Selective synthesis of natural and unnatural 5,6-disubstituted 2(2H)-pyranones via iodolactonization of 5-substituted (Z)-2-en-4-ynoic acids

Article abstract of DOI:10.1016/S0040-4020(01)00139-9

Reaction of 5-substituted (Z)-2-en-4-ynoic acids with iodine and NaHCO₃ in CH₃CN or with ICl in CH₂Cl₂ affords mixtures of (E)-5-(1-iodoylidene)-2(5H)-furanones and 6-substituted 5-iodo-2(2H)-pyranones in which these last compounds are the major products. The 5-iodo-2(2H)-pyranones, which are easily separated chromatographically from the corresponding regioisomers, are able to undergo Stille-type reactions with a variety of organotin compounds to give 5,6-disubstituted 2(2H)-pyranones in moderate to good yields. One of these compounds, i.e. 5-(1-butynyl)-2(2H)-pyranone, has been used as direct precursor to two substances produced by fungal culture LL-11G219, which function as androgen ligands, i.e. (Z)-5-(1-butenyl)-6-methyl-2(2H)-pyranone and 5-butyl-6-methyl-2(2H)-pyranone.

Full text of DOI:10.1016/S0040-4020(01)00139-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2857±2870
Selective synthesis of natural and unnatural 5,6-disubstituted
2(2H)-pyranones via iodolactonization of 5-substituted
(Z)-2-en-4-ynoic acids
Fabio Bellina,p Matteo Biagetti, Adriano Carpita and Renzo Rossip
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 7 November 2000; revised 11 January 2001; accepted 25 January 2001
AbstractÐReaction of 5-substituted (Z)-2-en-4-ynoic acids with iodine and NaHCO3 in CH3CN or with ICl in CH2Cl2 affords mixtures of
(E)-5-(1-iodoylidene)-2(5H)-furanones and 6-substituted 5-iodo-2(2H)-pyranones in which these last compounds are the major products.
The 5-iodo-2(2H)-pyranones, which are easily separated chromatographically from the corresponding regioisomers, are able to undergo
Stille-type reactions with a variety of organotin compounds to give 5,6-disubstituted 2(2H)-pyranones in moderate to good yields. One of
these compounds, i.e. 5-(1-butynyl)-2(2H)-pyranone, has been used as direct precursor to two substances produced by fungal culture
LL-11G219, which function as androgen ligands, i.e. (Z)-5-(1-butenyl)-6-methyl-2(2H)-pyranone and 5-butyl-6-methyl-2(2H)-pyranone.
q 2001 Elsevier Science Ltd. All rights reserved.
2(2H)-Pyranones are useful intermediates for the synthesis
of a variety of carbo-1 and heterocyclic compounds2 and
occur as structural subunits in a large number of natural
products, which display a wide range of biological activities
including antimicrobial,3 androgen like,4 phytotoxic,5
cardiotonic,6 antifungal7 and pheromonal effects.8 As a
consequence, much attention has been paid to the synthesis
of 2(2H)-pyranone derivatives either by the traditional
approaches9 or by procedures involving transition metal-
catalyzed reactions.10 Nevertheless, despite the plethora of
these synthetic processes it is rather disappointing to note
that no general procedure has been developed so far for
the regioselective synthesis of natural and unnatural
unsymmetrically 5,6-disubstituted 2(2H)-pyranones.
cally disubstituted)methylidene]-2(5H)-furanones 4 in
which, however, these last compounds are the major
products (Scheme 1).11
More recently, in continuation of our studies on the synthe-
sis of oxygen-containing heterocycles by approaches which
involve intramolecular additions of carboxylic acids to
alkynes,12 we developed a new and convenient procedure
for the synthesis of 5,6-disubstituted 2(2H)-pyranones of
general formula 5 (Fig. 1).
We now wish to report that, under suitable reaction condi-
tions, 5-iodo-2(2H)-pyranones 6 can be obtained as major
products by iodolactonization of (Z)-2-en-4-ynoic acids 1
and that these heterocyclic iodides, which represent a not
previously reported class of organic electrophiles, are useful
precursors to compounds 5. In fact, we found that
compounds 6 are able to undergo palladium-catalyzed reac-
tions with organostannanes 8 such as tetramethylstannane,
vinyltributylstannane, aryl- and 1-alkynyltributylstannanes
Recently, we began an investigation on this subject and we
found that treatment of (Z)-2-en-4-ynoic acids 1 with aryl
halides 2 in the presence of K2CO3 and a catalytic quantity
of Pd(PPh3)4 provides mixtures of 6-substituted 5-aryl-
2(2H)-pyranones 3 and stereode®ned 5-[(1,1-unsymmetri-
Scheme 1. (a) Pd(PPh3)4 (5 mol%), K2CO3 (4 equiv.), CH3CN, 70±808C.
Keywords: heterocycles; iodine; cross-coupling; organometallic compounds; natural products.
Corresponding authors. Tel.: 139-50-918214; fax: 139-50-918260; e-mail: rossi@dcci.unipi.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00139-9

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F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
Scheme 2. Retrosynthetic strategy used to prepare compounds 5 and 6.
1. Results and discussion
1.1. Synthesis of 6-substituted 5-iodo-2(2H)-pyranones
The starting materials for our synthesis of 5,6-disubstituted
2(2H)-pyranones 5 were (Z)-2-en-4-ynoic acids 1a±f
(Fig. 3).
Figure 1. Chemical structures of compounds of general formula 5.
The methyl esters corresponding to carboxylic acids 1b±1f,
i.e. compounds 9b±f, were prepared as shown in Scheme 3.
Thus, methyl (Z)-3-bromo-2-propenoate (10), which was
synthesized in 90% yield by reaction of methyl propiolate
with LiBr and acetic acid in CH3CN,12a was reacted with
1.2 equiv. of 1-alkynes 11b±f in Et3N at room temperature
in the presence of 2 mol% PdCl2(PPh3)2 and 4 mol% CuI to
give compounds 9b±f in yields ranging from 82 to 93%.
to give the corresponding 6-substituted 2(2H)-pyranones 5
in satisfactory yields (Scheme 2).
Finally, we will show that the 6-substituted 5-(1-alkynyl)-
2(2H)-pyranones 5a and 5b, which can be prepared from the
corresponding iodides, 6a and 6b respectively, by a Stille-
type reaction with 1-butynyltributylstannane, represent the
direct precursors to two substances produced by fungal
culture LL-11G219, which function as androgen receptor
ligands, i.e. compounds 5c and 5d,4 and to two of their
analogues, i.e. compounds 5e and 5f, respectively (Fig. 2).
It must be noted that the synthesis of naturally occurring 5c
has not been reported so far in the literature.
Alkynes 11b±e were commercially available and 98%
stereoisomerically pure (E)-3-hepten-1-yne (11f) was
diastereoselectively synthesized according to the literature13
from a diastereoisomeric mixture of 1-bromo-1-pentene. On
the other hand, since in the case of the preparation of 9a, the
Sonogashira reaction, which was employed to prepare
compounds 9b±f, involved the use of a gaseous 1-alkyne,
i.e. 1-propyne (11a), we preferred to prepare 9a by a proce-
dure in which a commercially available 0.5 M THF solution
of 1-propynylmagnesium bromide (12) was used. Thus,
transmetalation between 12 and ZnCl2, followed by treat-
ment of the resulting organozinc halide with 0.83 equiv. of
10 in THF at room temperature in the presence of 5 mol%
Pd(PPh3)4, provided 9a in 85% yield (Scheme 4).
Esters 9a±f were then treated with a molar excess of 1 M
aqueous LiOH solution and THF at room temperature for
Figure 2. Chemical structures of compounds 5a±f and 6a±b.
Figure 3. Chemical structures of compounds 1a±f and 9a±f.

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2859
5-iodo-2(2H)-pyranones 6. No literature data were available
for a similar transformation. On the other hand, it has been
reported that iodolactonization of 4-ynoic acids 13 by reac-
tion with N-iodosuccinimide (NIS) in CH3CN in the
14
Scheme 3. (a) PdCl2(PPh3)2 (2 mol%), CuI (4 mol%), Et3N, rt, 6±22 h (82±
93%).
presence of KHCO3 or by treatment with NIS utilizing a
two-phase system, with 2 mol% Bu4NOH as a phase trans-
fer agent and KHCO3 as the base,15 affords regio- and
stereoselectively (E)-5-(1-iodoalkylidene)tetrahydro-2-
furanones 14 (Fig. 4).
Nevertheless, as we had hoped for, compounds 1a±f proved
to be able to undergo reaction with 3 equiv. of iodine and
3.0 equiv. of NaHCO3 in CH3CN at room temperature for
1.5 h (Method A) to provide in high yields mixtures of (E)-
5-(1-iodoylidene)-2(5H)-furanones (E)-7a±f and 6-substi-
tuted 5-iodo-2(2H)-pyranones 6a±f in which these last
compounds were the major products (Scheme 5) (entries
1, 2, 4±6 and 10, Table 1).
Scheme 4. (a) ZnCl2 (1.3 equiv.), THF, 08C; (b) 0.83 equiv. 10, 5 mol%
Pd(PPh3)4, THF, rt, 20 h (85%).
Interestingly, a similar result was obtained when carboxylic
acids 1 were reacted with 1.0 equiv. of ICl in CH2Cl2 at
room temperature in the absence of a base (Method C). In
fact, iodolactonization of 1e under these conditions
provided a mixture of 6e and (E)-7e in a ca. 72:28 molar
ratio, respectively (entry 7, Table 1). On the contrary,
compounds (E)-7 were found to be the major products
when carboxylic acids 1 were reacted with 1.1 equiv. of
NIS and 1.0 equiv. of KHCO3 in CH3CN (Method B)
(entries 3 and 8, Table 1) or with 1.0 equiv. of NIS in
CH3CN in the absence of a base (Method D) (entry 9,
Table 1).
Figure 4. Chemical structures of compounds of general formula 13 and 14.
24±36 h followed by acidi®cation with diluted H2SO4 at
08C to give the corresponding carboxylic acids 1a±f in
95±100% yield.
We then examined the possibility to convert regio-
selectively these carboxylic acids into the corresponding
Scheme 5.
Table 1. Synthesis of 6-substituted 5-iodo-2(2H)-pyranones 6 and the corresponding (E)-5-(1-iodoylidene)-2(5H)-furanones (E)-7
Entry
Carboxylic acid
Method for iodolactonizationa
Products
1
R1
61(E)-7
6/(E)-7 molar ratiob
Yield (%) of 6c
Yield (%) of (E)-7c
1
2
3
4
5
6
7
8
9
10
1a
1b
1b
1c
1d
1e
1e
1e
1e
1f
CH3
A
A
Be
A
A
A
C
B
D
A
6a1(E)-7a
6b1(E)-7b
6b1(E)-7b
6c1(E)-7c
6d1(E)-7d
6e1(E)-7e
6e1(E)-7e
6e1(E)-7e
6e1(E)-7e
6f1(E)-7f
66/34
79/21
18/82
66/34
69/31
68/32
72/28
4/96
64
59
15
63
65
65
(60)
(3)
(16)
72
32d
17
C6H5
C6H5
C4H9
C5H11
C6H13
C6H13
C6H13
C6H13
73
32
30f
31
(27)
(75)
(77)
22g
17/83
79/21
(E)- C3H7±CHvCH
a
Four methods were used for iodolactonization of compounds 1: Method A involved treatment of 1 with 3.0 equiv. of iodine and 3.0 equiv. of NaHCO3 in
CH3CN for 1.5 h. Method B involved reaction of 1 with 1.1 equiv. of NIS and 1.0 equiv. of KHCO3 in CH3CN for 2.5 h. Method C involved treatment of 1
with 1.0 equiv. of ICl in CH2Cl2 for 1 h. Method D involved reaction of 1 with 1.0 equiv. of NIS in CH3CN for 2.5 h in the absence of a base. Unless
otherwise stated, all these reactions were performed at room temperature.
Molar ratio in the crude reaction mixture.
Isolated yield based on 1. Values in parentheses are referred to GLC yields.
Compound (E)-7a was contaminated by ca. 15% of the (Z)-7a.
This reaction was carried out at 08C for 1.5 h.
Compound (E)-7d was contaminated by ca. 13% of (Z)-7d.
Compound (E)-7f was contaminated by ca. 12% of (Z)-7f.
b
c
d
e
f
g

