Palladium-Catalysed Alkynylations of 2-Pyrone (Pyran-2-one) Halides

Article abstract of DOI:10.1055/s-2003-42405

The 2-pyrone sub-unit is found in a large number of natural products possessing broad-spectrum biological activity. As such, efficient synthetic methods are required to enable facile access to substituted 2-pyrone derivatives. Important conditions for the

Full text of DOI:10.1055/s-2003-42405

2
564
PAPER
Palladium-Catalysed Alkynylations of 2-Pyrone (Pyran-2-one) Halides
P
I
alladium
a
-Catalysed
n
Alkynylations of
J2 -Pyrone s. S. Fairlamb,* Feng Ju Lu, Jan Peter Schmidt
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax +44(1904)432516; E-mail: ijsf1@york.ac.uk
Received 25 July 2003; revised 1 August 2003
9
10
11
Pleixats, Rossi and our group has highlighted the uses
of halogenated 2-pyrones as substrates for organometallic
cross-coupling reactions. Furthermore, we have reported
the synthesis of bromo-2-pyrone tricarbonyliron com-
Abstract: The 2-pyrone sub-unit is found in a large number of nat-
ural products possessing broad-spectrum biological activity. As
such, efficient synthetic methods are required to enable facile ac-
cess to substituted 2-pyrone derivatives. Important conditions for
12
the Sonogashira alkynylation of 4-bromo-6-methyl-2-pyrone (3a) plexes and their uses in the Suzuki reaction. Such studies
have been developed, and compared against Negishi’s methodolo- have begun to overcome the limitations associated with
gy. The best conditions for Sonogashira alkynylation was found to
13
14
the chemistry of the 2-pyrone system. In this paper we
be the use of Pd/C with added Ph P as the catalyst, in the presence
15
3
report, in full, our investigations into the Sonogashira
of catalytic CuI, in a mixture of MeCN and Et N at reflux. Using
3
alkynylation reactions of brominated 2-pyrone 3a
Negishi’s standard conditions, terminal alkynylzinc reagents, gen-
erated in situ from terminal alkynes with LDA or n-BuLi and sub-
(
Scheme 1). The reactions are compared and contrasted
1
6
sequent reaction with anhydrous ZnBr , were reacted with 3a at with Negishi’s recently reported alkynylation proto-
2
col.17
room temperature using Pd(PPh ) as the catalyst in THF.
3
4
Key words: palladium, Negishi reaction, Sonogashira reaction, 2-
pyrones
R
X
Sonogashira
The 2-pyrone ring system 1 (pyran-2-one), a 6-membered
cyclic unsaturated ester, shares similar chemical and
physical properties reminiscent of alkene and aromatic
or
O
O
O
2
O
Negishi
O
O
1
1
X = Br, 3a
X = OTf, 3b
compounds (Scheme 1). The core structure is biodiverse
and found in many bacterial, microbial, plant, insect and
2
animal systems. 2-Pyrones demonstrate a vast array of Scheme 1
bioactivity and exhibit antifungal, antibiotic, cytotoxic,
3
neurotoxic and phytotoxic properties. Very recently we
We initially probed the Sonogashira reaction of 3a using
standard conditions (Table 1). The precatalyst, bis(triphe-
nylphosphine)palladium(II) chloride [(PPh ) PdCl ] is
commonly employed in the Sonogashira reaction, howev-
er, this proved unsuccessful in acetonitrile, THF or DMF
have identified 4-alkynyl-6-methyl-2-pyrones 2 that in-
hibit the growth of A2780 human ovarian carcinoma and
K562 human chronic myelogenous leukaemia cell lines at
the micromolar level. This promising bioactivity has en-
couraged us to identify useful synthetic protocols to these
derivatives.
3
2
2
4
(
entries 1–4, Table 1). The poor catalytic activity was sur-
prising, as the analogous Sonogashira coupling of pyrones
2
-Pyrones also find a wide variety of synthetic applica- at the 3- and 5-positions are facile using this catalyst, par-8
5
tions, in particular as a diene component in normal and ticularly where DMF is employed as the reaction solvent.
6
inverse electron demand Diels–Alder reactions, and as a Historically it has been assumed that (PPh ) PdCl is re-
3
2
2
precursor to other heterocyclic systems, such as 2-pyri- duced to (PPh ) Pd(0) in situ. Recent work by Amatore
3
2
7
dones. Despite the synthetic utility of 2-pyrones, the syn- and Jutand has demonstrated that there is the possibility
thesis and construction of substituted derivatives can be that the catalytic species produced from (PPh ) PdCl is
fraught with difficulties, often requiring multi-step syn- anionic, namely [(PPh ) Pd(0)Cl] . Palladium black is
3
2
2
–
18
2
2
theses via acyclic precursors. Ring-opening and rear- formed very quickly in our reactions, suggesting that such
rangements usually thwart high yielding transformations, a species is not formed under the conditions. Alternative
in some cases leaving the 2-pyrone ring impossible to re- methods for generating (PPh ) Pd(0) in situ proved supe-
3
2
generate. Direct substitutions onto the 2-pyrone ring, in rior. For example, use of Pd(OAc) /PPh gave the coupled
2
3
particular organometallic couplings (Suzuki, Sonogash- products in higher yields (entries 5–8, Table 1).
ira, Stille and amination reactions), offer a versatile ap- Switching to tetrakis(triphenylphosphine)palladium(0)
proach to the synthesis of a wide variety of 2-pyrones. [(PPh ) Pd(0)] resulted in similar yields (entries 9–12,
3
4
8
Recent work by the likes of Cho, Moreno-mañas and Table 1), whereas the commonly employed Pd(0) com-
plex, Pd dba ·CHCl (dba = dibenzylideneacetone) with
2
3
3
added PPh proved more efficient, albeit requiring a long-
er reaction time (entries 13–16, Table 1).
