Halogenated-2-pyrones in Sonogashira cross-coupling: limitations, optimisation and consequences for GC analysis of Pd-mediated reactions

Article abstract of DOI:10.1016/j.tet.2005.07.102

The Sonogashira couplings of 4-bromo-6-methyl-2-pyrone (5) with phenylacetylene, mediated by Pd(PPh₃)₂Cl₂ in the presence of a CuI co-catalyst, have been investigated in detail. The concentration of Pd dramatically influences the product yield, with lower Pd-loadings favouring higher conversions and purer cross-coupled product. A post reaction time-dependence in product conversion is seen in samples quenched solely on silica-gel (eluted with CH₂Cl₂). The effect is mirrored in reactions employing 4-nitro-bromobenzene (14) and to a lesser extent (E) and (Z)-ethyl 3-iodo-2-propenonate (16) under similar conditions. A more efficient quenching system (using excess dppe) has been developed to enable accurate determinations in product conversions. Alternatively, solvent and base (Et₃N) removal in vacuo, or quench with saturated aqueous ammonium chloride, prevents further turnover in Sonogashira coupling. An ESI-MS study on samples eluted through silica was undertaken to probe the nature of the soluble Pd/Cu species. The Sonogashira cross-coupling of 4-chloro- and 6-chloro-2-pyrone (18 and 20, respectively) has further been investigated. The former undergoes successful coupling, however the latter decomposes in polar aprotic and protic solvents under standard conditions, through a chlorine substitution process, making Pd-mediated reactions problematic.

Full text of DOI:10.1016/j.tet.2005.07.102

Tetrahedron 61 (2005) 9827–9838
Halogenated-2-pyrones in Sonogashira cross-coupling:
limitations, optimisation and consequences for GC analysis of
Pd-mediated reactions
*
¨
Ian J. S. Fairlamb, Adam F. Lee, Faidjiba E. M. Loe-Mie, Elina H. Niemela, Ciara T. O’Brien
and Adrian C. Whitwood
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 27 May 2005; revised 22 July 2005; accepted 25 July 2005
Available online 19 August 2005
Abstract—The Sonogashira couplings of 4-bromo-6-methyl-2-pyrone (5) with phenylacetylene, mediated by Pd(PPh3)2Cl2 in the presence
of a CuI co-catalyst, have been investigated in detail. The concentration of Pd dramatically influences the product yield, with lower
Pd-loadings favouring higher conversions and purer cross-coupled product. A post reaction time-dependence in product conversion is seen in
samples quenched solely on silica-gel (eluted with CH2Cl2). The effect is mirrored in reactions employing 4-nitro-bromobenzene (14) and to
a lesser extent (E) and (Z)-ethyl 3-iodo-2-propenonate (16) under similar conditions. A more efficient quenching system (using excess dppe)
has been developed to enable accurate determinations in product conversions. Alternatively, solvent and base (Et3N) removal in vacuo, or
quench with saturated aqueous ammonium chloride, prevents further turnover in Sonogashira coupling. An ESI-MS study on samples eluted
through silica was undertaken to probe the nature of the soluble Pd/Cu species. The Sonogashira cross-coupling of 4-chloro- and 6-chloro-2-
pyrone (18 and 20, respectively) has further been investigated. The former undergoes successful coupling, however the latter decomposes in
polar aprotic and protic solvents under standard conditions, through a chlorine substitution process, making Pd-mediated reactions
problematic.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives. Indeed, even with the current armory of
catalysts described in the literature to date, limitations are
known for many heterocyclic compounds.
Pd-Catalyzed carbon–carbon and carbon-heteroatom bond-
forming processes represent some of the most important and
routinely applied reactions in synthetic chemistry.1 Heck,2
Negishi,3 Sonogashira,4 Stille,5 Suzuki6 and the recently
developed Hartwig–Buchwald7 cross-coupling reactions
represent key examples. Some of these processes have
been comprehensively used in benchmarking transition
metal catalysts, particularly in Heck and Suzuki coupling,
where high catalyst activity, low catalyst loadings, catalyst
recycling, prolonged catalyst lifetime and selectivity are
important. The synthesis of biaryl compounds is integral to
establishing the efficacy of new Pd-catalysts, particularly
given the importance attached to these feedstocks in diverse
industrial and academic applications. Heterocyclic deriva-
tives have become the focus of attention in both materials
and pharmaceutical arenas, and new catalysts should be
broadly evaluated against these derivatives as well as more
traditional reactions testing their capacity to produce biaryl
We are interested in catalyst discovery for cross-coupling
processes and the employment of unusual heterocyclic
frameworks, for example, 2-pyrones (parent 2-pyrone is
structure I, Fig. 1), an unsaturated six-membered oxyge-
nated ring system, which exhibits both aromatic and alkenic
chemical properties (the latent polarities are shown in II).
The ring-system is an interesting choice, representing a
heterocyclic substrate (electrophilic or nucleophilic) for
employment in cross-coupling processes.8 The 2-pyrone
motif is found in many naturally occurring compounds,
Keywords: Palladium; Cross-coupling; Sonogashira.
*
Corresponding author. Tel.: C44 1904 434091; fax: C44 1904 432516;
e-mail: ijsf1@york.ac.uk
Figure 1. Parent 2-pyrone (I) and simple latent polarities in 2-pyrone (II).
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.102

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I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
which display a range of beneficial and exploitable
biological and medicinal effects (Fig. 2).9 Non-natural
substituted 2-pyrones (1 and 4), synthesized using cross-
coupling processes, have been shown to be effective
inhibitors of specific types of human ovarian carcinoma
(A2780) and human chronic myelogenous leukemia (K562)
cell lines (in an in vitro cell culture system).10 Simple
substituted 2-pyrones (2 and 3) exhibit anti-fungal and anti-
bacterial inhibitory activity. Derivatives of 4 also exhibit
pronounced solvatochromism in fluorescence, which could
be used to study the biological mode of action of these
compounds.11 Furthermore, transition metal carbonyl
complexes, containing the 2-pyrone ring-system, that are
h1-carbonyl12 and h4-diene13 coordinated, undergo Suzuki
coupling reactions. The latter complexes possess useful
biological properties.14
pheromone, supellapyrone (5-(20R,40R-dimethylheptanyl)-
3-methyl-2-pyrone).25 A reversal in the polarity of the
2-pyrone led to 3-(trimethylstannyl)-5-bromo-2-pyrone
being used as an effective organometallic reagent, which
facilitates incorporation of aryl groups at the 3-position.26
Further, stannylated variants at the 3- and 5-position of
2-pyrone are known.27 The Negishi coupling of
5-(iodozinc)-2-pyrones have been reported.28 3-Cuprio-2-
pyrone is a well known organometallic 2-pyrone—a
surprisingly poor nucleophile—described by Posner and
co-workers,29 although its use in Pd-coupling processes has
not been described to the best of our knowledge. Suzuki
coupling of 2-pyrone-5-boronate with aryl and heteroaryl
halides and triflates is known,30 and a high yielding route to
bufadienolide type steroids was achieved via Suzuki
coupling of steroid vinyl triflates with this boronate.31
4-Methoxy-6-methyl-3-chlorozinco-2-pyrone reacts with
aryl- and vinyl halides.32 In the same report, 4-bromo-2-
pyrone reacted with organozinc compounds such as aryl-,
heteroaryl- and ethynyl-zinc chlorides to give the corre-
sponding coupled products.