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F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
Figure 5. Con®gurational assignment of (Z)-7a and (Z)-7f by NOESY experiments.
Scheme 6. (a) PdCl2(PPh3)2 (3 mol%), THF, rt, 53 h (76%).
We also observed that the selectivity of the reaction of
compounds 1 with 3.0 equiv. of iodine in CH3CN for
1.0 h at room temperature, in the presence of 3.0 equiv. of
a base such as Na2CO3 or KHCO3, was lower than that
obtained when iodolactonization was carried out according
to Method A. In fact, whereas iodolactonization of 1e
according to this last method provided a mixture of 6e
and (E)-7e in a ca. 68:32 molar ratio, respectively (entry
6, Table 1), a similar reaction performed in the presence
of 3.0 equiv. of Na2CO3 gave these iodides in a ca. 45:55
molar ratio, respectively. On the other hand, this molar ratio
was found to be ca. 54:46 when iodolactonization of 1e was
performed in the presence of 3.0 equiv. of KHCO3.
76% yield by reaction of (E)-7a with phenylethynyltributyl-
stannane (8a) in THF at 208C in the presence of 3 mol%
PdCl2(PPh3)2 (Scheme 6), no cross peak was observed
between the resonances of its H-4 and H-7 protons.
On the other hand, the stereochemistry of (E)-7c could be
assigned on the basis of the stereochemistry of (E)-15b,
which was obtained in 85% yield by reaction of (E)-7c
with 4-methoxyphenyltributylstannane (8b) in NMP at
608C in the presence of 5 mol% of PdCl2(PhCN)2,
10 mol% CuI and 10 mol% AsPh3 (Scheme 7).
In fact, the stereochemistry of (E)-15b, which we had
previously synthesized by treatment of 1b with 4-methoxy-
phenyl iodide in CH3CN in the presence of K2CO3 and a
catalytic quantity of Pd(PPh3)4,11 was established to be E
taking into account that a NOESY 2D map exhibited cross-
peaks between the resonances either of its H-4 and H-12
protons or those of its H-4 and H-16 protons.
Compounds 6 were readily separated from the correspond-
ing regioisomers (E)-7 by MPLC on silica gel and were
differentiated from these last compounds on the basis of
1
their H NMR spectra. In fact, compounds (E)-7 displayed
3
values of the JH3±H4 coupling constant in the range 5.3±
5.9 Hz16 and in the 2(2H)-pyranones 6 the value of this
coupling constant was in the range 9.2±10.0 Hz.17 Interest-
ingly, compounds (E)-7 underwent partial stereomutation
when they were maintained for some hours at room
temperature and some of them, i.e (E)-7a, (E)-7d and (E)-
7f, could not be isolated in a stereoisomerically pure form
(entries 1, 5 and 10, Table 1). The (E)-stereochemistry of
compounds 7 was deduced from NOESY experiments on
(Z)-7a and (Z)-7f, which were obtained by partial stereo-
mutation of (E)-7a and (E)-7f, respectively. In fact, the
NOESY 2D maps of (Z)-7a and (Z)-7f exhibited a cross-
peak between the resonances of their H-4 and H-7 protons
(Fig. 5). On the contrary, NOESY experiments on (E)-7a
and (E)-7f showed the absence of this cross-peak.
1.2. Synthesis of 5,6-disubstituted 2(2H)-pyranones
With an ef®cient and selective route to compounds 6
established, the use of these iodo derivatives for the synthe-
sis of 5,6-disubstituted 2(2H)-pyranones of general formula
5 was investigated. Thus, it was found that compounds 6 are
able to undergo palladium-catalyzed cross-coupling reac-
tions with aryltributylstannanes, vinyltributylstannane, a
typical 1-alkynyltributylstannane and tetramethylstannane
to give the corresponding 5-aryl-, 5-vinyl-, 5-(1-alkynyl)-
and 5-methyl-2(2H)-pyranones in moderate to good yields
(Scheme 8).
Moreover, when a NOESY experiment was performed on
stereoisomerically pure (E)-15a, which was synthesized in
The results of some of these cross-coupling reactions are
summarized in Table 2.
Scheme 7. (a) PdCl2(PhCN)2 (5 mol%), AsPh3 (10 mol%), CuI (10 mol%), NMP, 608C, 22 h (85%).

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2861
Table 2. Palladium-catalyzed cross-coupling reactions between 5-iodo-2(2H)-pyranones 6 and organostannanes 8
Entry Reagents
Organic iodide
8/6 molar ratio Pd cata Solvent
Reaction conditions (8C h21
)
Product
Organotin derivative
5
Yield (%)
6
R1
8b
R2
1
2
3
4
6a CH3
6b C6H5
8c
C2H5CuC
C2H5CuC
4-CH3OC6H4
CH2vCH
C6H5
1.2
1.2
1.2
1.2
1.2
3.0
3.0
B
B
THF
THF
NMP
NMP
NMP
20/19 then 50/21
20/39 then 50/6
50/22.5
50/22.0
50/6.5
5a
5b
5g
5h
5i
75
82
88
85
8c
8b
8d
8e
8f
6c
6c
C4H9
C4H9
A
A
A
Cc
A
5
6b C6H5
55
6c
7d
6e
6f
C6H13
C4H9
CH3
Dioxane 100/24
NMP 23/80
5j
5k
±
(E)-C3H7CHvCH 8g
68
a
The following catalyst systems were used: catalyst A, which was used in entries 3±5 and 7, was constituted of 5 mol% PdCl2(PhCN)2, 10 mol% CuI and
10 mol% AsPh3; catalyst B, which was used in entries 1 and 2, was constituted of 3 mol% PdCl2(PPh3)2; catalyst C, which was used in entry 6, was
constituted of 0.5 mol% Pd2(dba)3 and 4 mol% PPh3.
Unless otherwise noted these reactions were performed using organotributylstannanes.
This reaction was performed in the presence of 6.0 equiv. of a 1 M THF solution of TBAF
Tetramethylstannane (8g) was the organotin compound used in this reaction.
b
c
d
to that recently employed for the coupling reaction between
b-tetronic acid tri¯ate and alkenyl- or cyclopropylboronic
acids.21 Thus, we found that treatment of 6a with 1.1 equiv.
of butylboronic acid in THF for 4 h at 708C, in the presence
of 3.0 equiv. of Ag2O, 5 mol% PdCl2(CH3CN)2 and
20 mol% AsPh3, provided a mixture of 5d and a byproduct,
Scheme 8.
which corresponded to 6-methyl-2(2H)-pyranone (16) in a
ca. 1:1 molar ratio (Scheme 9). However, compound 5d was
obtained in only 26% GLC yield. Unfortunately, no
improvement of this yield was obtained when 6a was
reacted with 1.3 equiv. of butylzinc chloride in THF at
208C for 24 h in the presence of 5 mol% PdCl2(dppf)
(Scheme 9). This reaction provided too a mixture of 5d
and 16 in which this last compound was largely predomi-
nant.
As shown in this table, the cross-coupling reactions
involving arylstannanes 8b and 8e (entries 3 and 5), vinyl-
tributylstannane 8d (entry 4) and tetramethylstannane 8g
(entry 7) were performed in NMP in the presence of
5 mol% PdCl2(PhCN)2, 10 mol% CuI and 10 mol%
AsPh3.18 On the other hand, the reactions involving
1-butynyltributylstannane (8c) (entries 1 and 2) were carried
out in THF in the presence of 3 mol% PdCl2(PPh3)2.19 As
shown in entry 6 of Table 2, we also tried to use tetrabutyl-
stannane (8f) for a palladium-catalyzed butylation reaction
of 6e. Since the butyl group is typically very reluctant to
participate in Stille reactions, we attempted to use the highly
coordinated organotin reagent prepared in situ by treatment
of 8f with a large molar excess of TBAF. Unfortunately,
even though similar hypervalent organotin species have
been successfully employed in palladium-catalyzed reac-
tions between haloanisoles and tetraorganotin reagents,20
in our case no trace of the expected cross-coupled product
was obtained.
Finally, taking into account that 5-(1-butynyl) substituted
2(2H)-pyranones 5a and 5b could be prepared in high
yield by palladium-catalyzed reaction of 8c with 6a and
6b, respectively (entries 1 and 2, Table 2), we examined
the possibility of utilizing either 5a as direct precursor of
5d as well as (Z)-5-(1-butenyl)-6-methyl-2(2H)-pyranone
(5c)4 or 5b as direct precursor to two analogues of these
natural products, i.e. 5f and 5e, respectively. In the event,
we found that partial catalytic hydrogenation of 5b in
toluene at room temperature, using pyridine-poisoned 10%
palladium on BaSO4, selectively provided a mixture of 5e
and the corresponding (E)-stereoisomer in a ca. 95:5 molar
ratio, respectively (Scheme 10). Puri®cation by MPLC on
silica gel allowed us to obtain analytically pure 5e in 88%
yield. A procedure very similar to that of this model reaction
was then used for the ®rst synthesis of naturally occurring 5c
(Scheme 10). This procedure allowed us to obtain 97% pure
5c in 81% yield.
Since the failure of this reaction precluded the use of 6a for
the synthesis of naturally-occurring 5-butyl-6-methyl-
2(2H)-pyranone (5d)4 via a Stille-type reaction, we
attempted to prepare 5d by Ag(I)-promoted palladium-
catalyzed butylation of iodide 6a using a protocol similar
On the other hand, when a toluene solution of 5b was hydro-
genated at room temperature in the presence of 10%
palladium on BaSO4, chemically pure 5f was selectively
obtained in quantitative yield (Scheme 10). However,
hydrogenation of 5a under similar experimental conditions
provided a mixture of three new compounds in a ca. 89:10:1
molar ratio in which the major and the minor components
Scheme 9. (a) n-BuB(OH)2 (1.1 equiv.), PdCl2(CH3CN)2 (5 mol%), AsPh3
(20 mol%), Ag2O (3 equiv.), THF, re¯ux, 4 h; (b) n-BuZnCl (1.3 equiv.),
PdCl2(dppf) (5 mol%), THF, 208C, 24 h.