3
SYNTHESIS 2003, No. 16, pp 2564–2570
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42405; Art ID: Z11303SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Palladium-Catalysed Alkynylations of 2-Pyrones
2565
We turned our attention to the use of 10% palladium on air stable and very convenient to use. We also altered the
charcoal with added PPh . The Pd-C (2 mol% Pd) and type of base and solvent in these reactions using Pd-C/
3
PPh (2.5 mol%) catalyst combination clearly has a dra- PPh (Table 2). It was found that THF in combination
3
3
matic effect on the Sonogashira reaction of 3a (entries 17– with i-Pr NEt (Hünig’s base) was as effective as MeCN
2
2
0, Table 1). We believe that this is the first time that such and Et N (entries 2 and, Table 2). Reactions conducted in
3
enhanced efficiency has been observed over standard Et O were lower yielding. Pyrrolidine functioned modest-
2
Pd(0) based catalysts in the Sonogashira reaction. Recent- ly as a base (entries 4 and 11, Table 2), whereas use of py-
ly it was reported that Pd-C is an efficient catalyst for the ridine failed to facilitate cross-coupling (entries 3, 10 and
Sonogashira reaction of aryl halides with the proper 14, Table 2).
choice of solvent.1 Our conditions clearly allow Pd-C/
9
A number of terminal alkynes were cross-coupled with 3a
PPh to act as a superior catalyst system with respect to
3
using the Pd-C/PPh catalyst combination in Et N and
3
3
3
a. The advantage of using this Pd(0) catalyst is that it is
MeCN at reflux (Table 3). Good to excellent yields were
observed for the vast majority of these 2-pyrones. Poor
yields were observed in reactions of 3a with propargyl al-
cohol and propargyl acetate to give 2g and 2l, respective-
ly. The structural complexity of 17 -ethynylesteradiol
posed no problems towards cross-coupling, with 2p iso-
lated in 85% yield. Changing to the pseudohalide sub-
strate triflate 3b, synthesised in 81% yield using N-
phenyltriflimide in the presence of potassium carbonate in
Table 1 Sonogashira Reactions of 3aa
R
Br
R = CH3(CH2)3, 2b
R = CH3(CH2)5, 2d
R = (CH3)3Si, 2e
R = Ph, 2f
R
Conditions
O
O
O
O
Entry
Catalyst System
R
Yield (%)
20
THF at 60 °C, improved the yields of the cross-coupled
b
products in the Sonogashira reaction (2a–c and 2f), and an
enhanced rate of reaction was seen. Complete loss of 3b
was noted after only 1 hour!
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(PPh ) Cl /CuI/Et N
Me Si
0
3
2
2
3
3
as above
Ph
trace
12
b
Pd(PPh ) Cl /CuI/Et N/THF
Ph
Ph
3
2
2
3
b
Table 2 Effect of Base and Solvent in Sonogashira Reactions of 3aa
Pd(PPh ) Cl /CuI/Et N/DMF
trace
50
3
2
2
3
b
Yield (%)b
88 (3)
91 (2)
0 (48)
43 (48)
68 (2)
95 (1)
59 (2)
61 (48)
98 (3)
0 (48)
58 (5)
23 (26)
36 (6)
0 (48)
74 (3)
Pd(OAc) /PPh /CuI/Et N
Me Si
Entry
1
Solvent
THF
Base
R
2
3
3
3
as above
as above
as above
Ph
43
Et N
Ph
3
Me(CH2)3 48
Me(CH2)5 27
2
THF
i-Pr NEt
Ph
2
3
THF
pyridine
Ph
c
Pd(PPh ) /CuI/Et N
Me Si
47
32
4
THF
pyrrolidine
Ph
3
4
3
3
1
1
1
1
1
1
1
1
1
1
as above
Ph
5
Et O
i-Pr NEt
Ph
2
2
as above
as above
Me(CH2)3 52
Me(CH2)5 53
6
MeCN
DMF
THF
THF
THF
THF
i-Pr NEt
Ph
2
7
i-Pr NEt
Ph
2
d
Pd dba ·CHCl /PPh /CuI/Et N
Me Si
69
73
8
Et N
Me
2
3
3
3
3
3
3
as above
as above
as above
Ph
9
i-Pr NEt
Me(CH2)5
Me(CH2)5
Me(CH2)5
Me(CH2)5
Me(CH2)5
Me(CH2)5
Me(CH2)5
2
Me(CH2)3 62
Me(CH2)5 56
10
11
12
13
14
pyridine
pyrrolidine
e
Pd-C/PPh /CuI/Et N
Me Si
82
74
Et O
Et N
3
3
3
2
3
as above
as above
as above
Ph
Et O
i-Pr NEt
2
2
Me(CH2)3 77
Me(CH2)5 81
Et O
pyridine
2
2
15
MeCN
i-Pr NEt
2
a
a
All coupling reactions were conducted at reflux in a mixture of an-
All coupling reactions were conducted at reflux with the appropriate
hyd Et N and MeCN (2.5:1.5) with CuI (4 mol%) under N for 3 h.
base and solvent (2.5:1.5), 10 % Pd/C (2 mol% Pd), PPh (2.5 mol%),
3
2
3
MeCN was used unless stated.