The application of halogenated 2-pyrones in cross-coupling
processes has attracted considerable recent interest.
4-Bromo-6-methyl-2-pyrone 5 can be cross-coupled reason-
ably well in Negishi, Sonogashira and Suzuki coupling
processes.15 In preliminary studies, our group has detailed a
useful protocol for the Suzuki coupling of 3-bromo-4-
methoxy-6-methyl-2-pyrone 6 and 5-bromo-4-methoxy-6-
methyl-2-pyrone 7 with several organoboronic acids.16 The
studies extend on the seminal work carried out by Pleixats
and Moreno-man˜as.17 In Suzuki coupling of 6, hydro-
debromination occurs as a minor side-reaction, presumably
due to the more forcing conditions. Cho and co-workers
have reported extensively on the cross-coupling reactions of
3,5-dibromo-2-pyrone, which undergoes facile regioselec-
tive Stille coupling reactions with aryl, heteroaryl and vinyl
stannanes to produce various 3-substituted-5-bromo-2-
pyrones.18 Similar regioselectivity for the 3-position is
reported in Sonogashira coupling,19 Suzuki coupling20 and
amination reactions.21 Other halogenated 2-pyrones in
cross-coupling processes include 6-chloro-2-pyrone,22
5-iodo-6-substituted-2-pyrones23 and 3-bromo-5-iodo-2-
pyrones.24 Meinwald and co-workers have coupled
3-methyl-5-bromo-2-pyrone to an alkylzinc reagent, which
was a key step in the synthesis of the cockroach sex
For the majority of these coupling processes, relatively high
catalyst loadings were employed, for example, 2.5–6 mol%,
under relatively classical conditions. In view of the recent
interest in active and selective Pd catalyst systems and in the
diverse applications of 2-pyrones, the Sonogashira coup-
lings of 5 and related derivatives have been reassessed. This
has led us to more active systems for these substrates using
standard Pd(II) precatalysts. Whilst conducting these
experiments it has been established that sampling reaction
mixtures for GC analysis must be performed with caution.
Reaction samples are commonly quenched by passage
through a silica plug. However, we demonstrate for 5,
4-nitrobromobenzene 14 and Z- and E-ethyl 3-iodo-2-
propenonate 16 that continued Sonogashira alkynylation
occurs in samples ‘quenched’ with silica alone. A more
efficient quenching system has thus been created for these
activated substrates. The Sonogashira couplings of
4-chloro- and 6-chloro-2-pyrone (18 and 20, respectively)
are further discussed.
2. Results
The first reactions of interest are Sonogashira couplings of
halogenated 2-pyrones shown in Scheme 1.
2.1. Synthesis of halogenated 2-pyrone precursors
Compound 5 was synthesized by bromination of 4-hydroxy-
6-methyl-2-pyrone using tetra-n-butylammonium bromide
(TBAB) and P2O5 in toluene at 100 8C with essential
vigorous mechanical stirring.33 The yield of the reaction
appears somewhat dependent on efficient mixing (varies
between 10 and 91% in our hands).
4-Iodo-6-methyl-2-pyrone 10 was synthesised using a
similar procedure, but employing tetra-n-butyl ammonium
iodide (TBAI), in place of TBAB, in 13% yield. 4-Chloro-6-
methyl-2-pyrone was accessed by reaction of 8 with POCl3
to give 9 in 27% yield. We have been unable to optimise
these poor yields. The triflate 11 was accessed by reaction of
Figure 2. Biologically active non-natural 2-pyrones and halogenated
2-pyrone precursors.

I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
9829
Scheme 2. Sonogashira coupling of 4-halogenated-6-methyl-2-pyrones.
terminal acetylenes, leading to only trace quantities of the
coupled products.15c Refluxing at this higher Pd loading
under the reaction conditions accelerates the agglomeration
of Pd and ultimately precipitation of Pd black.34 This led us
to probe the reactivity of this precatalyst at lower catalyst
loadings at 25 8C. An improved yield was obtained at
0.25 mol% Pd loading; similar results were observed for
both substrates 5 and 9 (entries 1 and 2). The more activated
substrate 10 furnishes lower yields of cross-coupled product
(entry 3). A higher yield is again seen at 0.25 mol% Pd
(79%). The same trend is apparent with triflate 11 (entry 4).
Difficulties were encountered purifying 4a from the reaction
using tosylate 13 (entry 5). In selected examples, 5 and 10
demonstrate higher turnover numbers at 0.025 mol% Pd
loading, although fail to reach completion. The turnover
frequencies (TOFs) were not calculated, as conversion
points were not taken in the initial linear portions of the
reaction profiles—a comparison of the final TOFs would be
misleading (the differences in the reaction times should be
noted against Pd/Cu loading).
Scheme 1. Synthesis of 4-halogenated-6-methyl-2-pyrones and related
derivatives. Reagents and conditions: (i) PhN(OTf)2, K2CO3, THF, 60 8C;
(ii) TsCl, Pyr., CH2Cl2, rt, 3 h; (iii) for XZBr or I, TBAB or TBAI, P2O5,
toluene, 100 8C, for XZCl, POCl3 (excess), 25 8C, 15 h, then 100 8C, 2 h.
8 with N-phenyltriflimide in 81% yield. The reaction was
accompanied by the formation of 12 (11%), presumably
formed by reaction of unreacted 8 with 11. The tosylate 13
was accessed in 68% yield by reaction of 8 with tosyl
chloride in the presence of pyridine (3 equiv) in CH2Cl2.
2.2. Sonogashira coupling reactions
In our first studies on the reactions of 5 with terminal
acetylenes we chose relatively high catalyst loadings
(2.5–6.0 mol%) and reflux conditions for several hours.15
The reaction of 5 with phenylacetylene to give 4a represents
our benchmark. In terms of monitoring the progress of
reaction, TLC analysis was hampered by almost identical Rf
values of product and substrate.
Recrystallisation of crude 4a is sufficient at 0.25 mol% Pd/
Cu catalyst loadings; whereas at 2.5 mol% Pd/Cu, purifi-
cation is required by flash chromatography (Pd black and
POPh3 are the main problem). Photographs of the reactions
at 2.5 and 0.25 mol% Pd loading illustrate a common
problem in Pd cross-coupling chemistry: clear differences
are presented in Figure 3.
High-resolution gas chromatography (HRGC) analysis was
therefore employed to follow the extent of reaction. On
comparing the reactions of 5, 9–11 and 13, we noticed that
the reactions were proceeding rapidly at room temperature
with 2.5 mol% Pd loading (entry 1, Table 1, Scheme 2). It
had previously been shown that Pd(PPh3)2Cl2 (6 mol%) was
a poor precatalyst for Sonogashira coupling with various
Prior to addition of phenylacetylene the solutions remain a
clear orange colour, which is more intense for the higher
catalyst loading (frame A). On addition of phenylacetylene,
the solutions at both catalyst loadings become black
immediately (frame B). On complete loss of 5, the lower
catalyst loading shows no sign of precipitated Pd black
(frame C).