2862
F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
Scheme 10. (a) H2, Pd±BaSO4, pyridine (cat), toluene, 208C; (b) H2, Pd±BaSO4, toluene, 208C.
were 5d and 5c, respectively, and the third component was
not identi®ed. Nevertheless, puri®cation of this mixture by
MPLC on silica gel allowed us to obtain chemically pure 5d
in 78% yield.22
(Z)-3-bromopropenoate (10),12a (E)-3-hepten-1-yne (11f),13
4-methoxyphenyl-tributylstannane (8b).27 1-Butynyltributyl-
stanne (8c) [bp 84±858C/0.04 Torr MS, m/z (%): 287 (19),
231 (28), 175 (54), 173 (100), 171 (68), 121 (36), 119 (26).
IR (®lm): n 2150, 1419, 1377, 1314, 1072, 878, 695,
1
670 cm21. H NMR (200 MHz, CDCl3): d 2.26 (2H, q,
Jˆ7.5 Hz), 1.59±1.47 (6H, m), 1.42±1.24 (6H, m), 1.15
(3H, t, Jˆ7.5 Hz), 0.99±0.83 (15H, m). Anal. Calcd for
C16H32Sn: C, 56.00.; H, 9.40. Found: C, 56.16; H 9.71]
was prepared in 94% yield by reaction of a THF solution
of 1-butyne with 0.68 equiv. of a 1.70 M hexane solution of
butyllithium at 2308C for 3 h followed by treatment with
0.59 equiv. of chlorotributylstannane at 2308C for 0.5 h, at
room temperature for 1 h and under re¯ux for 17 h.
2. Conclusions
The results summarized above conclusively demonstrate
that 6-substituted 5-iodo-2(2H)-pyranones 6, which repre-
sent a not previously described class of heterocyclic halides,
are selectively available by iodolactonizazion of the corre-
sponding (Z)-2-en-4-ynoic acids 1, and that these iodides are
ef®cient electrophiles for palladium-catalyzed cross-
coupling reactions with organostannanes. These reactions
allow one to prepare in moderate to high yields a variety
of unsymmetrically and symmetrically 5,6-disubstituted
2(2H)-pyranones 5 which would be quite dif®cult to prepare
by any other present methodology. One of these 2(2H)-pyra-
none derivatives, i.e. compound 5a, has been used as direct
precursor to two substances produced by fungal culture LL-
11G219, which function as androgen ligands, i.e. 5c and 5d.
The synthesis of the ®rst of these compounds has not been
previously reported. Further synthetic applications of
compounds 6 are currently under investigation in our
laboratory
3.1. General procedure for preparation of methyl (Z)-2-
en-4-ynoates 9
A mixture of a 1-alkyne 11 (48.0 mmol), methyl (Z)-3-
bromopropenoate (10) (6.60 g, 40.0 mmol), PdCl2(PPh3)2
(0.561 g, 0.80 mmol), CuI (0.305 g, 1.60 mmol) and dry
Et3N (100 ml) was stirred at room temperature under a
nitrogen atmosphere until a GLC analysis showed that
compound 10 had completely reacted. The reaction mixture
was then diluted with Et2O (200 ml), poured into a saturated
aqueous NH4Cl solution (200 ml) and the resulting mixture
was stirred open to the atmosphere until the aqueous phase
became deep blue. The organic phase was separated and the
aqueous phase was extracted with Et2O (2£50 ml). The
collected organic extracts were washed with water
(50 ml), dried over Na2SO4 and concentrated under reduced
pressure. The residue was diluted with hexane (300 ml) and
®ltered over Celite. The ®ltrate was concentrated under
reduced pressure and the residue was fractionally distilled
to give the desired methyl (Z)-2-en-4-ynoate 9 as a colorless
liquid. This procedure was employed to prepare compounds
9b±f.
3. Experimental
Melting points and boiling points are uncorrected. Precoated
silica gel sheets Merck 60 F254 were used for TLC analyses.
GLC analyses were performed on a Dani GC 1000 instru-
ment with a PTV injector, which was equipped with a Dani
data station 86.01. Two types of capillary columns were
used: an Alltech AT-1 bonded FSOT column
(30 m£0.25 mm i.d.) and an Alltech AT-35 bonded FSOT
column (30 m£0.25 mm i.d.). Puri®cations by MPLC on
silica gel (Merck silica gel 60, particle size 0.015±
0.040 mm) were performed on a BuÈchi instrument using a
Bischoff 8110 differential refractometer as detector. GLC/
MS analyses were performed using a Q-mass 910 spectro-
meter interfaced with a Perkin±Elmer gas-chromatograph.
IR spectra were recorded on a Perkin±Elmer 1725 FT-IR
spectrophotometer. NMR spectra were recorded on a Varian
Gemini 200 MHz spectrometer or on a Bruker AMX 600
spectrometer using TMS and CDCl3 as an internal standard,
respectively. All reactions of air and water sensitive
materials were performed in ¯ame-dried glassware under
an atmosphere of nitrogen or argon using standard syringe,
cannula and septa techniques. The following compounds
were prepared by published procedures: Pd(PPh3)4,23
3.1.1. Methyl (Z)-5-phenyl-2-penten-4-ynoate (9b). This
compound, which was prepared in 91% yield from 10 and
phenylethyne (11b) according to the above mentioned
general procedure, had: bp 95±968C/0.04 Torr MS, m/z
(%): 186 (31), 171 (21), 155 (14), 127 (17), 115 (27), 63
1
(27), 51 (100). H NMR (200 MHz, CDCl3): d 7.58±7.40
(2H, m, Harom), 7.36±7.25 (3H, m, Harom), 6.35 (1H, d,
Jˆ11.8 Hz, H-3 or H-2), 6.13 (1H, d, Jˆ11.8 Hz, H-2 or H-
3), 3.78 (3H, s, OCH3). Anal. Calcd for C12H10O2: C, 77.40;
H 5.41. Found: C, 77.18; H 5.55.
3.1.2. Methyl (Z)-2-nonen-4-ynoate (9c). This
compound,28 which was prepared in 91% yield from 10
and 1-hexyne (11c) according to the above mentioned
general procedure, had: bp 60±628C/0.05 Torr MS, m/z
PdCl2(PPh3)2,24 PdCl2(CH3CN)2, PdCl2(dppf),26 methyl
25

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2863
(%): 166 (1), 124 (15), 109 (16), 95 (8), 63 (35), 55 (43), 51
(100). 1H NMR (200 MHz, CDCl3): d 6.16 (1H, dt, Jˆ11.6
and 2.2 Hz, H-3), 6.03 (1H, d, Jˆ11.6 Hz, H-2), 3.76 (3H, s,
OCH3), 2.46 (2H, td, Jˆ7.0 and 2.2 Hz, H-6), 1.66±1.36
(4H, m, H-7 and H-8), 0.93 (3H, t, Jˆ7.0 Hz, H-9). Anal.
Calcd for C10H14O2: C, 72.26; H, 8.49. Found: C, 72.43; H
8.51.
6.15 (1H, dq, Jˆ11.4 and 2.6 Hz, H-3), 6.04 (1H, d, Jˆ
11.4 Hz, H-2), 3.76 (3H, s, OCH3), 2.10 (3H, d, Jˆ2.6 Hz,
H-6). The spectral properties of this compound were in
satisfactory agreement with those previously reported.30
3.1.7. (Z)-2-Hexen-4-ynoic acid (1a). Compound 9a
(8.42 g, 67.87 mmol) was dissolved in THF (250 ml) and
the resulting solution was added to an aqueous 1.0 M LiOH
solution (203 ml, 203 mmol). The resulting mixture was
stirred at room temperature for 16 h and then concentrated
under reduced pressure at 208C. The residue was diluted
with water (100 ml) and extracted with Et2O (3£50 ml).
The aqueous phase was cooled to 08C, acidi®ed with cold
10% H2SO4 and extracted with Et2O (350 ml). The organic
extract was dried over Na2SO4 and concentrated under
reduced pressure to give 1a (7.20 g, 97% yield) as a color-
3.1.3. Methyl (Z)-2-decen-4-ynoate (9d). This compound,
which was prepared in 82% yield from 10 and 1-heptyne
(11d) according to the above mentioned general procedure,
had: bp 76±788C/0.2 Torr MS, m/z (%): 180 (3), 149 (14),
137 (67), 124 (60), 109 (100), 105 (46), 95 (28). IR (®lm): n
1
1730, 1718, 1611, 1438, 1196, 1176, 818 cm21. H NMR
(200 MHz, CDCl3): d 6.16 (1H, dt, Jˆ11.5 and 2.1 Hz,
H-3), 6.02 (1H, d, Jˆ11.5 Hz, H-2), 3.75 (3H, s, OCH3),
2.45 (2H, td, Jˆ7.0 and 2.1 Hz, H-6), 1.65±1.32 (6H, m, H-7,
H-8 and H-9), 0.90 (3H, t, Jˆ7.0 Hz, H-10). These NMR data
were in agreement with those previously reported.29
1
less solid. Mp 108±1128C (lit. 30 mp 113±114.58C). H
NMR (200 MHz, CDCl3): dˆ10.76 (1H, br s, COOH),
6.25 (1H, dq, Jˆ11.5 and 2.4 Hz, H-3), 6.07 (1H, d,
Jˆ11.5 Hz, H-2), 2.11 (3H, d, Jˆ2.4 Hz, H-6). These
NMR data were in satisfactory agreement with those
previously reported.30 This crude product was used in the
next step without any further puri®cation and characteriza-
tion.
3.1.4. Methyl (Z)-2-undecen-4-ynoate (9e). This com-
pound, which was prepared in 93% yield from 10 and
1-octyne (11e) according to the above mentioned general
procedure, had: bp 728C/0.04 Torr MS, m/z (%): 194 (5),
137 (93), 124 (94), 111 (80), 108 (100), 95 (85), 79 (71). IR
(®lm): n 1732, 1718, 1611, 1438, 1195, 1176, 818 cm21. 1H
NMR (200 MHz, CDCl3): d 6.19 (1H, dt, Jˆ11.3 and
2.2 Hz, H-3), 6.03 (1H, d, Jˆ11.3 Hz, H-2), 3.76 (3H, s,
OCH3), 2.45 (2H, td, Jˆ6.9 and 2.2 Hz, H-6), 1.65±1.28
(8H, m, H-7, H-8, H-9 and H-10), 0.89 (3H, t, Jˆ6.7 Hz,
H-11). Anal. Calcd for C12H18O2: C, 74.22; H, 9.33. Found:
C, 73.99; H 9.39.
3.1.8. (Z)-5-Phenyl-2-penten-4-ynoic acid (1b). Com-
pound 9b was converted in quantitative yield into 1b
according to the same procedure used to prepare 1a from
9a. Crude 1b, which was a pale yellow solid, had: mp 127±
1
1288C. H NMR (200 MHz, CDCl3): d 9.30 (1H, br s,
COOH), 7.60±7.45 (2H, m, Harom), 7.40±7.27 (3H, m,
Harom), 6.48 (1H, d, Jˆ11.4 Hz, H-3 or H-2), 6.17 (1H,
d, Jˆ11.4 Hz, H-2 or H-3. This crude product was used in
the next step without any further puri®cation and character-
ization.
3.1.5. Methyl (2Z,6E)-2,6-decadien-4-ynoate (9f). This
compound, which was prepared in 86% yield from 10 and
(E)-3-hepten-1-yne (11f) according to the above mentioned
general procedure, had: bp 84±858C/0.2 Torr MS, m/z (%):
178 (10), 163 (44), 131 (59), 105 (72), 91 (100), 77 (82). IR
(®lm): n 1728, 1600, 1438, 1235, 1197, 1178, 816 cm21. 1H
NMR (200 MHz, CDCl3): d 6.33 (1H, dt, Jˆ15.7 and
6.9 Hz, H-7), 6.27 (1H, dd, Jˆ11.3 and 2.6 Hz, H-3), 6.05
(1H, d, Jˆ11.3 Hz, H-2), 5.72 (1H, ddt, Jˆ15.7, 2.6 and
1.5 Hz, H-6), 3.76 (3H, s, OCH3), 2.15 (2H, dtd, Jˆ7.3,
7.3 and 1.5 Hz, H-8), 1.45 (2H, tq, Jˆ7.3 and 7.3 Hz, H-9),
0.93 (3H, t, Jˆ7.3 Hz, H-10). Anal. Calcd for C11H14O2:
C,74.13; H 7.92. Found: C, 74.25; H 7.94.
3.1.9. (Z)-2-Nonen-4-ynoic acid (1c). Compound 9c was
converted in 98% yield into 1c according to the same proce-
dure used to prepare 1a from 9a. Crude 1c was a pale yellow
1
liquid which had: H NMR (200 MHz, CDCl3): d 10.76
(1H, br s, COOH), 6.27 (1H, dt, Jˆ11.3 and 2.2 Hz, H-3),
6.07 (1H, dd, Jˆ11.3 and 0.7 Hz, H-2), 2.46 (2H, td, Jˆ6.8
and 2.2 Hz, H-6), 1.66±1.36 (4H, m, H-7 and H-8), 0.93
(3H, t, Jˆ7.0 Hz, H-9). This crude carboxylic acid was
used in the next step without any further puri®cation and
characterization.
3.1.6. Methyl (Z)-2-hexen-4-ynoate (9a). A 0.50 M THF
solution of 1-propynylmagnesium bromide (12) (192 ml,
96 mmol) was added dropwise to a slurry of dry ZnCl2
(17.00 g, 124.8 mmol) in THF (230 ml), which was stirred
under argon at 08C. After stirring for 15 min at 08C a solu-
tion of 10 (13.20 g, 80.0 mmol) in THF (20 ml) and
Pd(PPh3)4 (4.62 g, 4.0 mmol) were sequentially added and
the resulting mixture was stirred for 20 h at room tempera-
ture. It was then poured into a saturated aqueous NH4Cl
solution (300 ml) and extracted with Et2O (4£100 ml).
The collected organic extracts were washed with brine
(100 ml), dried over Na2SO4 and concentrated. The residue
was diluted with pentane (300 ml) and ®ltered over Celite.
The ®ltrate was concentrated and the residue was fraction-
ally distilled to give 9a (8.50 g, 85% yield) as a colorless
3.1.10. (Z)-2-Decen-4-ynoic acid (1d). Compound 9d was
converted in quantitative yield into 1d according to the same
procedure used to prepare 1a from 9a. Crude 1d, which was
1
a pale yellow liquid, had: H NMR (200 MHz, CDCl3): d
9.75 (1H, br s, COOH), 6.26 (1H, dt, Jˆ11.6 and 2.2 Hz, H-3),
6.06 (1H, d, Jˆ11.6 Hz, H-2), 2.45 (2H, td, Jˆ7.0 and
2.2 Hz, H-6), 1.59±1.32 (6H, m, H-7, H-8 and H-9), 0.91
(3H, t, Jˆ6.9 Hz, H-10). The spectral properties of this
compound were in satisfactory agreement with those
previously reported.31 This crude carboxylic acid was used
in the next step without any further puri®cation and char-
acterization.
3.1.11. (Z)-2-Undecen-4-ynoic acid (1e). Compound 9e
was converted in 98% yield into 1e according to the same
procedure used to prepare 1a from 9a. Crude 1e, which was
1
liquid: bp 798C/17 Torr. H NMR (200 MHz, CDCl3): d