CuI (4 mol%), under N or Ar.
Refers to isolated yields. The reaction time is given in parenthesis.
2
b
b
6
6
2
1
mol% [Pd]-catalyst, 18 mol% PPh3.
mol% [Pd]-catalyst.
.5 mol% [Pd]-catalyst, 15 mol% PPh , 6–8 h.
c
d
e
3
0% Pd-C (2 mol% Pd), PPh (2.5 mol%).
3
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York

2
566
I. J. S. Fairlamb et al.
PAPER
a
b
Table 3 Sonogashira and Negishi Alkynylation of 3a and 3b
Coupled Product
Yield (%)c
Coupled Product
Yield (%)
Sonogashira Negishi
Sonogashira Negishi
O
O
O
O
2
a
72 (79)
79
2i
95
83
(
)2
HN
O
O
O
O
O
2b
2c
2d
2e
2f
77 (75)
79 (82)
81 (68)
82
83
72
51
91
81
2j
95
35
0
64
(
(
(
)3
)4
)5
O2N
O
O
O
O
2k
2l
78
O
O
O
O
O
AcO
40
O
O
O
2m
2n
61
84
52d
43d
TMS
O
OH
O
O
O
74 (90)
Ph
O
OH
O
O
O
HO
20d
85d
2
2
g
5
2o
2p
90
85
O
OH
O
O
O
THPO
O
OH
h
81
50
92d
HO
a
Sonogashira Conditions: Anhyd Et N and anhyd MeCN (2.5:1.5), CuI (4 mol%), 10% Pd-C (2 mol% Pd), Ph P (2.5 mol%), under N or argon
3
3
2
for 3 h at reflux. Isolated yields after column chromatography.
b
Negishi Conditions: n-BuLi or LDA, 78 to 0 °C, then ZnBr added; followed by 3a, Pd(PPh ) (5 mol%), THF, 25 25 °C.
Isolated yields using triflate 3b as the substrate are given in parenthesis.
2
3 4
c
d
Excess LDA (2 or 3 equiv) and ZnBr (2 or 3 equiv) were used with alkynes containing sensitive acidic functionalities.
2
A series of reactions of 3a with alkynylzinc reagents using with 3a, which is the only limitation. Pleasingly, we were
Negishi’s protocol was undertaken. The alkynylzinc re- able to employ 17 -ethynylesteradiol as the alkyne com-
agent was generated by reaction of the terminal alkyne ponent in these reactions using 3 equivalents of LDA and
with n-BuLi or LDA at –78 °C to 0 °C, followed by addi- 3 equivalents of ZnBr2.
tion of ZnBr . The resultant alkynylzinc was added to 3a
2
In conclusion, important reactions conditions for the So-
and Pd(PPh ) (5 mol%), (THF, 25 °C, 4 h) to give the
3
4
nogashira alkynylation of 3a have been developed, which
coupled products (Table 3). The yields fare well against
the Sonogashira reaction. Notable improvements were
seen for 2k and 2l. Being able to conduct reactions at
room temperature is an advantage, although the alkynyl-
zinc reagent has to be generated in situ prior to reaction
21
can be extended to other brominated 2-pyrones. The 2-
pyrone products will be useful for a number of reactions.
Negishi’s alkynylation protocol performs well in reac-
tions of 3a with terminal alkynes, containing varying de-
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York

PAPER
Palladium-Catalysed Alkynylations of 2-Pyrones
2567
grees of structural complexity. These studies represent the give an oil. The products were isolated by either direct recrystalli-
sation or by extraction into hot hexane, followed by chromatogra-
first Negishi alkynylation reactions of halogenated 2-py-
phy on silica gel using petroleum ether (40–60 °C)–EtOAc, 9:1) to
rones.
provide the products as crystalline solids or viscous oils (Tables 1
and 2).