Table 1. Sonogashira coupling of 4-halogenated-6-methyl-2-pyrones
Entry
Substrate
% Conv.a/TONb
2.5 mol%
Pd/Cuc
0.25 mol%
Pd/Cud
0.025 mol%
Pd/Cue
It has been determined that reactions of 5 can be performed
in the presence of air, albeit in a closed vessel, although
purified solvents are required for good yields (note:
1
2
3
4
5
RZBr, 5
RZCl, 9f
RZI, 10
99(88)/39
99(97)/396
61 (49)/2440
—
48 (41)/1920
—
—
99 (K)/39 99 (K)/396
92 (68)/37 90 (79)/360
89 (56)/36 83 (72)/332
RZOTf, 11
RZ OTs, 13f 95 (41)/38 62 (31)/248
Reagents and conditions are as for Scheme 2. Concentration Z0.1 M (w.r.t.
to halogenated 2-pyrone).
a Conversion (%) determined by HRGC against an internal standard.
Numbers in parenthesis are yields after purification.
b TONZturnover number calculated from HRGC yield.
c Reaction timeZ0.25 h.
Figure 3. Photographs from Sonogashira coupling reactions of 5 with
phenylacetylene at 2.5 mol% Pd/Cu (Left tube) and 0.25 mol% Pd/Cu
(Right tube): Frame A, tZ0 (no PhC^CH added); Frame B, tZ5 min
(PhC^CH added); Frame C, tZ8 h (complete conversion).
d Reaction timeZ3 h.
e Reaction time Z18 h.
Reaction carried out at 60 8C.
f

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commercial Et3N contains significant quantities of water,
which appears to cause problems with 5).
Of interest, while investigating these reactions vide supra,
we uncovered a time dependence in product conversions for
quenched samples analysed by GC. These results are
summarised below.
2.2.1. Consequences for gas chromatographic analysis of
the Sonogashira alkynylation of halogenated 2-pyrones.
The representative reaction chosen for closer analysis was
that of 5 with phenylacetylene to give 4a using 0.25 mol%
Pd/Cu at 25 8C (the reaction is pseudo-first order with
respect to 5—an excess of phenylacetylene was
employed).35 Samples for GC analysis were quenched by
passage through a small plug of silica, eluted with CH2Cl2.
The results of repeated GC analysis of a ‘quenched’ sample,
withdrawn from the reaction mixture after 1 h and stored at
25 8C, are shown in Figure 4. A clear and reproducible time-
dependence in product conversion was seen. After storing
the sample for 3 h, an additional w15% substrate conversion
was noted. In order to confirm that the striking effect arose
from the presence of residual Pd/Cu species in the eluted
sample, a solution of 1,2-bis(diphenylphosphino)ethane
(dppe) in CH2Cl2 was added to samples immediately after
their elution through the silica adsorbent.
Figure 5. Reaction profiles showing the consumption of 5 (0.25 mol% Pd/
Cu) with phenylacetylene at specified times (triplicate samples for each
sample time were run by GC): & Reaction sample quenched with a silica-
plug and elution with CH2Cl2; , Reaction sample quenched with a
silica-plug, elution with CH2Cl2, followed by addition of a dppe solution to
the GC sample vial.
into consideration). This finding also has implications for
initial rates and associated turnover frequencies from
studies wherein adsorption onto silica gel represents the
sole quenching step.
Although it is known that dppe can be employed as an
activating ligand for cross-coupling processes,36 it is clear in
this case, that it completely eliminated continued reaction
within stored samples, presumably by irreversibly binding
Pd(0) species, which are thereby unable to promote the
catalytic reaction. The importance of quenching samples for
GC analysis is evident from examining reaction profiles
obtained during the alkynylation of 5 (Fig. 5).
Generally the adsorption capacity of Kieselgel silica-gel
(typicallyO0.1 mmol Pd gK1) vastly exceeds the Pd and Cu
content of each reaction sample (0.08 mmol). Thus, the
observations made at 0.25 mol% Pd/Cu catalyst loading do
not reflect overloading of the silica plugs.37
A visible difference is seen for reactions quenched by silica
alone and those reactions quenched using the silica/dppe
combination at 0.25 mol% Pd/Cu catalyst loading (Fig. 6).
A higher catalyst loading (10-fold) intensifies the colour
difference, ultimately indicating that the Pd-species has
changed in the presence of dppe. The theoretical Pd and Cu
content of a withdrawn sample from the reaction mediated
with 2.5 mol% Pd is ca. 0.80 mmol.38
The silica/dppe tandem quenching protocol reveals that a
conventional silica treatment introduces a systematic error
of ca. 10% in calculated GC conversions (response factors
for substrate, product, symmetrical 1,3-diyne—the homo-
coupling product—and internal standard have been taken
Figure 4. A graph showing the consumption of 5 (0.25 mol% Pd/Cu) in a
sample prepared for GC analysis—sampling at specified times (withdrawn
from reaction mixture at 0.5 h): & reaction sample quenched with a silica-
plug and elution with CH2Cl2; , reaction sample quenched with a
silica-plug, elution with CH2Cl2, followed by addition of a dppe solution to
the GC sample vial.
Figure 6. Sample A: Quenched by silica with added dppe (2.5 mol% Pd);
Sample B: Quenched by silica without dppe (2.5 mol% Pd); Sample C:
Quenched by silica with added dppe (0.25 mol% Pd); Quenched by silica
without dppe (0.25 mol% Pd). Note: samples darken over time
(precipitation of Pd).

I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
9831
Recently, electrospray mass spectrometry (ESI-MS), which
is a soft-ionization technique, has been used to detect short-
lived reactive organometallic intermediates in catalytic
processes.39 ESI-MS permits use of dilute solutions, for
example, reaction mixtures. The technique has been used in
Pd-catalyst screening40 and for the determination of the
mechanism of the Heck reaction using aryldiazonium
salts.41 ESI-MS analysis (in Kve mode) of sample B
indicated the presence of two ions m/z 682 (100%) and 636
(81%). The observed isotopic pattern for 636 fits the
formula C34H26PCuPd, which is tentatively assigned as
[PPh3PdCu(PhC^C)2H]K. We did not observe the for-
mation of a PdBrK3 species, nor any related phosphine
ligated anionic Pd species; the former species has been
detected through ESI-MS analysis of the Heck reaction by
de Vries and co-workers (under phosphine-free con-
ditions).42 In the Cve mode, two major ions were observed
m/z Z967 (100%) and 921 (20%), which could be one of
several bimetallic species containing Pd and Cu.43
employed, using the conditions described for 5. In the
reaction of 14, a clear time-dependence in product
conversion was seen in GC samples quenched by silica
alone, mirroring the observations with 5 (Fig. 7). The
addition of dppe to samples eluted through silica again
inhibits further catalysis. The silica/dppe tandem quenching
protocol likewise reveals that a conventional silica
treatment introduces a systematic error for this substrate
in calculated GC conversions (ca. 20%).
The importance of quenching samples for GC analysis is
again evident from the examining reaction profile obtained
during the alkynylation of 14 (Fig. 8).45
For higher catalyst loadings (5 mol%), the errors were larger
(Fig. 9). In samples where excess dppe was added, turnover
is still seen to be occurring, albeit the numbers are within the
error generally associated with GC. In the sample where
solvent and base were removed in vacuo, negligible
turnover was observed.
Analysis of sample A by ESI-MS (in Cve mode), shows two
major ions m/z1027 (53%) and 875 (100%), which are assigned
as [Pd(dppe)(PPh3)2]C and [Pd(dppe)(PPh3)2–C12H10]C,
respectively.