2864
F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
1
a pale yellow liquid, had: H NMR (200 MHz, CDCl3): d
11.10 (1H, br s, COOH), 6.27 (1H, dt, Jˆ11.4 and 2.3 Hz,
H-3), 6.06 (1H, d, Jˆ11.4 Hz, H-2), 2.44 (2H, dt, Jˆ6.7 and
2.3 Hz, H-6), 1.70±1.20 (8H, m, H-7, H-8, H-9 and H-10),
0.89 (3H, t, Jˆ6.7 Hz, H-11). These NMR data were in
agreement with those previously reported.32 This crude
carboxylic acid was used in the next step without any further
puri®cation and characterization.
molar ratio, respectively (entry 3, Table 1). These crude
compounds were separated by MPLC on silica gel using
toluene as eluant. Concentration of the ®rst eluted chroma-
tographic fractions allowed to isolate stereoisomerically
pure (E)-7b (6.30 g, 73% yield) as a crystalline solid. On
the other hand, concentration of the last eluted chromato-
graphic fractions allowed to isolate pure 6b (1.30 g, 15%
yield) as a crystalline solid. A similar procedure was used
for iodolactonization of 1e, but the reaction was carried out
at room temperature for 3.5 h (entry 8, Table 1).
Compounds 6e and (E)-7e, which were present in the
crude reaction mixture in a ca. 4:96 molar ratio, were
obtained in 3 and 75% GLC yield, respectively.
3.1.12. (2Z,6E)-2,6-Decadien-4-ynoic acid (1f). Com-
pound 9f was converted in 95% yield into 1f according to
the same procedure used to prepare 1a from 9a. Crude 1f,
which was a yellow solid, had: mp 308C. 1H NMR
(200 MHz, CDCl3): d 9.90 (1H, br s, COOH), 6.37 (1H,
dd, Jˆ11.4 and 2.5 Hz, H-3), 6.34 (1H, dt, Jˆ15.7 and
6.9 Hz, H-7), 6.07 (1H, d, Jˆ11.4 Hz, H-2), 5.72 (1H, ddt,
Jˆ15.7, 2.5 and 1.5 Hz, H-6), 2.15 (2H, dtd, Jˆ7.0, 7.0 and
1.4 Hz, H-8), 1.44 (2H, tq, Jˆ7.3 and 7.3 Hz, H-9), 0.92
(3H, t, Jˆ7.3 Hz, H-10). This crude carboxylic acid was
used in the next step without any further puri®cation and
characterization.
Method C. To a solution of a compound 1 (1.95 mmol) in
CH2Cl2 (6 ml) was added a solution of ICl (1.95 mmol) in
CH2Cl2 (4 ml) and the reaction mixture was stirred in the
dark at room temperature for 5.0 h. It was then poured into a
10% aqueous NaHCO3 solution (10 ml) and extracted with
AcOEt (2£8 ml). The organic extract was washed with a
10% aqueous Na2S2O3 solution (15 ml) and water (20 ml),
dried and analyzed by GLC using biphenyl as an internal
standard. This method was used for iodolactonization of 1e
(entry 7, Table 1).
3.2. General procedures for the synthesis of 6-substituted
5-iodo-2(2H)-pyranones 6 and the corresponding (E)-5-
(1-iodoylidene)-2(5H)-furanones (E)-7
Method D. N-Iodosuccinimide (0.443 g, 1.95 mmol) was
added to a solution of a compound 1 (1.95 mmol) in
CH3CN (13 ml) and the mixture was stirred in the dark at
room temperature for 2.5 h. It was then poured into a 10%
aqueous Na2S2O3 solution (15 ml) and extracted with
AcOEt (2£10 ml). The organic extract was washed with
water, dried and analyzed by GLC using biphenyl as an
internal standard. This method was used for iodolactoniza-
tion of 1e (entry 9, Table 1).
The iodolactonization of carboxylic acids 1 was performed
according to four different methods. (Method A) To a
suspension of NaHCO3 (8.06 g, 96.0 mmol)) in CH3CN
(150 ml) were added sequentially a solution of a (Z)-2-en-
4-ynoic acid 1 (32.0 mmol) in CH3CN (50 ml) and iodine
(24.36 g, 96.0 mmol) and the mixture was stirred vigorously
under nitrogen at room temperature for 1.5 h at which time
the reaction was complete as shown by GLC and TLC
analyses. The reaction mixture was then diluted with
AcOEt (150 ml) and washed with a 10% aqueous Na2S2O3
solution (50 ml) and water (50 ml). The organic phase was
dried over Na2SO4 and concentrated under reduced pressure
to give a crude mixture of a 6-substituted 5-iodo-2(2H)-
pyranone 6 and the corresponding (E)-5-(1-iodoylidene)-
2(5H)-furanones (E)-7, where compound 6 was the major
component. Compounds 6 and (E)-7 were separated by
MPLC on silica gel. This procedure was employed for iodo-
lactonization of (Z)-2-en-4-ynoic acids 1a±f. Table 1
summarizes the 6/(E)-7 molar ratio found in the crude reac-
tion mixtures which were obtained from these carboxylic
acids as well as the isolated yields of compounds 6a±f and
(E)-7a±f prepared by this procedure (entries 1, 2, 4±6 and
10, Table 1). It must be noted that compounds (E)-7 under-
went a partial stereomutation at room temperature and that
some of these substances, i.e. (E)-7a, (E)-7d and (E)-7f,
could not be isolated in stereoisomerically pure form.
The physical and spectral properties of compounds 6a±f and
(E)-7a±f as well as the chromatographic conditions which
were used for their isolation are reported below.
3.2.1. 5-Iodo-6-methyl-2(2H)-pyranone (6a) and (E)-5-
(1-iodoethylidene)-2(5H)-furanone [(E)-7a].
A GLC
analysis of the crude reaction mixture, which was obtained
by iodolactonization of 1a according to Method A, showed
the presence of two compounds in a ca. 66:34 molar ratio,
which were subsequently identi®ed as 6a and (E)-7a,
respectively (entry 1, Table 1). This mixture was puri®ed
by MPLC on silica gel using a mixture of hexane, CH2Cl2
and AcOEt (80:15:5) as eluant. Concentration of the ®rst
eluted chromatographic fractions allowed to isolate in 32%
yield (E)-7a as a crystalline solid. Mp 75±768C. MS, m/z
(%): 236 (65), 127 (26), 109 (72), 81 (39), 63 (9), 55 (40), 53
(100). IR (KBr): n 1741, 1080, 1044, 914, 875, 823 cm21
.
GLC and NMR analyses showed that (E)-7a was contami-
nated by ca. 15% of the corresponding (Z)-stereoisomer.
The NMR parameters for (E)-7a were as follows. 1H
NMR (600 MHz, CDCl3): d 7.63 (1H, d, Jˆ5.5 Hz, H-4),
6.27 (1H, d, Jˆ5.5 Hz, H-3), 2.74 (3H, s, H-7). 13C NMR
(150 MHz, CDCl3): d 169.77 (C-2), 150.16 (C-5), 144.69
(C-4), 122.53 (C-3), 85.86 (C-6), 27.08 (C-7). The NMR
parameters for (Z)-7a were as follows. 1H NMR
(600 MHz, CDCl3): d 7.62 (1H, d, Jˆ5.5 Hz, H-4), 6.32
(1H, d, Jˆ5.5 Hz, H-3), 2.71 (3H, s, H-7). 13C NMR
(150 MHz, CDCl3): d 168.68 (C-2), 152.16 (C-5), 136.59
Method B. This method was used for iodolactonization of
1b and 1e (entries 3 and 8, Table 1). In particular, to a
deareated solution of 1b (5.0 g, 29.04 mmol) in CH3CN
(150 ml), which was maintained at 08C under nitrogen in
the dark, were added sequentially N-iodosuccinimide
(7.23 g, 32.26 mmol) and KHCO3 (2.91 g, 29.04 mmol)
and the resulting mixture was stirred at 08C for 1.5 h.
After usual work up a H NMR analysis of the crude reac-
tion product showed the presence of two compounds, which
were subsequently identi®ed as 6b and (E)-7b in a ca. 18:82
1