Terminal alkynes were purchased from Aldrich or Lancaster and re-
distilled or recrystallised. THF was dried over sodium-benzophe-
none ketyl (distilled prior to use). Anhyd CH Cl , Et N and MeCN
Negishi Reaction with 3a with Terminal Alkynes; General Pro-
cedure
2
2
3
were distilled over CaH . All reactions were conducted under an in-
To a solution of i-Pr
BuLi (1 mmol, 2.5 M solution in hexane) at 0 °C in a flame-dried
flask under an atmosphere of N or Ar. After 30 min, the terminal
2
NEt (1 mmol) in THF (5 mL) was added n-
2
ert atmosphere of argon or N on a Schlenk line. Pd(PPh ) was pre-
2
3 4
pared prior to use from Pd(OAc) and PPh (1:5) in Et O, stirring at
2
2
3
2
r.t. (1 h, in the dark!), then filtered through a sinter glass funnel (un-
der N ) to give Pd(PPh ) as a yellow solid. Pd(OAc) was pur-
alkyne (1 mmol) in THF (1 mL) was added to the LDA solution via
cannula at –78 °C, then stirred at this temperature for 0.5 h, and then
2
3 4
2
chased from Aldrich or Strem. PdCl was provided by Johnson
treated with a solution of anhyd ZnBr (1 mmol, dried at 60 °C un-
2
2
Matthey as a gift. (PPh ) PdCl was prepared from PdCl in reflux-
der vacuum at ca. 1 mmHg for 8 h) in THF (2 mL), and warmed
gradually to 0 °C over 0.5 h. After this time, 3a (1 mmol) and
3
2
2
2
2
2
ing DMSO and PPh (2 equiv) using a known procedure. 10% Pd-
3
C was purchased from Lancaster. Compound 3a was synthesised
Pd(PPh
was allowed to warm to r.t. (ca. 25 °C) and stirring was continued
for 2–4 h. The mixture was quenched with aq NH Cl, extracted with
EtOAc, which was washed with aq NaHCO and then brine, dried
(MgSO ), filtered, and concentrated in vacuo. Purification was car-
3 4
) were added to the reaction mixture at 0 °C. The mixture
2
3
according to the literature procedure(s). Melting points were re-
corded on an electrothermal IA9000 Digital Melting Point Appara-
tus and are uncorrected. TLC analysis was performed on Merck
4
3
5
554 aluminum backed silica gel plates and compounds visualised
4
by ultraviolet light (254 nm), phosphomolybdic acid solution (5%
in EtOH), or 1% ninhydrin in EtOH. The relative proportion of sol-
vents in mixed chromatography solvents refers to the volume/vol-
ume ratio. IR spectra were recorded on a ATI Mattson Genesis FT-
IR spectrophotometer. Mass spectrometry was carried out using a
Fisons Analytical (VG) Autospec instrument. High-resolution
ried out as above (Table 3).
4-Pentynyl-6-methyl-2-pyrone (2a)
Purified by extraction into hot hexane, followed by chromatography
on silica gel (Et O–hexane, 1:1) to give a dark oil.
2
IR (neat): 3096, 2934, 2224, 1729 (C=O), 1639, 1540, 1445, 1313,
1
masses are within 5 ppm of theoretical values. H NMR spectra
–1
1
135, 847 cm .
were recorded at 270 MHz using a Jeol EX270 spectrometer or at
1
1
3
H NMR (270 MHz, CDCl ): = 6.14 (1 H, s), 5.93 (1 H, s), 2.40
3
4
6
00 MHz using a Jeol ECX400 spectrometer; C NMR spectra at
3
3
1
9
(2 H, t, J = 7.3 Hz), 2.22 (3 H, s), 1.62 (2 H, sx, J = 7.3 Hz), 0.93
(
7.9 or 100.5 MHz; F NMR spectra at 376.3 MHz. Chemical
3
3 H, t, J = 7.3 Hz).
shifts are reported in parts per million ( ) downfield from an inter-
nal tetramethylsilane reference. Coupling constants (J values) are
reported in Hertz (Hz), and spin multiplicities are indicated by the
following symbols: s (singlet), d (doublet), t (triplet), q (quartet), qn
13C NMR (68 MHz, CDCl3): = 162.2, 161.5, 139.7, 113.9, 105.7,
101.0, 77.45, 21.4, 21.3, 19.6, 13.2.
+
+
+
LREI m/z = 176 ([M ]), 161 ([M – CH ]), 148 ([M – C≡O]), 133
3
(quintet), sx (sextet), m (multiplet), br (broad).
+
(
[M – C H ]), 119, 105, 93, 77, 65, 51, 43.
3 7
+
6
4
2
-Methyl-2-pyrone-4-trifluoromethanesulfonate (3b)
-Hydroxy-6-methyl-2-pyrone (1 g, 7.9 mmol), K CO (3.28 g,
3.8 mmol), and N-phenyltriflimide (2.97 g, 8.3 mmol) in anhyd
LRCI: m/z = 177 ([MH ]), 100).
2
3
HRCI: m/z calcd for C H O : 177.0915; found: 177.0912.
1
1
13
2
THF (15 mL) were magnetically stirred at 60 °C for 4 h. The reac-
tion mixture was cooled to r.t. and taken up in CH Cl (100 mL),
4
-Hexynyl-6-methyl-2-pyrone (2b)
2
2
Purified by extraction into hot hexane, followed by chromatography
on silica gel (Et O–hexane, 1:1) to give a dark oil.
and washed with 5% aq NH Cl (2 × 25 mL), H O (25 mL). The or-
4
2
2
ganic layer was dried (MgSO ), filtered, and concentrated in vacuo
4
IR (neat): 3097, 2934, 2872, 2230, 1738 (C = O), 1639, 1540, 1445,
1
to give an oil. Purification by column chromatography [petroleum
ether (40–60 °C)–EtOAc, 1:1] gave the product as a pale yellow oil
–
1
313, 1135, 849 cm .
1
(1.66 g, 81%).
H NMR (270 MHz, CDCl ): = 6.13 (1 H, s), 5.93 (1 H, s), 2.43
3
3
1
(2 H, t, J = 7.0 Hz), 2.20 (3 H, s), 1.36–1.62 (4 H, m), 0.93 (3 H, t,
H NMR (270 MHz, CDCl ): = 6.05 (1 H, s), 6.00 (1 H, s), 2.27
3
3
J = 7.3 Hz).