For Sonogashira coupling of Z-16 and E-16 with phenyla-
cetylene to give Z-17 and E-17, respectively, similar trends
were seen. These reactions took approximately 6 h to reach
completion. For the non-dppe quenched reaction (using
Z-16), 7% further conversion was seen by GC analysis (after
1 h reaction time) over a 3 h period after passage through
silica. Insignificant turnover was seen with added dppe.
It is conceded that residual Et3N/CH3CN solvent from the
sample could be hampering the adsorption of Pd/Cu onto
silica. Moreover, Et3N is required for Sonogashira coupling,
although Cu(I) is not. Indeed, a similar trend is seen in
reactions conducted with Pd alone. If one removes the base/
solvent from the sample in vacuo prior to GC analysis,
product conversion remains constant over several hours,
representing a valid quenching method in itself for these
Sonogashira alkynylation reactions. Samples can also be
quenched by treatment with a saturated aqueous solution of
NH4Cl in open air, followed by extraction into CH2Cl2 or
EtOAc. This procedure allows for elimination of Cu and the
accurate determination of product conversions.
2.2.2. Effect of copper loading in Sonogashira coupling.
The effect of Cu(I) loading was also assessed for the
Sonogashira coupling of 5 with phenylacetylene to give 4a
(Fig. 10 and Table 2). The turnover frequency (TOF)
improves with increasing Cu:Pd ratios. Based solely on the
consumption of 5, it appears that reactions are more efficient
at higher Cu(I) loadings. However, the isolated yields, after
column chromatography, dramatically decreases past
0.5 mol% Cu(I) (with respect to the 0.25 mol% Pd catalyst
loading). More oxidative coupled product (1,3-diyne) is
observed at 1.94 mol% Cu(I) loading, which could be
promoted by oxygen or by the formation of the
To assess whether this effect was generic to other activated
substrates, the reactions of 14 with phenylacetylene to give
15, and the cis- and trans- isomers of ethyl 3-iodo-2-
propenoate44 (Z-16 and E-16) with phenylacetylene to give
Z-17 and E-17, respectively, were investigated (Scheme 3).
Slightly higher 0.5 mol% Pd/Cu catalyst loadings were
Figure 7. A graph showing the consumption of 14 (0.5 mol% Pd/Cu) in a
sample prepared for GC analysis—sampling at specified times (taken from
reaction mixture at 1.5 h): & reaction sample quenched with a silica-plug
and elution with CH2Cl2; , reaction sample quenched with a silica-plug,
elution with CH2Cl2, followed by addition of a dppe solution to the GC
sample vial. (amount of dppe:Pdw4:1).
Scheme 3. Other Sonogashira couplings assessed for further reaction after
work-up by silica treatment alone.

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I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
Figure 8. Reaction profiles showing the consumption of 14 (0.5 mol% Pd/
Cu) with phenylacetylene at specified times (triplicate samples for each
sample time were run by GC): & reaction sample quenched with a silica-
plug and elution with CH2Cl2; , reaction sample quenched with a
silica-plug, elution with CH2Cl2, followed by addition of a dppe solution to
the GC sample vial.
Figure 10. Consumption of 5 in Sonogashira coupling with phenylacetyl-
ene to give 4a. Using identical conditions as Scheme 2. Pd(PPh3)2Cl2
(0.25 mol%) was employed. & CuI (0.25 mol%); , CuI (0.5 mol%); C
CuI (0.94 mol%); B CuI (1.94 mol%).
assessed (Table 3). Throughout the series of examples,
higher yields are observed at 0.25 mol% Pd/Cu loadings
(entries 1–6). The reactions do slow down at 0.025 mol%
Pd/Cu loadings. However, significant conversions were still
recorded. The excellent reactivity of 1-ethynyl-1-cyclopen-
tanol, 1-ethynyl-1-cyclohexanol and 1-ethynyl-1-hydroxy-
fluorene towards 5 is notable (entries 3–5)—these results
compare favourably with phenylacetylene. The formation of
a Pd(II)(h1-4-2-pyrone)alkoxide species could account for
the increased reactivity, although we have not detected any
carbonyl products that could result from a b-carbon
elimination pathway, if such species were formed.
Ethynylferrocene coupled with 5 to give 4f in 59% yield
(entry 6). Lower loadings were not recorded for this reaction
as incomplete conversion was seen at 0.25 mol% Pd/Cu
loading.
hydrodebrominated 2-pyrone.46 We have not detected the
latter compound by GC/MS. Other side reactions must
account for the complete consumption of 5, but lower
isolated yields of 4a. The benefit gained from employing
increased loadings of Cu(I) with respect to Pd presumably
stems from the in situ formation of higher concentrations of
alkynylcuprate. It is unlikely that Cu(I) is acting as a
phosphine scavenger, and promoting the transmetallation
step in the catalytic cycle, in this polar-solvent combination.
However, Cu(I) could influence the stability and reactivity
of Pd interemediates, for example, in bimetalic species.
With this new information to hand, various other terminal
acetylenes were coupled with 5 to provide several
substituted acetylene 2-pyrones (4b–f), allowing the effect
of lower catalyst loadings on other terminal acetylenes to be
Crystals amenable to X-ray diffraction studies were grown
from an ether layered solution of CH2Cl2 containing 4f. The
structure is shown in Figure 11 and confirms the proposed
structural connectivity. A slight deviation in planarity is
observed for the 2-pyrone ring with respect to the acetylene
moiety. The bonding in the 2-pyrone is substantially
localised, as seen in unsubstituted 2-pyrone.47 The O(1)–
C(15) (1.380(5)), C(13)–C(14) (1.349(5)) and C(13)–C(17)
(1.431(5)) bonds in 4f are slightly longer (in unsubstituted
˚
2-pyrone: 1.384(3), 1.339(4) and 1.424(4) A, respectively).
Table 2. Effect of Cu(I) loading on Sonogashira coupling of 5/4aa
Entry
CuI loading/
mol%b
Turnover frequency
(TOF)/mol hK1
Isolated yield of
coupled product
(4a)/%
Figure 9. A graph showing the consumption of 14 (5 mol% Pd/Cu) in a
sample prepared for GC analysis—sampling at specified times (taken from
reaction mixture at 0.25 h): & reaction sample quenched with a silica-plug
and elution with CH2Cl2; , reaction sample quenched with a silica-plug,
elution with CH2Cl2, followed by addition of a dppe solution to the GC
sample vial (amount of dppe:Pdw4:1); C reaction sample was
concentrated in vacuo (ensuring complete removal of Et3N) and then
re-dissolved in CH2Cl2 (dotted line).
1
2
3
4
0.25 (1:1)
0.50 (2:1)
0.94 (3.8:1)
1.94 (7.8:1)
420
510
640
1280
O99
97
78
54
a As for Figure 9; TOF were calculated from the initial linear portion of the
reaction profiles, normalised to the molar Pd content.
b The ratio in brackets represents the Cu:Pd ratio.

I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
Table 3. Sonogashira coupling of 5 at low Pd/Cu catalyst loadings
9833
Entry
Coupled product
% Conv./TON
10 wt%
Pd/C,
0.25 mol% 0.025 mol%
Pd/Cub
Pd/Cuc
4 mol %
Cua
1
2
3
74/37
82/41
84/42
97/388
61/2440
4a
89/356
98/392
58/2320
46/1840
Figure 11. X-ray structure for complex 4f. Thermal elipsoids are shown at
50% probability level.