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2865
(C-4), 120.55 (C-3), 84.28 (C-6), 26.60 (C-7). A NOESY
experiment showed a cross-peak between the resonances of
the H-4 and H-7 protons. Anal. Calcd for C6H5IO2: C, 40.67;
H, 2.13. Found: C, 40.82; H 2.19. On the other hand,
concentration of the last eluted chromatographic fractions
allowed to isolate in 64% yield pure 6a as a crystalline solid.
Mp 72±738C. MS, m/z (%): 236 (49), 208 (100), 165 (33),
127 (19), 81 (48), 66 (11), 53 (28). IR (KBr): n 1735, 1715,
95 (39), 81 (69). IR (®lm): n 1735, 1601, 1542, 1189, 1012,
822, 599 cm21. 1H NMR (200 MHz, CDCl3): d 7.43 (1H, d,
Jˆ9.8 Hz, H-4), 5.98 (1H, d, Jˆ9.8 Hz, H-3), 2.71 (2H, t,
Jˆ7.7 Hz, H-6a), 1.66 (2H, quint, Jˆ7.7 Hz, H-6b), 1.39
(2H, sext, Jˆ7.7 Hz, H-6c), 0.94 (3H, t, Jˆ7.7 Hz, H-6d).
Anal. Calcd for C9H11IO2: C 38.87; H, 3.99. Found: C,
39.09; H 4.18.
1
1599, 1541, 1010, 828, 599 cm21. H NMR (600 MHz,
3.2.4. 5-Iodo-6-pentyl-2(2H)-pyranone (6d) and (E)-5-(1-
iodohexylidene)-2(5H)-furanone [(E)-7d]. A GLC analy-
sis of the crude reaction mixture, which was obtained by
iodolactonization of 1d according to Method A, showed the
presence of two compounds in a ca. 69:31 molar ratio,
which were subsequently identi®ed as 6d and (E)-7d,
respectively (entry 5, Table 1). This mixture was puri®ed
by MPLC on silica gel using a mixture of toluene and
hexane (90:10) as eluant. Concentration of the ®rst eluted
chromatographic fractions allowed to isolate in 30% yield
stereoisomerically pure (E)-6d as a red liquid. MS, m/z (%):
292 (4), 147 (10), 109 (100), 81 (28), 50 (10). IR (®lm): n
CDCl3): d 7.43 (1H, d, Jˆ9.6 Hz, H-4), 5.99 (1H, d,
Jˆ9.6 Hz, H-3), 2.47 (3H, s, CH3). 13C NMR (150 MHz,
CDCl3): d 162.58 (C-6), 161.24 (C-2), 151.62 (C-4), 114.68
(C-3), 67.96 (C-5), 23.48 (C-7). Anal. Calcd for C6H5IO2: C,
40.67; H, 2.13. Found: C, 40.83; H 2.28.
3.2.2. 5-Iodo-6-phenyl-2(2H)-pyranone (6b) and (E)-5-
[1-iodobenzylidene)-2(5H)-furanone [(E)-7b]. A GLC
analysis of the crude reaction mixture, which was obtained
by iodolactonization of 1b according to Method A, showed
the presence of two compounds in a ca. 79:21 molar ratio,
which were subsequently identi®ed as 6b and (E)-7b,
respectively (entry 2, Table 1). This mixture was puri®ed
by MPLC on silica gel using a mixture of benzene and
hexane (95:5) as eluant. Concentration of the ®rst eluted
chromatographic fractions allowed to isolate in 17% yield
(E)-7b as an orange solid. Mp 64±678C. MS, m/z (%): 298
(76), 171 (100), 143 (14), 115 (77), 89 (41), 77 (15), 63 (27).
IR (KBr): n 1774, 1766, 1749, 948, 899, 760, 699 cm21. 1H
NMR (200 MHz, CDCl3): d 7.91 (1H, d, Jˆ5.6 Hz, H-4),
7.72±7.63 (2H, m, Harom), 7.44±7.32 (3H, m, Harom),
6.34 (1H, d, Jˆ5.6 Hz, H-3). Anal. Calcd for C11H7IO2:
C, 44.32; H 2.37. Found: C, 44.45; H 2.48. On the other
hand, concentration of the last eluted chromatographic frac-
tions allowed to isolate in 59% yield 6b as a pale yellow
solid. Mp 101±1038C. MS, m/z (%): 298 (100), 270 (83),
143 (12), 115 (33), 105 (55), 77 (62), 63 (8). IR (KBr): n
1
1779, 1751, 1632, 1553, 1379, 1196, 728 cm21. H NMR
(200 MHz, CDCl3): d 7.65 (1H, d, Jˆ5.5 Hz, H-4), 6.28
(1H, d, Jˆ5.5 Hz, H-3), 2.81 (2H, t, Jˆ7.3 Hz, H-6a),
1.61±1.54 (2H, m, H-6b), 1.35±1.27 (4H, m, H-6c and
H-6d), 0.90 (3H, t, Jˆ6.6 Hz, H-6f). Anal. Calcd for
1
C10H13IO2: C, 41.11. H 4.49. Found: C, 40.95; H 4.61. H
NMR analysis showed that (E)-7d was contaminated by ca.
13% of the corresponding (Z)-stereoisomer. On the other
hand, concentration of the last eluted chromatographic frac-
tions allowed to isolate in 65% yield pure 6d as a red liquid.
MS, m/z (%): 292 (18), 221 (36), 165 (60), 119 (24), 109
(30), 95 (56), 81 (100). IR (®lm): n 1735, 1600, 1541, 1465,
1189, 1011, 820 cm21. 1H NMR (200 MHz, CDCl3): d 7.43
(1H, d, Jˆ9.8 Hz, H-4), 5.99 (1H, d, Jˆ9.8 Hz, H-3), 2.71
(2H, t, Jˆ7.7 Hz, H-7), 1.72±1.65 (2H, m, H-8), 1.38±1.31
(4H, m, H-9 and H-10), 0.91 (3H, t, Jˆ5.5 Hz, H-11). Anal.
Calcd for C10H13IO2: C 41.11; H 4.49. Found: C, 41.26; H
4.65.
1
1717, 1601, 1539, 1486, 1024, 834, 706 cm21. H NMR
(200 MHz, CDCl3): d 7.78±7.69 (2H, m, Harom), 7.64
(1H, d, Jˆ9.9 Hz, H-4), 7.52±7.44 (3H, m, Harom), 6.11
(1H, d, Jˆ9.9 Hz, H-3). Anal. Calcd for C11H7IO2: C,44.32;
H 2.37. Found: C, 44.37; H, 2.41.
3.2.5. 6-Hexyl-5-iodo-2(2H)-pyranone (6e) and (E)-5-(1-
iodoheptylidene)-2(5H)-furanone [(E)-7e]. A GLC analy-
sis of the crude reaction mixture, which was obtained by
iodolactonization of 1e according to Method A, showed the
presence of two compounds in a ca. 68:32 molar ratio,
which were subsequently identi®ed as 6e and (E)-7e, respec-
tively (entry 6, Table 1). This mixture was puri®ed by
MPLC on silica gel using a mixture of toluene and hexane
(90:10) as eluant. Concentration of the ®rst eluted chroma-
tographic fractions allowed to isolate in 31% yield stereo-
isomerically pure (E)-7e as a red liquid. MS, m/z (%): 306
(2), 133 (8), 109 (100), 95 (15), 82 (12), 81 (17), 55 (16). IR
(®lm): n 1781, 1755, 1554, 1242, 1106, 936, 811 cm21. 1H
NMR (200 MHz, CDCl3): d 7.65 (1H, d, Jˆ5.4 Hz, H-4),
6.28 (1H, d, Jˆ5.4 Hz, H-3), 2.80 (2H, t, Jˆ7.4 Hz, H-7),
1.60±1.20 (8H, m, H-8, H-9, H-10 and H-11), 0.89 (3H, t,
Jˆ6.4 Hz, H-12). Anal. Calcd for C12H15IO2: C, 43.15; H
4.94. Found: C, 43.32; H 5.12. On the other hand, concen-
tration of the last eluted chromatographic fractions allowed
to isolate in 65% yield pure 6e as a red liquid. MS, m/z (%):
306 (17), 236 (20), 221 (29), 165 (31), 133 (35), 109 (22), 95
(47), 81 (100). IR (®lm): n 1739, 1599, 1542, 1465, 1189,
3.2.3. 6-Butyl-5-iodo-2(2H)-pyranone (6c) and (E)-5-(1-
iodopentylidene)-2(5H)-furanone [(E)-7c]. A GLC analy-
sis of the crude reaction mixture, which was obtained by
iodolactonization of 1c according to Method A, showed the
presence of two compounds in a ca. 66:34 molar ratio,
which were subsequently identi®ed as 6c and (E)-7c, respec-
tively (entry 4, Table 1). This mixture was puri®ed by
MPLC on silica gel using toluene as eluant. Concentration
of the ®rst eluted chromatographic fractions allowed to
isolate in 32% yield stereoisomerically pure (E)-7c as a
red liquid. MS, m/z (%): 278 (40), 235 (15), 179 (9), 153
(7), 109 (100), 81 (10), 54 (15). IR (®lm): n 1777, 1754,
1105, 959, 915, 881, 814 cm21 1H NMR (200 MHz,
.
CDCl3): d 7.65 (1H, d, Jˆ5.4 Hz, H-4), 6.29 (1H, d,
Jˆ5.4 Hz, H-3), 2.82 (2H, t, Jˆ7.0 Hz, H-7), 1.63±1.28
(4H, m, H-8 and H-9), 0.94 (3H, t, Jˆ7.0 Hz, H-10).
Anal. Calcd for C9H11IO2:C, 38.87; H, 3.99. Found: C,
39.01; H 4.09. On the other hand, concentration of the last
eluted chromatographic fractions allowed to isolate in 63%
yield chemically pure 6c as an orange liquid. MS, m/z (%):
278 (88), 236 (49), 221 (100), 207 (54), 165 (53), 109 (24),
1
1012, 820 cm21. H NMR (200 MHz, CDCl3): d 7.43 (1H,
d, Jˆ9.7 Hz, H-4), 5.98 (1H, d, Jˆ9.7 Hz, H-3), 2.70 (2H, t,