(
3 H, s).
13C NMR (68 MHz, CDCl
01.3, 77.3, 30.0, 21.8, 19.6, 19.1, 13.3.
): = 162.2, 161.5, 139.7, 113.9, 105.7,
13C NMR (68 MHz, CDCl3): = 20.4, 99.6, 102.4, 161.2, 162.4,
3
1
1
65.3.
+
+
+
19F NMR (376 MHz, CDCl3): = –72.17 (3 F, s).
LREI: m/z = 190 ([M ]), 175 ([M – CH
3
]), 161 ([M – C
H ]), 147
2 5
+
+
(
[M – C H ]), 133 ([M – C H ]), 119, 105, 93, 73, 65.
3
7
4
9
+
+
LRCI: m/z = 276 ([M + NH ], 100), 259 ([MH ], 15), 144, 127,
4
+
LRCI: m/z = 191 ([MH ], 100).
HRCI: m/z calcd for C H O : 191.1072; found: 191.1070.
1
09, 72.
1
2
14
2
HRCI: m/z calcd for C H F O S: 258.9888; found: 258.9889.
7
6
3
5
4
-Heptynyl-6-methyl-2-pyrone (2c)
Sonogashira Reaction of 3a with Terminal Alkynes; General
Procedure
Purified by extraction into hot hexane, followed by chromatography
on silica gel (Et O–hexane, 2:3) to give a dark oil.
2
To a flame-dried flask under an atmosphere of N or argon was add-
2
ed 3a (1 mmol), the terminal alkyne (1 mmol), 10% Pd-C (20 mol%,
IR (neat): 3095, 2929, 2228, 1730 (C = O), 1639, 1544, 1445, 1313,
1136, 849 cm .
–
1
2
mol% based on Pd), PPh (2.5 mol%) and CuI (4 mol%). Anhyd
3
Et N (2.5 mL) and anhyd MeCN (1.5 mL) were added via cannula
1
3
H NMR (270 MHz, CDCl ): = 6.14 (1 H, s), 5.92 (1 H, s), 2.41
3
and the mixture was magnetically stirred and heated to reflux for 3
h. The mixture was cooled to r.t., and filtered through Celite,
washed with CH Cl and the filtrate was concentrated in vacuo to
3
(
2 H, t, J = 7.0 Hz), 2.21 (s, 3 H), 1.60 (2 H, m), 1.30–1.45 (4 H,
3
m), 0.92 (3 H, t, J = 7.0 Hz).
2
2
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York

2
568
I. J. S. Fairlamb et al.
PAPER
1
3
+
C NMR (68 MHz, CD Cl ): = 162.2, 140.1, 114.9, 114.3, 105.9,
LRCI: m/z = 207 ([MH ], 100), 149, 142.
HRCI: m/z calcd for C H O : 207.0657; found: 207.0660.
2
2
1
01.6, 77.7, 31.4, 28.2, 22.5, 20.0, 19.9, 14.0.
1
1
11
4
+
LRCI: m/z 205 ([MH ], 100).
6
-Methyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl-2-
HRCI: m/z calcd for C H O : 205.1228; found: 205.1227.
1
3
17
2
pyrone (2h)
Purified by extraction into hot hexane, followed by chromatography
4
-Octynyl-6-methyl-2-pyrone (2d)
on silica gel (Et O–hexane, 1:1) to give a dark oil.
2
Purified by extraction into hexane, followed by chromatography on
silica gel (Et O–hexane, 2:3) to give a dark oil.
IR (neat): 3097, 2943, 2871, 2231, 1727 (C=O), 1640, 1542, 1443,
2
–
1
1
388, 1314, 1238, 1122, 1029, 902, 870 cm .
IR (neat): 3097, 2930, 2859, 2230, 1733 (C=O), 1640, 1542, 1444,
–
1
1
1
313, 1135, 849 cm .
H NMR (270 MHz, CDCl ): = 6.14 (1 H, s), 5.89 (1 H, s), 4.74
3
3
3
1
(1 H, t, J = 3.5 Hz), 4.40 (2 H, d, J = 3.5 Hz), 3.78 (1 H, m), 3.49
H NMR (270 MHz, CDCl ): = 6.12 (1 H, s), 5.91 (1 H, s), 2.40
3
3
3
(1 H, m), 2.16 (3 H, s), 1.40–1.85 (6 H, m).
13C NMR (68 MHz, CDCl3): = 161.9, 161.8, 138.3, 114.7, 105.1,
97.1, 95.1, 81.6, 61.8, 54.2, 30.0, 25.1, 19.6, 18.7.
(
0
2 H, t, J = 6.8), 1.58 (2 H, qn, J = 7.6 Hz), 1.26–1.46 (m, 6 H),
3
.89 (3 H, t, J = 6.8 Hz).
13C NMR (68 MHz, CDCl3): = 162.2, 140.0, 114.4, 105.9, 101.6,
+
7
7.7, 31.6, 28.9, 28.5, 22.9, 20.0, 19.9, 14.2.
LRCI: m/z = 249 ([MH ], 25), 211, 165, 102. 85 (100).
+
+
+
LREI: m/z = 218 ([M ]), 203 ([M – CH ]), 175 ([M – C H ]), 161
HRCI: m/z calcd for C H O : 249.1126; found: 249.1123.