4b
2.3. Sonogashira coupling of 4-chloro and 6-chloro-2-
pyrone
4c
4
5
61/31
90/45
85/340
97/388
54/2160
62/2480
4d
To our knowledge, the Sonogashira coupling of 4-chloro-2-
pyrone with terminal acetylenes remains unreported (18/
19). Using similar reaction conditions described for
6-chloro-2-pyrone 20,22 several terminal acetylenes were
evaluated for Sonogashira coupling (Table 4). The reaction
of phenylacetylene with 18 gave 19a in 62% yield (entry 1).
The product was accompanied by substantial quantities of
the 1,3-diyne (26%), which is formed from either oxygen or
a hydrodechlorination process. We have not detected or
isolated the volatile 2-pyrone that would result from the
latter side-reaction. The yield (82%) of 19a was improved
by heating to 60 8C, which also reduced the amount of
1,3-diyne formed. Although the room temperature protocol
gave a high yield of 19c from reaction of 18 with 1-pentyne
(entry 3), all further reactions were low yielding (entries 2,
4–6). This was to some extent based on incomplete reaction.
Thus, reactions at 60 8C gave improved yields throughout
the series. Here, trimethylsilylacetylene was more reactive
than 1-hexyne, 1-heptyne and 1-octyne, reaching com-
pletion at 60 8C in 3 h.
4e
4f
6
—
59/118d
—
a Isolated yields obtained using 10 wt% Pd/C (2 mol% Pd), PPh3
(2.5 mol%), CuI (4 mol%), Et3N/CH3CN (2.5:1.5), 3 h, reflux.
b Reagents and conditions: as for Scheme 2 and Table 1, but using
0.5 mol% CuI (3 h reaction time).
c As for footnote b, but using 0.05 mol% CuI for 15 h.
d Pd (0.5 mol%) was employed for this reaction.
The C(11)^C(12) bond (1.193(5)) is shorter and the
adjacent single bonds longer (C(10)–C(11) and C(12)–
C(13): 1.419(5) and 1.429(5), respectively) in 4f than in the
same bonds in 4-[40-(N,N-dimethylaminophenyl)ethynyl]-
6-methyl-2-pyrone.11
Comments on the cross-coupling reactions of 20: The
reaction of 20 with trimethylsilylacetylene to give 21a has
been reported (Scheme 4).22
Table 4. Sonogashira coupling of 18a
Entry
Coupled product
% Conv. (25 8C)
% Conv. (60 8C)
1
2
3
4
5
6
RZPh, 19a
RZTMS, 19b
RZ(CH2)2CH3, 19c
RZ (CH2)3CH3, 19d
RZ (CH2)4CH3, 19e
RZ (CH2)4CH3, 19f
62b
82c
68d
85c
79c
81c
69c
25 (47)
72 (84)
32 (48)
20 (31)
24 (50)
a Reagents and conditions: (PPh3)2PdCl2 (5 mol%), CuI (3 mol%), Et3N (3 equiv), toluene, 21 h. Number in brackets is the yield based on recovered 18.
b Phenylacetylene dimer yield (26%).
c After 21 h.
d After 3 h.

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I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
accounts for the difficulties that we encountered in under-
taking Sonogashira couplings, as well as in many types of
Stille and Suzuki couplings under standard50 and less standard
conditions.51 We believe that a one-step phosphine-catalyzed
annulation between aldehydes and ethyl allenoate represents
the most versatile method for the formation of 6-substituted
2-pyrones at the present time.52
Scheme 4. Sonogashira alkynylation of 6-chloro-2-pyrone 20.
Benzene or toluene may be used as solvent, with Et3N
employed as base. We were unable to accomplish these
couplings, until further information was disclosed.48 The
instruction required for successful coupling is to add slowly
a solution of Et3N (1.5 equiv) in benzene over 1.5 h 0 8C,
then allowed to warm to room temperature and stirred for
21 h. In our hands, however, using these conditions, we
obtained a mixture of 21a and 21b in 21 and 16% yield,
respectively. These yields are also variable. Previous studies
in our research group49 showed that 20 decomposes in many
organic solvents, the exception being toluene (dry or wet),
benzene, CHCl3 (ethanol-free) and hexane (Scheme 5).
3. Discussion and conclusions
In this paper, the Sonogashira coupling of 4-halogenated-6-
methyl-2-pyrones with terminal acetylenes has been
reinvestigated. Previous experiments showed that relatively
high loadings of Pd(PPh3)2Cl2 (6 mol%)/CuI (4 mol%)
were hampering the coupling process for several terminal
acetylenes at reflux. Pd agglomeration and precipitation was
the major problem. Lowering the catalyst loading to ca.
0.25–0.5 mol% Pd/Cu has ultimately shown that this
previously ineffective catalyst combination promoted
Sonogashira coupling with an identical solvent/base system
and reactant concentration at 25 8C. In uncovering this it
was established that sampling reaction mixtures of 5, as well
as 14 and E/Z-16, which were analysed by GC, should be
performed with some caution. Passage of reaction samples
through a silica plug and eluting with CH2Cl2 is not
sufficient to quench further reaction—an implication for
other activated substrates, particularly with respect to Pd-
catalyst screening, where misleading results could be
collected. Efficient quenching systems for these substrates
are: (1) quench GC sample by addition of a CH2Cl2 solution
containing excess dppe (w.r.t. the total theoretical Pd
concentration in sample); (2) concentrate the GC sample in
vacuo, and then redisolve in CH2Cl2; (3) quench the
reaction sample by addition of saturated aqueous NH4Cl (in
air), then extract into CH2Cl2.
Scheme 5. Decomposition products derived from 20.
The decomposition to other products was established by
monitoring the decay of solutions of 20 with time by
UV spectroscopy. The rapid decomposition in benzene
containing 1% Et3N (lmaxZ303 nm) is shown in
Figure 12 (t1⁄2Z19 min at 25 8C). The solvent/base
combination mimics the Sonogashira reaction conditions
in the absence of Pd, Cu and terminal acetylene. Note:
negligible decomposition was observed in the absence of
Et3N. The new product is 22 (lmaxZ361 nm), confirmed by
1H NMR and MS.
The rapid decomposition in many solvents (see Fig. 13)
Figure 12. Decomposition of 6-chloro-2-pyrone 20 in benzene containing
1% Et3N at 25 8C.
Figure 13. Decomposition of 6-chloro-2-pyrone 20 against various solvents
at 25 8C (decay monitored by UV spectroscopy).

I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
9835
We have shown that relatively low catalyst loadings can be
used to produce 4-alkynyl-6-methyl-2-pyrones—good turn-
over numbers can be accomplished with the standard
Pd(PPh3)2Cl2/CuI catalyst combination. This catalyst
system still remains the most popular for Sonogashira
coupling; here we have demonstrated that lower catalyst
loadings maybe used to ease purification of the coupled
products.
solid (613 mg, 27%). Mp 82–84 8C, lit. 85 8C;55 dH
(400 MHz, CDCl3) 6.22 (1H, s, H5), 6.06 (1H, s, H3),
2.26 (3H, s, CH3); dC (100 MHz, CDCl3) 162.59 (48),
161.12 (48), 151.76 (48), 110.99 (CH), 106.13 (CH), 19.85
(CH3); nmax (CH2Cl2, cmK1) 1734 (C]O), 1630, 1554; m/z
(CI) 162/164 (MCNHC4 , Cl35/Cl37, 62), 145/147 (MHC,
Cl35/Cl37, 100).