2866
F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
Jˆ7.7 Hz, H-6a), 1.71±1.59 (2H, m, H-6b), 1.45±1.20 (6H,
m, H-6c, H-6d and H-6e), 0.89 (3H, t, Jˆ6.6 Hz, H-6f).
Anal. Calcd for C12H15IO2: C, 43.15; H 4.94. Found: C,
43.17; H 5.23.
AcOEt (2£100 ml). The organic extract was stirred at 208C
with an aqueous 8 M solution of KF (150 ml) for 4 h. The
mixture was then ®ltered over Celite and the ®ltrate was
extracted with AcOEt (3£60 ml). The organic extract was
washed with water (80 ml), dried over Na2SO4 and concen-
trated in vacuo. The residue was puri®ed by MPLC on silica
gel using a mixture of toluene and hexane (80:20) as eluant to
give (E)-15a (1.52 g, 76% yield) as a crystalline solid. Mp
71±728C. MS, m/z (%): 210 (93), 181 (50), 153 (100), 128
(74), 127 (39), 102 (41), 77 (32). IR (KBr): n 1785, 1757,
1545, 1256, 1111, 1097, 886, 764 cm21. 1H NMR (600 MHz,
CDCl3): d 7.80 (1H, d, Jˆ5.4 Hz, H-4), 7.48 (2H, m, H-11
and H-15), 7.37 (2H, m, H-12 and H-14), 7.36 (1H, m, H-13),
6.22 (1H, d, Jˆ5.4 Hz, H-3), 2.20 (3H, s, H-7). 13C NMR
(150 MHz, CDCl3): dˆ169.23 (C-2), 153.85 (C-5), 141.125
(C-4), 131.61 (C-11 and C-15), 129.11 (C-13), 128.54 (C-12
and C-14), 122.29 (C-10), 119.52 (C-3), 107.14 (C-6), 96.55
(C-9), 86.57 (C-8), 17.37 (C-7). Anal. Calcd for C14H10O2: C,
79.98; H, 4.79. Found: C, 80.12; H 5.04.
3.2.6. 5-Iodo-6-[(E)-1-pentenyl]-2(2H)-pyranone (6f) and
(E)-5-[1-iodo-(E)-2-hexenylidene)-2(5H)-furanone [(E)-
7f]. A GLC analysis of the crude reaction mixture, which
was obtained by iodolactonization of 1f according to
Method A, showed the presence of two compounds in a
ca. 79:21 molar ratio, which were subsequently identi®ed
as 6f and (E)-7f, respectively (entry 10, Table 1). This
mixture was puri®ed by MPLC on silica gel using toluene
as eluant. Concentration of the ®rst eluted chromatographic
fractions allowed to isolate in 22% yield stereoisomerically
pure (E)-7f as an orange liquid. A GLC analysis showed
that (E)-7f was contaminated by ca. 12% of (Z)-7f. Stereo-
isomerically pure (E)-7f had: MS, m/z (%): 290 (19), 248
(40), 121 (95), 117 (44), 91 (52), 71 (100), 55 (40). 1H NMR
(600 MHz, CDCl3): d 7.78 (1H, d, Jˆ5.5 Hz, H-4), 6.42
(1H, dt, Jˆ14.4 and 1.4 Hz, H-7), 6.25 (1H, d, Jˆ5.5 Hz,
H-3), 6.24 (1H, dt, Jˆ14.4 and 7.3 Hz, H-8), 2.30 (2H,
dquart, Jˆ7.3 and 1.4 Hz, H-9), 1.52 (2H, sext, Jˆ7.3 Hz,
H-10), 0.94 (3H, t, Jˆ7.3 Hz, H-11). 13C NMR (150 MHz,
CDCl3): dˆ169.32 (C-2), 148.91 (C-5), 147.65 (C-8),
145.34 (C-4), 125.61 (C-7), 121.42 (C-3), 90.92 (C-6),
34.87 (C-9), 22.18 (C-10), 13.74 (C-11). A NOESY experi-
ment showed a cross-peak between the resonance of the H-4
and H-7 protons. Some spectral data for (Z)-7f are as
follows. MS, m/z (%): 290 (16), 248 (30), 121 (83), 117
(36), 91 (55), 70 (100), 65 (56). 1H NMR (600 MHz,
CDCl3): d 7.76 (1H, d, Jˆ5.5 Hz, H-4), 6.34 (1H, d,
Jˆ5.5 Hz, H-3), 6.29 (1H, dt, Jˆ14.4 and 7.3 Hz, H-8),
6.06 (1H, dt, Jˆ14.4 and 1.4 Hz, H-7), 2.29 (2H, dquart,
Jˆ7.3 and 1.4 Hz, H-9), 1.51 (2H, sext, Jˆ7.3 Hz, H-10),
0.95 (3H, t, Jˆ7.3 Hz, H-11). 13C NMR (150 MHz, CDCl3):
d 168.05 (C-2), 152.24 (C-5), 146.12 (C-8), 136.91 (C-4),
124.45 (C-7), 119.99 (C-3), 91.03 (C-6), 34.86 (C-9), 22.28
(C-10), 13.74 (C-11). The IR and elemental analysis data for
(E)-7f contaminated by (Z)-7f were as follows. IR (®lm): n
1782, 1751, 1623, 1542, 1107, 944, 885 cm21. Anal. Calcd
for C10H11IO2: C, 41.40; H 3.82. Found: C, 41.78; H 3.81.
On the other hand, concentration of the last eluted chroma-
tographic fractions allowed to isolate in 72% yield 6f as a
red oil. MS, m/z (%): 290 (12), 236 (35), 106 (52), 91 (27),
79 (29), 78 (47), 55 (100). IR (®lm): n 1740, 1637, 1515,
1192, 1015, 964, 816 cm21. 1H NMR (200 MHz, CDCl3): d
7.48 (1H, d, Jˆ9.5 Hz, H-4), 6.80 (1H, dt, Jˆ15.4 and
7.3 Hz, H-8), 6.38 (1H, dt, Jˆ15.4 and 1.5 Hz, H-7), 5.99
(1H, d, Jˆ9.5 Hz, H-3), 2.26 (2H, dtd, Jˆ7.3, 7.3 and
1.5 Hz, H-9), 1.52 (2H, tq, Jˆ7.3 and 7.3 Hz, H-10), 0.96
(3H, t, Jˆ7.3 Hz, H-11). Anal. Calcd for C10H11IO2: C,
41.40; H 3.82. Found: C, 41.65; H 4.01.
3.2.8. (E)-5-[1-(4-Methoxyphenyl)pentylidene]-2(5H)-fura-
none ((E)-15b). A ¯ame-dried reaction vessel, which was
maintained under an argon atmosphere, was charged with
PdCl2(PhCN)2 (0.25 g, 0.66 mmol), AsPh3 (0.40 g,
1.32 mmol), CuI (0.25 g, 1.32 mmol), compound (E)-7c
(3.68 g, 13.23 mmol) and N-methylpyrrolidinone (NMP)
(15 ml). A deaerated solution of 4-methoxyphenyltributyl-
stannane (8b) (6.31 g, 15.88 mmol) in NMP (5 ml) was then
added and the mixture was stirred at 608C for 22 h. It was then
cooled to 208C, poured into an aqueous NH4Cl solution
(150 ml) and extracted with AcOEt (4£50 ml). The organic
extract was stirred for 4 h with an aqueous 8 M solution of KF
(100 ml) and the resulting mixture was ®ltered over Celite.
The ®ltrate was extracted with AcOEt (4£30 ml) and the
organic extract was washed with water (50 ml), dried over
Na2SO4 and concentrated in vacuo. The residue was puri®ed
by MPLC on silica gel using a mixture of toluene and Et2O
(97:3) as eluant to give (E)-15b (2.91 g, 85% yield) as a pale
yellow liquid. MS, m/z (%): 258 (100), 215 (71), 201 (23), 187
(43), 133 (27), 91 (17), 77 (16). IR (®lm): n 1777, 1756, 1752,
1606, 1512, 1251, 1106 cm21. 1H NMR (600 MHz, CDCl3): d
7.37 (1H, d, Jˆ5.6 Hz, H-4), 7.21 (2H, d, Jˆ8.7 Hz, H-12 and
H-16), 6.93 (2H, d, Jˆ8.7 Hz, H-13 and H-15), 6.13 (1H, d,
Jˆ5.6 Hz, H-3), 3.85 (3H, s, OCH3), 2.77 (2H, t, Jˆ7.4 Hz,
H-7), 1.38 (2H, quint, Jˆ7.4 Hz, H-8), 1.32 (2H, sext,
Jˆ7.4 Hz, H-9), 0.86 (3H, t, Jˆ7.4 Hz, H-10). A NOESY
experiment showed the presence of a cross-peak between
the resonances of the H-4 and H-12 (H-16) protons. 13C
NMR (150 MHz, CDCl3): d 170.38 (C-2), 159.99 (C-12 and
C-16), 147.10 (C-5), 142.29 (C-4), 131.78 (C-11), 130.30
(C-14), 129.09 (C-6), 118.68 (C-3), 114.06 (C-13 and C-15),
55.35 (OCH3), 31.95 (C-7), 30.31 (C-8), 22.56 (C-9), 13.80
(C-10). Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found:
C, 74.51; H 7.24. The spectral properties of this compound
were in agreement with those of a sample of (E)-15b prepared
by reaction of 1c with 4-methoxyphenyl iodide in CH3CN in
the presence of 4 equiv. of K2CO3 and 5 mol% Pd(PPh3)4.11
3.2.7. (E)-5-[1-(Phenylethynyl)ethylidene]-2(5H)-furanone
((E)-15a). A ¯ame-dried reaction vessel, which was main-
tained under an argon atmosphere, was charged with (E)-7a
(2.24 g, 9.51 mmol), PdCl2(PPh3)2 (0.20 g, 0.28 mmol) and
deareated THF (40 ml) and the mixture was stirred. A
deaerated solution of phenylethynyltributylstannane (8a)
(4.46 g, 11.42 mmol) in THF (10 ml) was then added and
the mixture was stirred at 208C for 53 h. It was then poured
into an aqueous NH4Cl solution (200 ml) and extracted with
3.3. Procedures for the palladium-catalyzed cross-
coupling reactions of 5-iodo-2(2H)-pyranones 6 with
organostannanes 8
The palladium-catalyzed reactions between compounds 6

