as the ligand11 gave
the best yields of the products (Table 4). Higher con-
centrations of Pd catalyst (up to 20 mol%) were of no
benefit, indeed this seemed to have a negative effect on
both the reaction rate and product yields. It is well
known that the alkenyl stereochemistry of the starting
We thank the EPSRC for a PhD studentship to L.R.M.
and M.M.U. for funding. I.J.S.F. acknowledges the
University of York for financial support in the form of
an IRPF grant. We gratefully acknowledge a generous
loan of palladium salts from Johnson Matthey PLC.
References
1. For a comprehensive review, see: Dickinson, J. M. Nat.
Prod. Rep. 1993, 10, 71–98.
2. Staunton, J. In Comprehensive Organic Chemistry; Bur-
ton, D. H.; Ollis, W. D., Eds.; Pergamon Press, 1979;
Vol. 4, pp. 629–658.
3. (a) Bu’Lock, J. D.; Smith, H. E. J. Chem. Soc. 1960,
502–503; (b) Effenberger, F.; Ziegler, T. Chem. Ber. 1987,
120, 1339–1346; (c) Tam, T. F.; Coles, P. Synthesis 1988,
383–386; (d) Moody, C. J.; Rahimtoola, K. F. J. Chem.
Soc., Perkin Trans. 1 1990, 673–679; (e) Moody, C. J.;
Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990,
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4. (a) Afridi, A. S.; Katritzky, A. R.; Ramsden, C. A. J.
Chem. Soc., Perkin Trans. 1 1977, 1428–1436; (b) Kiang,
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2721–2726.
1
materials are conserved in such reactions and H NMR
coupling constants and quantitiative NOE studies12
confirm the formation of the E-alkenylpyrones. For
comparison we were also able to selectively reduce
4-phenylethynyl-6-methyl-2-pyrone to Z-4-phenyl-
ethenyl-6-methyl-2-pyrone 12 using Pd/C, H2 and quin-
oline (87% yield).
Table 4 illustrates that higher yields are obtained from
reactions where boronic acids were employed. This is
advantageous, as the boronic acids are not air sensitive,
unlike the benzodioxaboroles. Similar yields were also
observed employing Pd(PPh3)4 as the catalyst.
In conclusion, we have found a variety of conditions
for the Songashira coupling of terminal alkynes with
4-bromo-6-methyl-2-pyrone 2, which we were able to
extend to a modified Stille procedure. The Sonogashira
method was more beneficial, in that the product purity
was easier to maintain. A surprising result was the use
of Pd/C as the most efficient catalyst for the majority of
the alkynes—an unprecedented result. It was only when
the alkyne possessed strongly electron-withdrawing
substituents was the standard Pd(0) catalysts,
Pd(OAc)2/PPh3 and Pd(PPh3)4, more effective. The syn-
thesis of alkenylpyrones using Suzuki methodology and
the employment of alkenylbenzodioxaboroles and
5. (a) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetra-
hedron Lett. 2001, 42, 2859–2863; (b) Danieli, B.; Lesma,
G.; Martinelli, M.; Passarella, D.; Peretto, I.; Silvani, A.
Tetrahedron 1998, 54, 14081–14088; (c) Cerezo, S.;
Moreno-Manas, M.; Pleixats, R. Tetrahedron 1998, 54,
7813–7818; (d) Liu, Z.; Meinwald, J. J. Org. Chem. 1996,
61, 6693–6699.
6. (a) Lee, J.-H.; Kim, W.-S.; Lee, Y. Y.; Cho, C.-G.
Tetrahedron Lett. 2002, 43, 5779–5782; (b) Lee, J.-H.;
Park, J.-S.; Cho, C.-G. Org. Lett. 2002, 4, 1171–1173.
7. Marrison, L. R.; Dickinson, J. M.; Fairlamb, I. J. S.,
unpublished results. Complete biological studies will be
reported in due course.

L. R. Marrison et al. / Tetrahedron Letters 43 (2002) 8853–8857
8857
8. Reaction of 2 and (phenylethynyl)zinc chloride in THF at
60°C under Pd(PPh3)4 catalysis has been reported to give
the coupled product in 76% yield: Kalinin, V. N.; Shilova,
O. S.; Okladnoi, D. S.; Schmidhamer, H. Dokl. Chem. Engl.
Transl. 1996, 351, 276–278; Dokl. Akad. Nauk. 1996, 351,
67–69.
9. Representative procedure: A magnetically stirred mixture of
2 (1 mmol), alkyne (1.1 mmol), 10% Pd/C (20 mol%), PPh3
(25 mol%) and CuI (4 mol%) in dry Et3N (2.5 mL) and dry
CH3CN (1.5 mL) were heated at reflux under N2 for 3 h.
The mixture was cooled to room temperature and filtered
over a pad of Celite, washed with CH2Cl2 and the filtrate
concentrated in vacuo to give an oil. The coupled products
were isolated by either direct recrystallisation or by extrac-
tion with hexane, followed by flash chromatography.
10. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771–1780; (b)
Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524.
11. Representative procedure: Pd(OAc)2 (6 mol%), PPh3 (18
mol%) and 2 (1 mmol) in benzene (2 mL) and aq. Na2CO3
(1 mL, 2 M) were magnetically stirred under N2 for
0.5 h. To this was added a solution of the boronic acid
(1.1 mmol) in EtOH (1 mL) and the solution was
refluxed for 6 h, and then allowed to cool to room
temperature. The excess boronic acids were oxidised with
30% H2O2 (0.1 mL) for 1 h. The mixture was extracted into
hexane (2×10 mL) and the combined extracts washed with
saturated aq. NaCl (2×10 mL), dried (MgSO4) and con-
centrated in vacuo to give the crude product which
was purified by flash chromatography to give pale oils or
solids.
12. For 4-phenylethenyl-6-methyl-2-pyrone, the E-isomer 11e
gave an 8% NOE to the methyl at the 6-position (CHꢁCH,
3J=16.48 Hz) whereas the Z-isomer 12 gave a 2.5% NOE
3
(CHꢁCH, J=12.09).