4.2.2. 4-Iodo-6-methyl-2-pyrone (10). 4-Hydroxy-6-
methyl-2-pyrone (5.08 g, 40 mmol), P2O5 (13.63 g,
96 mmol) and tetra-n-butylammonium iodide (16.25 g,
44 mmol) were heated to reflux and stirred vigorously for
6 h. The reaction was cooled to room temperature and the
resulting upper toluene layer was collected. The remaining
mixture was extracted with toluene (2!75 mL) and the
combined organic layers washed with and saturated aqueous
NaCl (150 mL), dried (MgSO4), filtered and the solvent
removed in vacuo. Recrystallisation from hot PE afforded
the title compound as a cream solid (1.3 g, 13%). Mp 70–72 8C;
dH (400 MHz, CDCl3) 6.75 (1H, s, H5), 6.35 (1H, s, H3),
2.21 (3H, s, CH3); dC (100 MHz, CDCl3) 161.25 (48),
159.94 (48), 121.97 (48), 115.35 (CH), 113.0 (CH), 19.84
(CH3); nmax (CH2Cl2, cmK1) 1726 (C]O), 1616, 1538; m/z
(EI) 236 (MC, 16%); HRCI m/z exact mass calculated for
C6H6O2I (MHC): 236.9413. Found: 236.9411.
Finally, the first Sonogashira couplings on 18 have been
conducted. In comparison with 20, 18 is considerably less
reactive under identical Sonogashira conditions, requiring
60 8C and extended reaction times (compared to 25 8C for
20). The decomposition of 20 represents a hindrance in
Sonogashira coupling, and as a consequence the conditions
described by Bellina et al.,22b which were elegantly applied
in target directed synthesis, are key to successful coupling.
We have determined that other coupling processes on this
2-pyrone have limited utility.
4. Experimental
4.1. General details
All solvents were dried prior to use and stored under an
argon atmosphere. Acetonitrile and triethylamine were
distilled from calcium hydride and stored in the dark.
Phenylacetylene was purchased from Aldrich and redistilled
(stored in the dark at 0 8C). 1,2-Bis(diphenylphosphino)
ethane (dppe) was purchased from Avocado. CuI was
purchased from Aldrich and used as received. PE refers to
petroleum ether (40–60 8C), EtOAc to ethyl acetate and
ether to diethyl ether. Pd(PPh3)2Cl2 was prepared from
PdCl2 in refluxing DMSO and PPh3 (2 equiv).53 Ethynyl-
ferrocene was synthesised according to a known pro-
cedure.54 Compounds 5,15c 11,15c 21a22b and 21b22b have
been previously reported.
4.2.3. 4-Tosyloxy-6-methyl-2-pyrone (13). 4-Hydroxy-6-
methyl-2-pyrone (1.26 g, 0.01 mol) and pyridine (2.4 mL,
0.03 mol) were stirred for 0.5 h at 0 8C in CH2Cl2 (30 mL).
p-Toluenesulfonyl chloride (2.1 g, 0.011 mol) was dis-
solved in CH2Cl2 (30 mL) and added dropwise over 0.5 h.
The mixture was allowed to warm to 25 8C and stirred for
16 h. H2O (50 mL) was added and the product extracted into
EtOAc (3!50 mL). The combined organic layers were
washed with 1 M HCl (50 mL), H2O (50 mL), dried
(MgSO4), filtered and the solvent removed in vacuo.
Recrystallisation from hot ethanol afforded the title
compound as pale pink crystals (1.90 g, 68%). dH
(400 MHz, CDCl3) 7.78 (2H, m, C6H4), 7.36 (2H, m,
C6H4), 5.97 (1H, m, H5), 5.78 (1H, m, H3), 2.44 (3H, s,
C6H4–CH3), 2.20 (3H, s, py-CH3); dC (100 MHz, CDCl3)
164.23, 162.87, 161.92, 146.68, 131.51, 130.24, 128.33,
100.72, 100.59, 21.76 (CH3), 20.13 (CH3); m/z (EI) 280
(MC, 50); nmax (CH2Cl2, cmK1) 1742, 1645, 1574, 1387,
971. This data is consistent with that reported.56
Analysis of reaction samples was performed using a Varian
CP-3800 GC equipped with a CP-8400 Autosampler.
Separation was achieved using a DB-1 column (30 m!
0.32 mm, 0.25 mm film thickness) with carrier gas flow rate
of 3 mL minK1 and a temperature ramp from 50 to 250 8C at
20 8C minK1. The injection volume was 1 mL with a split
ratio of 50.
4.3. Experiments for gas chromatographic analysis of
Sonogashira cross-coupling reactions
4.2. Synthesis of halogenated 2-pyrones
4.2.1. 4-Chloro-6-methyl-2-pyrone (9). To a two necked
flask (100 mL) fitted with a reflux condenser and a calcium
chloride drying tube, 4-hydroxy-6-methyl-2-pyrone (2.01 g,
0.016 mol) was dissolved in phosphorous oxychloride
(15 mL, 0.160 mol) and stirred overnight at room tempera-
ture. The temperature was raised to 100 8C over the course
of 2.5 h, and maintained at this temperature for a further 2 h.
The reaction was allowed to cool and poured onto ice
(100 g), extracted with ether (2!100 mL) and EtOAc (2!
100 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (100 mL), dried (MgSO4),
filtered and the solvent removed in vacuo. Purification by
sublimation (60 8C; 7 mbar) onto a liquid nitrogen cold
finger, afforded the title compound as a white crystalline
Sonogashira procedure-using silica-plug quench only.
4-Bromo-6-methyl-2-pyrone 5 (0.189 g, 1 mmol) and
PdCl2(PPh3)2 (1.9 mg, 0.25 mol%) was placed in a Radleys
carousel reactor vessel and flushed with nitrogen. Hex-
adecane (11.3 mg, 0.05 mmol) was added as an internal
standard. Dry CH3CN (5 mL) and dry Et3N (3 mL) was
added via syringe. Stirring was switched on at this point and
a zero-point sample taken for GC analysis, then CuI
(0.5 mg, 0.25 mol%) and phenylacetylene (139 mL,
1.2 equiv) were added immediately (phenylacetylene last).
The reaction was kept under nitrogen and followed by GC
analysis. Sample quenching. (1) Using silica-plug and dppe
quench: elution of the analysis sample through silica-gel,
1,2-bis(diphenylphosphino)ethane (dppe) in CH2Cl2

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I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
(100 mL, 3.3 mM) was added immediately. (2) Using silica-
plug and concentration in vacuo: As above for standard
silica quench, but all solvents were removed in vacuo.
Sample was then immediately taken up in CH2Cl2 for GC
analysis. (3) The sample was treated with a saturated
aqueous solution of NH4Cl (0.5 mL), which was then
extracted with EtOAc (1 mL). The organic layer was dried
(MgSO4) and then analysed by GC.
vacuo. Purification by column chromatography on silica
using hexane–ethyl acetate (9/1–7/3), gave the coupled
products as crystalline solids or viscous oils.