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2867
and 8 were carried out using three different procedures.
The ®rst of these (Procedure A) was used for reactions
involving aryltributylstannanes, i.e. compounds 8b and
phenyltributylstannane (8e), vinyltributylstannane (8d),
and tetramethylstannane (8g). According to this procedure,
a ¯ame-dried ¯ask ¯ushed with argon was charged with
PdCl2(PhCN)2 (0.16 g, 0.41 mmol), CuI (0.16 g,
0.83 mmol), AsPh3 (0.25 g, 0.83 mmol), a 5-iodo-2(2H)-
pyranone 6 (8.27 mmol) and deaerated NMP (55 ml). A
deaerated solution of an organostannane 8 in NMP
(15 ml) was then added and the mixture was stirred at the
temperature and for the period of time reported in Table 2.
The reaction involving 8g (entry 7) was carried out using a
3:1 molar ratio between this organometallic reagent and 6,
but the coupling reactions involving 8b, 8d and 8e (entries
3±5) were performed using a 1.2:1 molar ratio between
these organometallics and compounds 6. After completion
of the reaction, which was periodically monitored by GLC,
the reaction mixture was allowed to cool to 208C and poured
into a saturated aqueous NH4Cl solution (150 ml). After
stirring for 0.5 h the mixture was extracted with AcOEt
(4£50 ml). The organic extracts derived from reactions
involving organotributylstannanes were stirred for 3±4 h
with an aqueous 8 M solution of KF (150 ml), ®ltered
over Celite and the ®ltrate was extracted with AcOEt. The
organic extract was washed with brine, dried and concen-
trated under reduced pressure. The residue was puri®ed
by MPLC on silica gel. Procedure A was used for the
synthesis of compounds 5g, 5h, 5i and 5k (entries 3, 4,
5 and 7, Table 2). The second procedure (Procedure B),
which was used for the cross-coupling reactions involving
1-butynyltributylstannane (8c), was very similar to that
employed for the synthesis of (E)-15a from (E)-7a and 8a.
This procedure was used for the synthesis of compounds
5a and 5b (entries 1 and 2, Table 2). Table 2 summarizes
the reaction conditions used for the preparation of these
5,6-disubstituted 2(2H)-pyranones. Finally a third pro-
cedure (Procedure C) was employed in an attempt to use
tetrabutylstannane (8f) in a palladium-catalyzed reaction
with 6e. Thus, a deaerated solution of Pd2(dba)3 (0.039 g,
0.042 mmol) and PPh3 (0.089 g, 0.338 mmol) in dioxane
(45 ml), which was stirred under argon, were added
sequentially 6e (2.59 g, 8.46 mmol), 8f (2.93 g,
8.46 mmol) and a 1 M THF solution of TBAF (50.8 ml,
50.80 mmol) and the resulting mixture was re¯uxed
under stirring for 22 h. After this period of time GLC
and GLC/MS analyses of a sample of the reaction
mixture, which was washed with water, showed that
6e had completely reacted. However, no trace of the
expected cross-coupled product was present. Thus, this
trial was interrupted.
t, Jˆ7.5 Hz, H-5d). Anal. Calcd for C10H10O2: C, 74.06; H
6.21. Found: C, 74.21; H, 6.48.
3.3.2. 5-(1-Butynyl)-6-phenyl-2(2H)-pyranone (5b). The
crude reaction mixture, which was obtained from the
palladium-catalyzed reaction between 6b and 8c according
to Procedure B (entry 2, Table 2), was puri®ed by MPLC on
silica gel, using a mixture of petroleum ether and AcOEt
(90:10) as eluant, to give in 82% yield 5b as a yellow crys-
talline solid. Mp 70±728C. MS, m/z (%): 224 (24), 181 (11),
153 (13), 105 (80), 77 (100), 65 (10). IR (KBr): n 2235,
1726, 1528, 1138, 853, 820, 694 cm21. 1H NMR (200 MHz,
CDCl3): d 8.19±8.14 (2H, m, Harom), 7.47±7.41 (3H, m,
Harom), 7.39 (1H, d, Jˆ9.5 Hz, H-4), 6.25 (1H, d,
Jˆ9.5 Hz, H-3), 2.42 (2H, q, Jˆ7.5 Hz, H-5c), 1.22 (3H,
t, Jˆ7.5 Hz, H-5d). Anal. Calcd for C15H12O2: C, 80.34; H
5.39. Found: C, 80.36; H, 5.47.
3.3.3. 6-Butyl-5-(4-methoxyphenyl)-2(2H)-pyranone (5g).
The crude reaction mixture, which was obtained from the
palladium-catalyzed reaction between 6c and 8b according
to Procedure A (entry 3, Table 2), was puri®ed by MPLC on
silica gel, using a mixture of toluene and Et2O (90:10) as
eluant, to give in 88% yield 5g as a yellow liquid. MS, m/z
(%): 258 (55), 201 (100), 187 (30), 173 (13), 159 (5), 145
(50), 102 (11). IR (®lm): n 1732, 1610, 1544, 1513, 1249,
1179, 826 cm21. 1H NMR (200 MHz, CDCl3): d7.30 (1H, d,
Jˆ9.5 Hz, H-4), 7.16 (2H, dt, Jˆ9.0 and 2.2 Hz, Harom),
6.95 (2H, dt, Jˆ9.0 and 2.2 Hz, Harom), 6.22 (1H, d,
Jˆ9.5 Hz, H-3), 3.85 (3H, s, OCH3), 2.50 (2H, t,
Jˆ7.7 Hz, H-6a), 1.78±1.57 (2H, m, H-6b), 1.28 (2H,
sext, Jˆ7.3 Hz, H-6c), 0.85 (3H, t, Jˆ7.3 Hz, H-6d).
Anal. Calcd for C16H18O3: C, 74.40; H 7.02. Found: C,
74.09; H, 6.92. The spectral properties of this compound
were in agreement with those of 5g prepared by treatment
of 1c with 4-methoxyphenyl iodide in CH3CN in the
presence of K2CO3 and a catalytic quantity of Pd(PPh3)4.11
3.3.4. 5-Ethenyl-6-butyl-2(2H)-pyranone (5h). The crude
reaction mixture, which was obtained from the palladium-
catalyzed reaction between 6c and 8d according to Pro-
cedure A (entry 4, Table 2), was puri®ed by MPLC on silica
gel, using a mixture of hexane and AcOEt (85:15) as eluant,
to give in 85% yield 5h as an orange liquid. MS, m/z (%):
178 (82), 163 (23), 149 (24), 136 (56), 121 (100), 70 (70), 65
(34). IR (®lm): n 1734, 1551, 1091, 1065, 985, 907,
1
829 cm21. H NMR (200 MHz, CDCl3): d 7.57 (1H, d,
Jˆ9.7 Hz, H-4), 6.58 (1H, dd, Jˆ17.7 and 11.0 Hz, H-5a),
6.24 (1H, d, Jˆ9.7 Hz, H-3), 5.47 (1H, d, Jˆ17.3 Hz,
H-5b(E)), 5.26 (1H, d, Jˆ11.0 Hz, H-5b(Z)), 2.61 (2H, t,
Jˆ7.5 Hz, H-6a), 1.75±1.57 (2H, m, H-6b), 1.38 (2H,
sext, Jˆ7.1 Hz, H-6c), 0.93 (3H, t, Jˆ7.1 Hz, H-6d).
Anal. Calcd for C11H14O2: C, 74.13; H 7.92. Found: C,
74.25; H, 7.99.
3.3.1. 5-(1-Butynyl)-6-methyl-2(2H)-pyranone (5a). The
crude reaction mixture, which was obtained from the
palladium-catalyzed reaction between 6a and 8c according
to Procedure B (entry 1, Table 2), was puri®ed by MPLC on
silica gel, using a mixture of toluene and AcOEt (95:5) as
eluant, to give in 75% yield 5a as a crystalline solid. Mp 48±
508C. MS, m/z (%): 162 (63), 147, (54), 119 (83), 105 (18),
91 (100), 65 (39), 43 (43). IR (KBr): n 1733, 1633, 1547,
1305, 1073, 857, 823 cm21. 1H NMR (200 MHz, CDCl3): d
7.24 (1H, d, Jˆ9.6 Hz, H-4), 6.13 (1H, d, Jˆ9.6 Hz, H-3),
2.40 (2H, q, Jˆ7.5 Hz, H-5c), 2.39 (3H, s, H-6a), 1.21 (3H,
3.3.5. 5,6-Diphenyl-2(2H)-pyranone (5i). The crude reac-
tion mixture, which was obtained from the palladium-
catalyzed reaction between 6b and 8e according to Pro-
cedure A (entry 5, Table 2), was puri®ed by MPLC on silica
gel, using a mixture of hexane and AcOEt (85:15) as eluant,
to give in 55% yield 5i as a pale yellow crystalline solid. Mp
93±968C. MS, m/z (%): 248 (100), 220 (96), 207 (19), 191
(38), 115 (34), 105 (39), 77 (61). IR (KBr): n 1730, 1535,

2868
F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
1486, 1010, 839, 770, 697 cm21
.
1H NMR (200 MHz,
(0.41 g, 81% yield) as a colorless oil. MS, m/z (%): 164 (35),
CDCl3): d 7.47 (1H, d, Jˆ9.5 Hz, H-4), 7.40±7.15 (10, m,
Harom), 6.38 (1H, d, Jˆ9.5 Hz, H-3). The spectral proper-
ties of 5i were in good agreement with those previously
reported.9f
135 (13), 121 (86), 107 (46), 93 (20), 78 (46), 44 (100). IR
(®lm): n 1740, 1546, 1191, 1123, 1067, 864, 829 cm21. 1H
NMR (200 MHz, CDCl3): d 7.20 (1H, d, Jˆ9.5 Hz, H-4),
6.16 (1H, d, Jˆ9.5 Hz, H-3), 6.00 (1H, d, Jˆ11.1 Hz, H-5a),
5.71 (1H, dt, Jˆ11.1 and 7.4 Hz, H-5b), 2.20 (3H, s, H-6a),
2.18±1.97 (2H, m, H-5c), 1.01 (3H, t, Jˆ7.5 Hz, H-5d).
These NMR data were in good agreement with those of
the natural product.4
3.3.6. 5-Methyl-6-[(E)-1-pentenyl]-2(2H)-pyranone (5k).
The crude reaction mixture, which was obtained from the
palladium-catalyzed reaction between 6f and 8g according
to Procedure A (entry 7, Table 2), was puri®ed by MPLC on
silica gel, using a mixture of toluene and AcOEt (90: 10) as
eluant, to give in 68% yield 5k as a pale yellow liquid. MS,
m/z (%): 178 (32), 136 (42), 124 (64), 121 (100), 108 (64),
93 (32), 77 (44). IR (®lm): n 1729, 1646, 1533, 1098, 963,
940, 820 cm21. 1H NMR (200 MHz, CDCl3): d 7.15 (1H, d,
Jˆ9.2 Hz, H-4), 6.71 (1H, dt, Jˆ15.4 and 7.4 Hz, H-6b),
6.17 (1H, d, Jˆ15.4 Hz, H-6a), 6.14 (1H, d, Jˆ9.2 Hz, H-3),
2.23 (2H, q, Jˆ7.2 Hz, H-6c), 2.05 (3H, s, H-5a), 1.50 (2H,
sext, Jˆ7.3 Hz, H-6d), 0.95 (3H, t, Jˆ7.3 Hz, H-6e). Anal.
Calcd for C11H14O2: C, 74.13; H 7.92. Found: C, 73.94; H
8.06.
3.3.9. 5-Butyl-6-phenyl-2(2H)-pyranone (5f). A deaerated
solution of 5b (0.37 g, 1.60 mmol) in toluene (10 ml) was
added to a suspension of 10% palladium on BaSO4
(35.71 mg) in toluene (10 ml). The mixture was vigorously
stirred under a hydrogen atmosphere and the uptake of gas
monitored. After 1 h and 45 min uptake had ceased and the
reaction mixture was ®ltered and the ®ltrate concentrated in
vacuo. The residue was puri®ed by MPLC on silica gel,
using a mixture of toluene and AcOEt (92.5:7.5) as eluant,
to give 5f (0.37 g, 100% yield) as a colorless liquid. MS, m/z
(%): 228 (11), 185 (28), 157 (34), 129 (23), 105 (100), 77
(81), 51 (8). IR (®lm): n 1736, 1632, 1546, 1491, 1099, 827,
1
698 cm21. H NMR (200 MHz, CDCl3): d 7.58±7.40 (5H,
3.3.7. (Z)-5-(1-Butenyl)-6-phenyl-2(2H)-pyranone (5e). A
deaerated solution of 5b (0.35 g, 1.56 mmol) in toluene
(10 ml) was added to a suspension of 10% palladium on
BaSO4 (35.71 mg) in toluene (10 ml), poisoned by addition
of pyridine (25 drops) followed by stirring for 5 min. The
m, Harom), 7.35 (1H, d, Jˆ9.6 Hz, H-4), 6.30 (1H, d,
Jˆ9.6 Hz, H-3), 2.43 (2H, t, Jˆ7.6 Hz, H-5a), 1.60±1.49
(2H, m, H-5b), 1.40±1.21 (2H, m, H-5c), 0.87 (3H, t,
Jˆ7.3 Hz, H-5d). Anal. Calcd for C15H16O2: C, 78.92; H,
7.06. Found: C, 79.05; H 7.12.
mixture was vigorously stirred under
a hydrogen
atmosphere and the uptake of gas monitored. After 2 h
uptake had ceased and the reaction mixture was ®ltered
and the ®ltrate concentrated in vacuo. A GLC/MS analysis
of the residue showed the presence of two compounds in a
ca. 95:5 molar ratio. The ®rst of these was subsequently
identi®ed as 5b and the minor component of this mixture,
which had a MS spectrum very similar to that of 5b, corre-
sponded likely to the (E)-stereoisomer of this substance.
The residue was puri®ed by MPLC on silica gel, using a
mixture of toluene and AcOEt (92.5:7.5) as eluant, to give
stereoisomerically pure 5e (0.31 g, 88% yield) as a colorless
solid. Mp 50±528C. MS, m/z (%): 226 (6), 197 (31), 169
(12), 141 (17), 105 (97), 91 (14), 77 (100). IR (KBr): n
3.3.10. 5-Butyl-6-methyl-2(2H)-pyranone (5d). A deaer-
ated solution of 5a (0.35 g, 2.16 mmol) in toluene (13 ml)
was added to a suspension of 10% palladium on BaSO4
(47.34 mg) in toluene (14 ml) and the mixture was vigor-
ously stirred under a hydrogen atmosphere and the uptake of
gas monitored. After 25 min uptake of gas, which was not
complete, had ceased and 10% palladium on BaSO4
(47.34 mg) was added to the mixture which was stirred
under a hydrogen atmosphere. After 0.5 h uptake of gas
was complete and the reaction mixture was ®ltered and
the ®ltrate was concentrated under reduced pressure. A
GLC analysis of the residue showed the presence of three
compounds in a ca. 89:10:1 molar ratio, in which the major
and the minor component corresponded to compounds 5d
and 5c, respectively, and the third component was not
identi®ed. The residue was puri®ed by MPLC on silica
gel, using a mixture of petroleum ether, CH2Cl2 and
AcOEt (80:15:5) as eluant, to give 5d (0.28 g, 78% yield)
as a colorless liquid. MS, m/z (%): 166 (22), 138 (12), 123
(100), 95 (92), 82 (12), 68 (7), 44 (77). IR (®lm): n 1740,
1
1736, 1526, 1109, 1079, 996, 825, 698 cm21. H NMR
(200 MHz, CDCl3): d 7.70±7.60 (2H, m, Harom), 7.50±
7.35 (3H, m, Harom), 7.37 (1H, d, Jˆ9.3 Hz, H-4), 6.29
(1H, d, Jˆ9.3 Hz, H-3), 6.09 (1H, d, Jˆ11.4 Hz, H-5a),
5.68 (1H, dt, Jˆ11.4 and 7.3 Hz, H-5b), 2.13 (2H, dquint,
Jˆ7.5 and 1.6 Hz, H-5c), 1.00 (3H, t, Jˆ7.5 Hz, H-5d).
Anal. Calcd for C15H14O2: C, 79.62; H 6.24. Found: C,
79.68; H 6.31.
.
1642, 1557, 1466, 1104, 867, 827 cm21 1H NMR
(200 MHz, CDCl3): d 7.17 (1H, d, Jˆ9.6 Hz, H-4), 6.14
(1H, d, Jˆ9.6 Hz, H-3), 2.29 (2H, t, Jˆ7.5 Hz, H-5a),
2.23 (3H, s, H-6a), 1.51±1.21 (4H, m, H-5b and H-5c),
0.93 (3H, t, Jˆ7.2 Hz, H-5d). These NMR data were in
agreement with those of the natural product.4
3.3.8. (Z)-5-(1-Butenyl)-6-methyl-2(2H)-pyranone (5c).
A deaerated solution of 5a (0.50 g, 3.08 mmol) in toluene
(20 ml) was added to a suspension of 10% palladium on
BaSO4 (67.63 mg) poisoned by addition of pyridine (47
drops) followed by stirring for 10 min. The mixture was
vigorously stirred under a hydrogen atmosphere and the
uptake of gas monitored. After 3.5 h uptake had ceased
and the reaction mixture was ®ltered and concentrated
under reduced pressure. A GLC analysis of the residue
showed the presence of unreacted 5a and three new
compounds in a ca. 8:88:2:2 molar ratio, respectively. The
residue was puri®ed by MPLC on silica gel, using a mixture
of toluene and AcOEt (90:10) as eluant, to give 97% pure 5c
Acknowledgements
Á
This work was supported by the Ministero dell'Universita e
della Ricerca Scienti®ca e Tecnologica (MURST) and the
University of Pisa. We thank Dr Luisa Mannina of the
University of Molise for obtaining the H NMR spectra at
1