3
3
7
14 17
4
+
(
[M – C H ]), 148, 135, 120, 105, 91, 77, 65, 55, 43 (100).
4 9
+
N-[4-(6-Methyl-2-oxo-2H-pyran-4-ylethynyl)phenyl]acetamide
2i)
Purified by extraction into hot hexane, followed by chromatography
LRCI: m/z = 219 ([MH ], 100), 205.
HRCI: m/z calcd for C H O : 219.1385; found: 219.1384.
(
1
4
19
2
on silica gel (Et O–hexane, 1:1) to give a yellow solid; mp 224–225
2
4
-(Trimethylsilylethynyl)-6-methyl-2-pyrone (2e)
°
C.
Purified by extraction into hot hexane, followed by chromatography
on silica gel (Et O–hexane, 1:1) to give a dark oil.
–
1
IR (CH Cl ): 1726 (C=O), 1706 (C=O), 1511 cm .
2
2
2
1
H NMR (400 MHz, DMSO-d ) 7.51–7.66 (5 H, br m), 6.32 (1 H,
6
IR (neat): 3095, 2961, 2900, 2112, 1745 (C=O), 1638, 1538, 1312,
1
–1
s), 5.75 (1 H, s), 3.32 (3 H, s), 2.47 (3 H, s).
252, 964, 846 cm .
+
+
1
LRCI: m/z = 279 ([M + NH
4
], 100), 268 ([MH ], 62), 210, 102.
H NMR (270 MHz, CDCl ): = 6.11 (1 H, s), 5.92 (1 H, s), 2.21
3
(
3 H, s), 0.25 (9 H, s).
HRCI: m/z calcd for C H NO : 268.0975; found: 268.0974.
16 14 3
13C NMR (68 MHz, CDCl3): = 161.9, 138.5, 115.1, 114.7, 108.3,
4
-(4 -Nitrophenylethynyl)-6-methyl-2-pyrone (2j)
1
05.3, 100.1, 19.7, –0.6.
Purified directly by chromatography on silica gel (CHCl ), followed
by recrystallisation from MeCN; mp 189–191 °C (dec.).
3
+
+
LREI: = m/z 206 ([M ]), 191 ([M – CH ]), 163, 84, 75, 49 (100).
3
+
LRCI: m/z = 207 [M +1] (100), 191, 178, 90.
IR (neat): 3099, 2210, 1721 (C=O), 1644, 1590, 1538, 1512, 1340,
1
–
1
213, 1102, 958, 845, 749 cm .
HRCI: m/z calcd for C H O Si: 207.0841; found: 207.0838.
1
1
15
2
1
3
H NMR (270 MHz, CDCl ): = 8.27 (2 H, d, J = 8.8), 7.70 (2 H,
3
4
-(Phenylethynyl)-6-methyl-2-pyrone (2f)
3
d, J = 8.8), 6.36 (s, 1 H), 6.07 (s, 1 H), 2.28 (s, 3 H).
13C NMR (68 MHz, CDCl3): = 162.5, 161.6, 148.0, 137.6, 132.9,
1
Isolated by extraction into hot hexane and recrystallised to give a
pale brown solid; mp 85–86 °C.
27.8, 123.7, 115.5, 104.8, 95.2, 89.3, 19.9.
IR (KBr): 3086, 2203, 1723 (C = O), 1705, 1642, 1535, 1439, 1310,
+
+
–
1
LREI: m/z = 255 ([M ]), 227 ([M – C≡O]), 197, 181, 152, 137, 115,
9, 43.
1
135, 956, 840, 763 cm .
6
1
H NMR (270 MHz, CDCl ): = 7.38–7.59 (5 H, m), 6.30 (1 H, s),
3
+
LRCI: m/z = 256 ([MH ], 28), 226 (100).
HRCI: m/z calcd for C14 : 256.0609; found: 256.0605.
Anal. Calcd for C H NO : C, 65.88; H, 3.53. Found: C, 65.64; H,
6
.05 (1 H, s), 2.26 (3 H, s).
13C NMR (68 MHz, CDCl3): = 162.1, 161.9, 138.9, 132.1, 129.9,
H10NO
4
1
28.6, 121.3, 114.5, 105.3, 98.5, 85.4, 19.8.
1
4
10
4
+
+
+
3.62.
LREI: m/z = 210 ([M ]), 195 ([M – CH ]), 182 ([M – C≡O]), 153,
3
1
39 (100), 127, 113, 87, 69, 51.
4
-(4 -Acetylphenylethynyl)-6-methyl-2-pyrone (2k)
+
LRCI: m/z = 211 ([MH ], 100), 182.
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a pale yellow solid; mp 155–157 °C.
HRCI: m/z calcd for C H O : 211.0759; found: 211.0765.
1
4
11
2
–
1
IR (KBr): 3037, 1716 (C=O), 1680 (C=O), 1628, 1536 cm .
Anal. Calcd for C H O : C, 79.98; H, 4.80. Found: C, 79.65; H,
4
14
10
2
.98.
1
3
H NMR (270 MHz, CDCl ): = 7.97 (2 H, d, J = 8.4 Hz), 7.62 (2
3
3
H, d, J = 8.4 Hz), 6.33 (s, 1 H), 6.07 (s, 1 H), 2.63 (2 H, s), 2.27 (3
H, s).