4.4.3. 4-Phenylethynyl-2-pyrone (19a). The title com-
pound was isolated as a brown solid. Mp 94–96 8C; RfZ
0.55 (hexane/ethyl acetate, 7:3 v/v); dH (400 MHz, CDCl3)
7.65 (1H, m, Ph), 7.36–7.55 (5H, br m, Ph and H6), 6.45
(1H, m, H3), 6.25 (1H, dd, 4JZ1.6 Hz, 3JZ5.3 Hz, H5); dC
(100 MHz, CDCl3) 161.2, 151.0, 138.2, 130.3, 128.7, 121.2,
118.1, 108.2, 99.4, 85.1; nmax (CH2Cl2, cmK1) 2927, 2853,
2218, 1726, 1631, 1535, 1176, 1118; m/z (CI) 214 (MC
NHC4 , 25), 197 (MHC, 100); HRCI m/z exact mass
calculated for C13H9O2 (MHC): 197.0602. Found:
197.0600.
4.4. Standard Sonogashira coupling (preparative)
The characterisation data for compounds 4a–e have been
previously reported.15c
Using standard Schlenk techniques: 4-bromo-6-methyl-2-
pyrone 5 (0.189 g, 1 mmol) and Pd(PPh3)2Cl2 (1.9 mg,
0.25 mol%) were placed in a Schlenk tube purged with N2.
Dry CH3CN (5 mL) and dry Et3N (3 mL) was added via
syringe. Phenylacetylene (139 mL, 1.2 equiv) and CuI
(0.5 mg, 0.25 mol%) was added. The solvents were
removed in vacuo and the residue dissolved in diethyl
ether (10 mL) or CH2Cl2 (the latter for more polar
compounds). The organic phase was washed with 10%
aqueous HCl (1!5 mL), water (1!5 mL), then dried
(MgSO4) and concentrated in vacuo to give an oil. For
arylacetylenes, the products could be recrystallised from hot
hexane. For the other terminal acetylenes, purification was
usually done by flash chromatography using hexane/EtOAc
or hexane/CH2Cl2 solvent mixtures.
4.4.4. 4-Trimethylsilyethynyl-2-pyrone (19b). The title
compound was isolated as a yellow solid. Mp 102–104 8C;
RfZ0.59 (hexane/ethyl acetate, 7:3 v/v); dH (400 MHz,
5
3
CDCl3) 7.34 (1H, dd, JZ1.0 Hz, JZ5.4 Hz, H6), 6.32
4
3
(1H, br s, H3), 6.10 (1H, dd, JZ1.5 Hz, JZ5.4 Hz, H5),
0.19 (9H, s); dC (100 MHz, CDCl3) 149.9, 139.0, 117.8,
107.1, 105.5, 100.7, 98.6, K1.59; nmax (CH2Cl2, cmK1
)
2962, 2340, 2167, 1762 (C]O), 1735, 1420, 1317, 1215,
1200, 1026; m/z (CI) 192 ([MHC], 11), 177 ([MCKCH3],
100); HRCI m/z exact mass calculated for C10H13O2Si
(MHC): 193.0684. Found: 193.0678.
4.4.5. 4-Pentynyl-2-pyrone (19c). The title compound was
isolated as a brown oil. RfZ0.45 (hexane/ethyl acetate, 7:3
v/v); dH (400 MHz, CDCl3) 7.37 (1H, dd, 5JZ1.0 Hz, 3JZ
5.4 Hz, H6), 6.30 (1H, br s, H3), 6.11 (1H, dd, 4JZ1.6 Hz,
4.4.1. 4-Ethynylferrocene-6-methyl-2-pyrone (4f). Syn-
thesised by the standard procedure, using 0.25 mol% of
Pd(PPh3)2Cl2 and 0.5 mol% CuI (conducted on a 1 mmol
scale w.r.t. 5). Purification was performed by chromato-
graphy using hexane first, to remove unreacted
ethynylferrocene, followed by a hexane–CH2Cl2 (9/1)
mixture to remove unreacted 5; increasing the polarity to
1:1 gave the product as a red solid (0.22 g, 59%). A small
amount of this was crystallised from CH2Cl2. Mp 129–
130 8C; dH (400 MHz, CDCl3) 6.21 (1H, s, H5), 5.99 (1H, s,
H3), 4.52 (2H, br s, Cp), 4.34 (2H, br s, Cp), 4.24 (5H, s,
Cp), 2.23 (3H, s, CH3); dC NMR (100 MHz, CDCl3) 19.8
(CH3), 62.4 (Cp), 70.2 (Cp), 70.4 (Cp), 72.3 (Cp), 82.8
(C^C), 100.5 (C^C), 105.6 (C3), 113.1 (C5), 139.7 (C4),
161.7 (C6), 162.7 (C2); nmax (KBr, cmK1) 3105, 2921,
2847, 2206, 1703 (C]O), 1621, 1536, 1315, 1213, 960,
808 cmK1; m/z (CI) 319 (MC, 100%); HRCI m/z exact mass
calculated for C18H15O2Fe (MHC): 319.0421. Found:
319.0421.
3
3JZ5.4 Hz, H5), 2.40 (2H, t, JZ7.0 Hz, CH2(30)), 2.23
3
(2H, m, CH2(40)), 1.02 (3H, t, JZ7.3 Hz, CH3(50)); dC
(100 MHz, CDCl3) 158.5, 150.8, 139.1, 137.0, 117.9, 108.7,
102.0, 21.7, 21.6, 13.6; nmax (CH2Cl2, cmK1) 2937, 2360,
2229, 1726 (C]O), 1632, 1536, 1427, 1230; m/z (CI) 180
(MCNHC4 , 5), 163 (MHC, 100); HRCI m/z exact mass
calculated for C10H11O2 (MHC): 163.0759. Found:
163.0756.
4.4.6. 4-Hexynyl-2-pyrone (19d). The title compound was
isolated as a red oil. dH (400 MHz, CDCl3) 7.33 (1H, dd,
3
5JZ1.0 Hz, JZ5.4 Hz, H6), 6.29 (1H, m, H3), 6.06 (1H,
4
3
3
dd, JZ1.5 Hz, JZ5.4 Hz, H5), 2.38 (2H, t, JZ7.0 Hz,
CH2(30)), 1.54 (2H, m, CH2(40)), 1.43 (2H, m, CH2(50)),
0.88 (3H, t, JZ7.3 Hz, CH3(60)); dC NMR (100 MHz,
3
CDCl3) 161.4, 150.7, 139.0, 132.1, 117.8, 108.6, 102.3,
30.0, 21.9, 19.31, 13.5; nmax (CH2Cl2, cmK1) 2935, 2875,
2340, 2229, 1726 (C]O), 1632, 1536, 1427, 1224, 1154;
m/z (CI) 194 (MCNHC4 , 17), 177 (MHC, 100); HRCI m/z
exact mass calculated for C11H13O2 (MHC): 177.0915.
Found: 177.0912.