F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
2869
600 MHz and the 13C NMR spectra at 150 MHz and Profes-
sor Annalaura Segre for the use of NMR facilities of the
Servizio NMR dell'Area della Ricerca di Roma (CNR). We
wish also to thank Dr Jean-Luc Parrain (C.N.R.S.Ð
Marseille) for useful suggestions and comments.
(h) Tsuda, T.; Morikawa, S.; Sumiya, R.; Saegusa, T. J. Org.
Chem. 1988, 53, 3140±3145. (i) Ref. 8. (j) Cerezo, S.;
Moreno-ManÄas, M.; Pleixats, R. Tetrahedron Lett. 1998, 54,
7813±7818. (k) Cho, S. K.; Liebeskind, L. S. J. Org. Chem.
1987, 52, 2631±2634. (l) Izumi, T.; Kasahara, A. Bull. Chem.
Soc. Jpn 1975, 48, 1673±1674.
11. Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L.
Tetrahedron Lett. 2000, 41, 5281±5286.
References
12. (a) Rossi, R.; Bellina, F.; Catanese, A.; Mannina, L.; Valensin,
D. Tetrahedron 2000, 56, 479±487. (b) Bellina, F.; Ciucci, D.;
Vergamini, P.; Rossi, R. Tetrahedron 2000, 56, 2533±2545.
(c) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron Lett. 1998, 39, 7799±7802. (d) Rossi, R.; Bellina,
F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998, 39,
7599±7602. (e) Rossi, R.; Bellina, F.; Mannina, L.
Tetrahedron Lett. 1998, 39, 3017±3020. (f) Rossi, R.; Bellina,
F.; Bechini, C.; Mannina, L.; Vergamini, P. Tetrahedron 1998,
54, 135±156.
1. (a) Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33,
7839±7842. (b) Posner, G. H.; Nelson, T. D.; Kinter, Ch. M.;
Afarinkia, K. Tetrahedron Lett. 1991, 32, 5295±5298.
(c) Ram, V. J.; Goel, A. J. Chem. Res. (S) 1997, 460±461.
2. (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.;
Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690±691.
(b) Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.;
Peretto, I.; Silvani, A. Tetrahedron 1998, 54, 14081±14088.
(c) Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61, 6693±6699.
(d) Ram, V. J.; Haque, N.; Singh, S. K.; Hussaini, F. A.;
Shoeb, A. Indian J. Chem. 1993, 32B, 924±928. (e) Tominaga,
Y.; Ushirogochi, A.; Matsuda, Y.; Kobayashi, G. Chem.
Pharm. Bull. 1984, 32, 3384±3395. (f) Chen, C.-H.; Liao,
C.-C. Org. Lett. 2000, 2, 2049±2052.
13. Argenti, L.; Bellina, F.; Carpita, A.; Rossi, E.; Rossi, R. Synth.
Commun. 1994, 24, 2281±2297.
14. So®a, M. J.; Chakravarty, P. K.; Katznellenbogen, J. A. J. Org.
Chem. 1983, 48, 3318±3325.
15. Krafft, G. A.; Katznellenbogen, J. A. J. Am. Chem. Soc. 1981,
103, 5459±5466.
3. (a) Barrero, A. F.; Oltra, J. E.; Herrador, M. M.; Sanchez, J. F.;
Quilez, J. F.; Rojas, F. J.; Reyes, J. F. Tetrahedron 1993, 49,
141±150. (b) Abraham, W. R.; Arfmann, H.-A. Phytochemistry
1988, 27, 3310±3311.
16. For similar values of this coupling constant in 5-ylidene-
2(5H)-furanones, see: (a) Kundu, N. G.; Pal, M.; Nandi, B.
J. Chem. Soc., Perkin Trans 1 1998, 561±568. (b) Rousset,
Ã
M.; Abarbri, M.; Thibonnet, J.; Duchene, A.; Parrain, J.-L.
Org. Lett. 1999, 1, 701±703.
4. Schlingmann, G.; Milne, L.; Carter, G. T. Tetrahedron 1998,
54, 13013±13022.
17. For similar values of this coupling constant in 5-substituted
and/or 5,6-disubstituted 2(2H)-pyranones, see: (a) Pirkle,
W. H.; Dines, M. J. Heterocycl. Chem. 1969, 6, 1±3.
(b) Ref. 4.
5. Sato, H.; Konoma, K.; Sakamura, S. Agric. Biol. Chem. 1981,
45, 1675±1679.
6. Chen, K. K.; Kovarikova, A. J. Pharm. Sci. 1967, 56, 1535±
1541.
18. For other Stille reactions performed in NMP in the presence of
catalytic amounts of PdCl2(PhCN)2, CuI and AsPh3, see:
(a) Bellina, F.; Carpita, A.; Ciucci, D.; De Santis, M.; Rossi,
R. Tetrahedron 1993, 49, 4677±4698. (b) Farina, V.; Kapadia,
S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem.
1994, 59, 5905±5911. (c) Rossi, R.; Bellina, F.; Raugei, E.
Synlett 2000, 1749±1752.
7. (a) Simon, A.; Dunlop, R. W.; Ghisalberti, E. L.; Sivasitham-
param, K. Soil Biol. Biochem. 1988, 20, 263±264. (b) Claydon,
N.; Asllan, M.; Hanson, J. R.; Avent, A. G. Trans. Br. Mycol.
Soc. 1987, 88, 503±513. (c) Cutler, H. G.; Cox, R. H.;
Crumley, F. G.; Cole, P. O. Agric. Biol. Chem. 1986, 50,
2943±2948.
8. Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald, J.
Tetrahedron Lett. 1995, 36, 71±74.
19. For some typical Stille reactions involving the use of 1-
alkynyltributylstannanes, which have been recently performed
in the presence of catalytic amounts of PdCl2(PPh3)2, see:
(a) Rossi, R.; Bellina, F.; Biagetti, M. Synth. Commun.
1999, 29, 3415±3420. (b) Hoffmann, H. M. R.; Gerlach, K.;
Lattmann, E. Synthesis 1996, 164±170.
9. For a review on the synthesis of dehydroacetic acid, triacetic
acid lactone and related 2(2H)-pyranones, see: (a) Moreno-
ManÄas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry;
Academic: San Diego, 1992; Vol. 53, p. 1±84. For a review on
the synthesis of 6-unsubstituted 2(2H)-pyranones, see:
(b) Kvita, V.; Fischer, W. Chimia 1992, 46, 457±468.
(c) Kotretsou, S. I.; Georgiadis, M. P. Org. Prep. Proc. Int.
2000, 32, 161±167. (d) Stanovnik, B. J. Heterocycl. Chem.
1999, 36, 1581±1593. (e) Kepe, V.; Polanc, S.; Kocevar, M.
Heterocycles 1998, 48, 671±678. (f) Dubuffet, T.; Cimetiere,
B.; Lavielle, G. Synth. Commun. 1997, 27, 1123±1131.
(g) Dieter, R. K.; Fishpaugh, J. R. J. Org. Chem. 1988, 53,
20. Fugami, K.; Ohnuma, S.; Kameyama, M.; Saotome, T.;
Kosugi, M. Synlett 1999, 63±64.
21. Yao, M.-L.; Deng, M.-Z. J. Org. Chem. 2000, 65, 5034±5036.
22. For a previous synthesis of 5-butyl-6-methyl-2(2H)-pyranone
(5d), see: Shusherina, N. P.; Levina, Ya.; Sidenko, Z. S.;
Lur'e, M. Yu. Zhur. Obshchei. Khim. 1959, 29, 403±407.
23. Coulson, D. R. Inorg. Synth. 1972, 13, 121±124.
24. Itatani, H.; Bailar, J. C. J. Am. Chem. Oil Soc. 1967, 44, 127±
151.
Â
2031±2046. (h) Belanger, A.; Brassard, P. Can. J. Chem.
1975, 53, 195±200.
25. Heck, R. F. In Palladium Reagents in Organic Synthesis;
Academic: London, 1985; p. 17.
10. (a) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64,
8770±8779. (b) Rousset, S.; Abarbri, M.; Thibonnet, J.;
Ã
Duchene, A.; Parrain, J.-L. Chem. Commun., submitted for
26. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158±162.
27. Rossi, R.; Bellina, F.; Carpita, A.; Mazzarella, F. Tetrahedron
1996, 52, 4095±4110.
publication (c) Ref. 2b. (d) Ref. 1a. (e) Kalinin, V. N.; Shilova,
O. S.; Okladnoy, D. S.; Schmidhammer, H. Mendeleev
Commun. 1996, 9±10. (f) Liebeskind, L. S.; Wang, J.
Tetrahedron 1993, 49, 5461±5470. (g) Tsuda, T.; Morikawa,
S.; Saegusa, T. J. Chem. Soc. Chem. Commun. 1989, 9±10.
28. For previous syntheses of this compound, see: (a) Weir, J. R.;
Patel, B. A.; Heck, R. F. J. Org. Chem. 1980, 45, 4926±4931.

2870
F. Bellina et al. / Tetrahedron 57 (2001) 2857±2870
(b) Lu, X.; Huang, X.; Ma, S. Tetrahedron Lett. 1992, 33,
2535±2538. (c) Patel, V.; Schlosser, M. Synlett 1993, 125±
126.
30. Struve, G.; Selzer, S. J. Org. Chem. 1982, 47, 2109±2113.
Ã
31. Abarbri, M.; Parrain, J.-L.; Cintrat, J.-C.; Duchene, A.
Synthesis 1996, 82±86.
32. Dabdoub, M. J.; Dabdoub, V. B. Tetrahedron 1995, 51, 9839±
9850.
È
29. Baeckstrom, P.; Jacobson, U.; Norin, T.; Unelius, C. R.
Tetrahedron 1988, 44, 2541±2548.