4
-(3 -Hydroxyprop-2 -ynyl)-6-methyl-2-pyrone (2g)
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a light yellow solid; mp 119–121 °C.
1
3
C NMR (68 MHz, CDCl ): 196.9, 162.2, 161.8, 138.2, 137.5,
3
1
32.2, 128.3, 125.8, 115.0, 105.0, 96.9, 87.8, 26.6, 19.9.
–
1
IR (CH Cl ): 3443 (br, OH), 1718 cm (C=O).
2
2
+
+
LREI: m/z = 252 ([M ]), 237 ([M – CH ]), 209, 181, 159, 138, 123,
103, 89, 71, 57 (100), 41.
3
1
4
H NMR (400 MHz, CDCl ): = 5.81 (1 H, d, J = 2.1 Hz), 5.53 (1
3
4
H, d, J = 2.1 Hz), 4.66 (2 H, s), 2.63 (1 H, s), 2.22 (3 H, s).
+
LRCI: m/z 253 ([MH ], 100).
1
3
C NMR (100 MHz, CDCl ): = 19.9, 56.3, 75.9, 77.3, 88.9, 100.2,
3
HRCI: m/z calcd for C H O : 253.0864; found: 253.0863.
1
6
13
3
1
62.5, 164.5, 169.1.
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York

PAPER
-(3 -Acetoxy-prop-2 -ynyl)-6-methyl-2-pyrone (2l)
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a pale yellow oil.
Palladium-Catalysed Alkynylations of 2-Pyrones
2569
4
Acknowledgement
I.J.S.F is grateful to the University of York for start-up funds and to
Johnson and Matthey for their generous gift of palladium salts.
1
H NMR (270 MHz, CDCl ): = 6.24 (1 H, s), 5.96 (1 H, s), 4.88
3
(
2 H, s), 2.26 (3 H, s), 2.14 (3 H, s).
1
3
References
C NMR (100 MHz, CDCl ): = 19.9, 20.6, 52.0, 81.7, 91.9, 104.5,
3
1
14.9, 137.3, 161.4, 161.8, 169.5.
(
1) Staunton, J. In Comprehensive Organic Chemistry, Vol. 4;
Burton, D. H.; Ollis, W. D.; Sammes, P. G., Eds.; Pergamon:
New York, 1979, 629.
+
LRCI: m/z = 207 ([MH ], 100), 149, 142.
HRCI: m/z calcd for C H O : 207.0657; found: 207.0660.
1
1
11
4
(2) Moreno-Mañas, M.; Pleixats, R. In Naturally Occurring
Oxygen Ring Systems; Academic Press: New York, 1992,
4
-(Ethynylcyclopentan-1 -ol)-6-methyl-2-pyrone (2m)
21.
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a light brown viscous oil.
(
(
3) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71.
4) Marrison, L. R.; Dickinson, J. M.; Fairlamb, I. J. S. Bioorg.
Med. Chem. Lett. 2002, 12, 3509.
–
1
IR (CH Cl ): 3599 (s, OH), 1727 (C=O), 1637 cm .
2
2
1
(5) (a) Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33,
839. (b) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan,
C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690.
c) Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.;
H NMR (270 MHz, CDCl ): = 6.20 (1 H, s), 5.96 (1 H, s), 3.08
3
7
(1 H, br), 2.23 (3 H, s), 1.68–2.02 (8 H, br m).
1
3
C NMR (68 MHz, CDCl ): = 19.7, 23.4, 42.1, 74.4, 79.2, 103.3,
3
(
1
05.6, 114.4, 139.1, 161.9, 162.5.
Peretto, I.; Silvani, A. Tetrahedron 1998, 54, 14081.
(d) Chen, C.-H.; Liao, C.-C. Org. Lett. 2000, 2, 2049.
6) For an excellent review, see: (a) Afarinkia, K.; Vinader, V.;
Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111.
+
LRCI: m/z = 219 ([MH ], 100).
(
HRCI: m/z calcd for C H O : 219.1021; found: 219.1021.
1
3
15
3
(
(
(
b) Bu’Lock, J. D.; Smith, H. E. J. Chem. Soc. 1960, 502.
c) Effenberger, F.; Ziegler, T. Chem. Ber. 1987, 120, 1339.
d) Tam, T. F.; Coles, P. Synthesis 1988, 383. (e) Moody,
4
-(Ethynylcyclohexan-1 -ol)-6-methyl-2-pyrone (2n)
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a viscous yellow oil.
C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990,
73.
–
1
IR (Nujol): 1731, 1623, 1551, 1298, 1068 cm .
1H NMR (270 MHz, CDCl3): = 6.20 (1 H, s), 5.97 (1 H, s), 3.42
6
(7) (a) Afridi, A. S.; Katritzky, A. R.; Ramsden, C. A. J. Chem.
Soc., Perkin Trans. 1 1977, 1428. (b) Kiang, A. K.; Tang, S.
F.; Wang, W. S. J. Chem. Soc. 1971, 2721.
8) (a) Lee, J.-H.; Kim, W.-S.; Lee, Y. Y.; Cho, C.-G.
Tetrahedron Lett. 2002, 43, 5779. (b) Lee, J.-H.; Park, J.-S.;
Cho, C.-G. Org. Lett. 2002, 4, 1171.