The characterisation data for E- and Z-5-phenyl-2-penten-4-
ynoic acid ethyl ester (E-17 and Z-17) agrees with that
reported in the literature.36a
4.4.2. Sonogashira coupling of 4-chloro-2-pyrone (18).
To a degassed solution of 4-chloro-2-pyrone (50 mg,
0.38 mmol, 1 equiv) and terminal acetylene (0.42 mmol,
1.1 equiv) in toluene (2 mL), under a nitrogen atmosphere,
was added Et3N (0.16 mL, 1.15 mmol, 3 equiv), followed
by Pd(PPh3)2Cl2 (1.3 mg, 1.9!10K6 mol, 5 mol%) and CuI
(0.2 mg, 1.1!10K6 mol, 3 mol%). The solution was
allowed to stir for 21 h at the temperature indicated in
Table 4. After this time, the mixture was concentrated in
4.4.7. 4-Heptynyl-2-pyrone (19e). The title compound was
isolated as a red oil. dH (400 MHz, CDCl3) 7.31 (1H, dd,
5JZ0.9 Hz, 3JZ5.4 Hz, H6), 6.25 (1H, br s, H3), 6.06 (1H,
4JZ1.5 Hz, 3JZ5.4 Hz, H5)0, 2.35 (2H, t, 3JZ7.0 Hz,
CH2(30)), 1.74 (2H, m, CH2(4 )), 1.26 (4H, m, CH2(50 and
3
60)), 0.85 (3H, t, JZ7.1 Hz, CH3(70)); dC (100 MHz,
CDCl3) 171.0, 161.3, 138.9, 117.7, 108.6, 102.3, 30.9, 27.6,
22.0, 19.5, 13.8; nmax (CH2Cl2, cmK1) 2903, 2341, 2256,
1725 (C]O), 1632, 1562, 1452, 1381, 1170, 1096. m/z (CI)

I. J. S. Fairlamb et al. / Tetrahedron 61 (2005) 9827–9838
9837
208 (MC NHC4 , 8), 191 (MHC, 100); HRCI m/z exact mass
calculated for C12H15O2 (MHC): 191.1072. Found:
191.1070.
Negishi, E.; Xu, C. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; pp 531–549.
4. (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (b)
Sonogashira, K. In Negishi, E.-i., Ed.; Organopalladium
Chemistry for Organic Synthesis; Wiley-Interscience: New
York, 2002; Vol. 1, p 493.
4.4.8. 4-Octynyl-2-pyrone (19f). The title compound was
isolated as a red oil. dH (400 MHz, CDCl3) 7.31 (1H, dd,
5JZ1.0 Hz, 3JZ5.4 Hz, H6), 6.24 (1H, br s, H3), 6.07 (1H,
4
3
3
5. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1.
dd, JZ1.6 Hz, JZ5.4 Hz, H5), 2.36 (2H, t, JZ7.0 Hz,
CH2(30)), 1.51 (2H, m, CH2(40)), 1.30 (2H, m, CH2(50)),
1.23 (4H, m, CH2(60 and 70)), 0.83 (3H, t, 3JZ6.9 Hz,
CH2(80)); dC (100 MHz, CDCl3) 160.5, 149.7, 138.1, 116.8,
107.7, 101.5, 30.2, 27.6, 27.0, 21.5, 18.6, 13.1; nmax
(CH2Cl2, cmK1) 2961, 2932, 2860, 2228, 1726 (C]O),
1631, 1536, 1457, 1313, 1158; m/z (CI) 222 (MC NHC4 ,
11), 205 (MHC, 100); HRCI m/z exact mass calculated for
C13H17O2 (MHC): 205.1228. Found: 205.1225.
6. (a) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; VCH: Weinheim, 1998; p 49.
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (d) Zapf, A.
In Beller, M., Bohm, C., Eds.; Transition Metals for Organic
Synthesis: Building Blocks and Fine Chemicals; Wiley-VCH:
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7. (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (b) Hartwig,
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4.4.9. 6-(Triethylammonium)-2-pyrone chloride (22). dH
(400 MHz, CDCl3) 7.19 (1H, t, 3JZ8.3 Hz, H4), 5.30 (1H,
d, 3JZ8.7 Hz, H5), 5.03 (1H, d, 3JZ7.9 Hz, H3), 3.33 (6H,
3
3
q, JZ7.1 Hz, 3!CH2) 1.15 (9H, t, JZ7.1 Hz, 3!CH3);
m/z (CI) 196 (MC, 61), 168 (MKCH2CHC3 , 100).
8. Ram, V. J.; Srivastava, P. Curr. Org. Chem. 2001, 5, 571.
9. For reviews in the area, see: (a) McGlacken, G. P.; Fairlamb,
I. J. S. Nat. Prod. Rep. 2005, 22, 369. (b) Dickinson, J. M. Nat.
Prod. Rep. 1993, 10, 71.
4.4.10. (E)-Dimethyl pent-2-ene-dioate (24). dH
3
(400 MHz, CDCl3) 6.99 (1H, td, JZ7.3, 15.8 Hz, H3),
4
3
5.92 (1H, td, JZ1.5 Hz, JZ15.7 Hz, H2), 3.70 (3H, s,
OCH3), 3.72 (3H, s, OCH3), 3.23 (2H, dd, 3JZ1.5, 7.3 Hz,
CH2(4)); dC NMR (100 MHz, CDCl3) 170.28, 166.29,
139.87, 124.41, 52.26, 51.72, 37.28. m/z (CI) 176 (MC
NHC4 , 100).
10. Fairlamb, I. J. S.; Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.;
Schmidt, J.-P. Bioorg. Med. Chem. 2004, 12, 4285.
`
11. Collings, J. C.; Parsons, A. C.; Porres, L.; Beeby, A.;
Batsanov, A. S.; Howard, J. A. K.; Lydon, D. P.; Low, P. J.;
Fairlamb, I. J. S.; Marder, T. B. Chem. Commun. 2005, 2666.
12. Fairlamb, I. J. S.; Lynam, J. M.; Taylor, I. E.; Whitwood, A. C.
Organometallics 2004, 23, 4964.
¨
13. Fairlamb, I. J. S.; Syvanne, S. M.; Whitwood, A. C. Synlett
2003, 1693.
4.4.11. (E)-Diethyl pent-2-ene-dioate (25). dH (400 MHz,
3
CDCl3) 6.98 (1H, td, JZ7.2, 15.7 Hz, H3), 5.90 (1H, td,
4JZ1.5 Hz, 3JZ15.7 Hz, H2), 4.16 (4H, m, 2!CH2), 3.20
3
(2H, dd, JZ1.5, 7.2 Hz, CH2(4)), 1.25 (6H, m, 2!CH3);
14. Fairlamb, I. J. S.; Duhme-Klair, A.-K.; Lynam, J. M.; Moulton,
B. E.; O’Brien, C. T.; Sawle, P.; Hammad, J.; Motterlini, R.
Unpublished results. Presented at OMCOS-13, Geneva (July
2005).
dC NMR (100 MHz, CDCl3) 169.93, 165.91, 139.74,
124.73, 61.23, 60.55, 37.544, 14.28, 14.21; m/z (CI) 204
(MCNHC4 , 100).
15. (a) Marrison, L. R.; Dickinson, J. M.; Fairlamb, I. J. S. Bioorg.
Med. Chem. Lett. 2002, 12, 3509. (b) Marrison, L. R.;
Dickinson, J. M.; Ahmed, R.; Fairlamb, I. J. S. Tetrahedron
Lett. 2002, 43, 8853. (c) Fairlamb, I. J. S.; Lu, F. J.; Schmidt,
J. P. Synthesis 2003, 2564.
Acknowledgements
We are grateful to Ben E. Moulton and Jan-Peter Schmidt
for initial synthetic experiments and Wendy Hunt for kinetic
experiments. Professor Todd B. Marder is thanked for
discussions regarding Sonogashira coupling and their side-
reactions. Johnson Matthey (UK) are acknowledged for a
generous loan of palladium(II) salts. We would also like to
thank the referees for their careful reading of this
manuscript.
16. Marrison, L. R.; Dickinson, J. M.; Fairlamb, I. J. S. Bioorg.
Med. Chem. Lett. 2003, 13, 2667.
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