(1 H, br), 2.23 (3 H, s), 1.25–2.02 (10 H, br m).
13C NMR (68 MHz, CDCl3): = 19.7, 23.1, 24.9, 39.3, 68.9, 80.3,
1
(
03.0, 105.7, 114.5, 139.0, 162.0, 162.4.
+
LRCI: m/z = 233 ([MH ], 100).
(
9) Cerezo, S.; Moreno-mañas, M.; Pleixats, R. Tetrahedron
HRCI: m/z calcd for C H O : 233.1177; found: 233.1175.
1
4
17
3
1998, 54, 7813.
(
(
10) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron
Lett. 2001, 42, 2859.
11) (a) Marrison, L. R.; Dickinson, J. M.; Ahmed, R.; Fairlamb,
I. J. S. Tetrahedron Lett. 2002, 43, 8853. (b) Marrison, L.
R.; Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. S. Bioorg.
Med. Chem. Lett. 2003, 13, 2667.
4
-(Ethynyl-9H-fluorenyl-9 -ol)-6-methyl-2-pyrone (2o)
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a yellow solid; mp 145–147 °C.
–
1
IR (CH Cl ): 3425, 1727 (C=O), 1693, 1625 cm .
2
2
1
3
H NMR (270 MHz, CDCl ): = 7.60 (2 H, d, J = 7.8 Hz), 7.52 (2
3
3
H, d, J = 7.8 Hz), 7.23–7.32 (4 H, m), 5.95 (1 H, s), 5.77 (1 H, s),
.80 (1 H, br), 2.01 (3 H, s), 1.25–2.02 (10 H, br m).
(12) Fairlamb, I. J. S.; Syvänne, S. M.; Whitwood, A. C. Synlett
2003, 1693.
3
(
13) (a) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R.
Tetrahedron Lett. 2001, 42, 2859. (b) Liu, Z.; Meinwald, J.
J. Org. Chem. 1996, 61, 6693.
13C NMR (68 MHz, CDCl3): = 19.6, 74.7, 78.5, 99.5, 105.4, 114.8,
1
20.2, 124.4, 128.5, 129.9, 138.4, 139.0, 146.1, 161.8, 162.2.
+
LRCI: m/z = 315 ([MH ], 100).
(14) Some of this work has appeared in a preliminary
1
1a
communication, see: Ref.
.
HRCI: m/z calcd for C H O : 315.1021; found: 315.1021.
2
1
15
3
(
15) (a) For an overview and historical note, see: Sonogashira, K.
J. Organomet. Chem. 2002, 653, 46. (b) For a recent
review, see: Sonogashira, K. In Handbook of
4
-(17 -Ethynylestradiol)-6-methyl-2-pyrone (2p)
Purified by chromatography on silica gel (EtOAc–hexane, 1:1) to
give a light brown soild; mp 112–114 °C.
Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002, 493–
–
1
IR (Nujol): 3440, 1728 (C=O), 1693, 1142 cm .
529.
1
3
H NMR (270 MHz, CDCl ): = 7.13 (1 H, d, J = 5.6 Hz), 6.66 (1
(16) (a) For an overview and historical note, see: Negishi, E. J.
Organomet. Chem. 2002, 653, 34. (b) For a recent review,
see: Negishi, E.; Xu, C. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002, 531–549.
3
3
H, d, J = 5.6 Hz), 6.58 (1 H, s), 6.23 (1 H, s), 5.97 (1 H, s), 5.45 (1
H, br), 4.11 (1 H, m), 2.82 (2 H, br m), 2.41 (1 H, br s), 2.23 (3 H,
br s), 1.25–1.95 (12 H, br m), 0.98 (3 H, s).
13C NMR (68 MHz, CDCl3): = 12.8, 19.8, 26.3, 27.8, 29.7, 33.7,
(
(
(
17) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D.
Org. Lett. 2003, 5, 1597.
3
1
9.0, 39.3, 44.0, 47.9, 50.1, 81.0, 82.4, 103.2, 105.6, 112.5, 114.6,
15.3, 126.6, 132.0, 138.4, 139.2, 153.7, 162.1, 162.5.
18) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314; and
references cited therein.
+
LRCI: m/z = 405 ([MH ], 4), 263, 127 (100).
19) Novák, N.; Szabó, A.; Répási, J.; Kotschy, A. J. Org. Chem.
HRCI: m/z calcd for C H O : 405.2066; found: 405.2066.
2
6
29
4
2003, 68, 3327.
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York

2
570
I. J. S. Fairlamb et al.
PAPER
(
(
20) (a) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002,
reaction is regioselective for the 3-position, previously noted
in Ref.
(22) Mann, F. G.; Purdie, D. J. Chem. Soc. 1935, 1549.
(23) (a) Cervera, M.; Moreno-mañas, M.; Pleixats, R.
Tetrahedron 1990, 46, 7885. (b) Kato, Y.; Okada, S.;
Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4849.
8
b
4
5
, 1231. (b) Crisp, G. T.; Turner, P. D. Tetrahedron 2000,
6, 407.
21) We have employed these conditions in Sonogashira
reactions of 5-bromo-2-pyrone and 3,5-dibromo-2-pyrone
with several terminal alkynes with similar success. The latter
Synthesis 2003, No. 16, 2564–2570 © Thieme Stuttgart · New York