Selective synthesis of 5,6-disubstituted 3-methyl-2(2H)-pyranones and 6-substituted 3-methyl-2(2H)-pyranones, including fusalanipyrone and gibepyrone A

Article abstract of DOI:10.1002/1099-0690(200203)2002:6<1063::AID-EJOC1063>3.0.CO;2-M

The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11, prepared by iodolactonization of the corresponding 5-substituted (E)-2-bromo-2-en-4-ynoic acids 10, were used as precursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones 8 and 6-substituted 3-methyl-2(2

Full text of DOI:10.1002/1099-0690(200203)2002:6<1063::AID-EJOC1063>3.0.CO;2-M

FULL PAPER
Selective Synthesis of 5,6-Disubstituted 3-Methyl-2(2H)-pyranones and
6-Substituted 3-Methyl-2(2H)-pyranones, Including Fusalanipyrone and
Gibepyrone A
[a]
[a]
[a]
[b]
[c]
´
Matteo Biagetti,* Fabio Bellina, Adriano Carpita, Stephane Viel, Luisa Mannina,
and Renzo Rossi*[a]
Keywords: CϪC coupling / Lactones / Natural products / Cyclizations / Synthetic methods
The 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11, pre- merically pure fusalanipyrone (7a), a natural product isolated
pared by iodolactonization of the corresponding 5-substi- from Fusarium solani. Nevertheless, 7a and gibepyrone A
tuted (E)-2-bromo-2-en-4-ynoic acids 10, were used as pre- (7b), which is a natural product isolated from Gibberella fuji-
cursors to 5,6-disubstituted 3-methyl-2(2H)-pyranones 8 and
6-substituted 3-methyl-2(2H)-pyranones 7. The synthesis of
kuroi, could be synthesized in stereoisomerically pure form
by reaction sequences involving iodolactonization of easily
compounds 8 involved two consecutive Stille-type reactions, available (2Z,6Z)- and (2Z,6E)-2,6-dimethyl-2,6-octadien-4-
whereas the approach followed to prepare compounds 7 con- ynoic acids (16a) and (16b), respectively, followed by Pd-
sisted of the selective reduction of the dihalogen derivatives catalysed triethylammonium formate reduction of the thus
11 to the corresponding 6-substituted 3-bromo-2(2H)-pyr- obtained 6-substituted 5-iodo-3-methyl-2(2H)-pyranones 17a
anones 12, followed by a Pd/Cu-catalysed reaction with
tetramethyltin. However, this synthetic approach to com-
and 17b, respectively.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
pounds 7 proved to be unsuitable for preparing stereoiso- 2002)
Introduction
Recently, in the course of our studies on the synthesis of
biologically active, naturally occurring oxygen-containing
Over the past few decades, many 2(2H)-pyranone derivat- heterocycles and their analogues,[13] we became interested
ives have been isolated from natural sources. These com- in developing a regioselective route to unsymmetrically 5,6-
pounds include 2(2H)-pyranones that are 6-substituted,[1] disubstituted 2(2H)-pyranones 4. In fact, no general pro-
3,5-,[2] 3,6-,[3] 4,6-,[4] and 5,6-disubstituted,[5] 3,4,6-[6] and cedure to prepare these compounds had been reported in
4,5,6-trisubstituted,[7] and 3,4,5,6-tetrasubstituted,[8] and the literature. We succeeded in developing a convenient two-
many of them have been shown to display a wide range of step procedure for the synthesis of these derivatives.[14] In
biological activities including antifungal,[9] antimicro- particular, we found that treatment of 5-substituted (Z)-2-
bial,[3b] androgen-like,[5b] phytotoxic,[10] cardiotonic,[1e] and en-4-ynoic acids 1 with iodine and NaHCO3 in acetonitrile
pheromonal effects[2] and the ability to induce morpholo- or with ICl in CH2Cl2 afforded mixtures of compounds 2
gical and physiological differentiation of tumour cells.[1f] and 3 in which these derivatives were the major products
2(2H)-Pyranones have also been shown to be useful syn- and that compounds 3, easily separated chromatographic-
thetic intermediates.[11] As a consequence, numerous reports ally from iodides 2, were able to undergo Stille-type reac-
on the preparation of these heterocycles have been pub- tions with a variety of organotin derivatives to give the de-
lished.[12]
sired 5,6-disubstituted 2(2H)-pyranones 4 in moderate to
good yields (Scheme 1).[14]
[a]
Dipartimento di Chimica e Chimica Industriale
We also searched for an alternative and practical route to
compounds 4, and we found that 6-alkyl-5-iodozinc-2(2H)-
pyranones 5, available from the corresponding iodides 3 by
insertion of activated zinc metal into their carbonϪiodine
bonds, underwent Pd-catalysed reaction either with activ-
ated alkenyl halides or with activated and deactivated (het-
ero)aryl halides to provide compounds 4 in fair to good
yields (Scheme 2).[15] Moreover, we observed that acidic hy-
drolysis of the organometallic derivatives 5 gave 6-substi-
via Disorgimento 35, 56126 Pisa, Italy
Fax: (internat.) ϩ 39-050/918260
E-mail: rossi@dcci.unipi.it
[b]
[c]
Istituto di Chimica Nucleare, CNR, Area della Ricerca di
Roma
Via Salaria Km 29.3, 00016 Monterotondo Stazione, Roma,
Italy
Fax: (internat.) ϩ 39-06/90672477
E-mail: NMR@mlib.cnr.it
`
`
Facolta di Scienze M.F.N., Universita del Molise,
Via Mazzini 8, 86170 Isernia, Italy
Eur. J. Org. Chem. 2002, 1063Ϫ1076
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0306Ϫ1063 $ 17.50ϩ.50/0
1063

M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
carbonϪcarbon bond-forming reaction at the iodine-bear-
ing carbon atom 5 of these dihalogen derivatives, followed
by a methylation reaction of the resultant 5,6-disubstituted
3-bromo-2(2H)-pyranones 13 (Scheme 3).
Scheme 1. Synthesis of 5,6-disubstituted 2(2H)-pyranones; re-
agents: a) I2 (3 equiv.), NaHCO3 (3 equiv.), MeCN, 1.5 h, room
temp.; b) ICl (1 equiv.), CH2Cl2, 1.5 h, room temp.; c) R2SnBu3 or
R2SnMe3 (1.2Ϫ3.0 equiv.), NMP, PdCl2(PhCN)2 (5 mol %), CuI
(10 mol %), AsPh3 (10 mol %), 20Ϫ80 °C, 22Ϫ80 h; d) R2SnBu3
(1.2 equiv.), THF, PdCl2(PPh3)2 (3 mol %), 20Ϫ50 °C, 40Ϫ46 h
Scheme 3. Retrosynthetic analysis of compounds 7 and 8
Moreover, we also considered the alternative possibility
of synthesizing compounds 7 from methyl esters 9 by a re-
action sequence based on the retrosynthetic analysis de-
picted in Scheme 4, involving the preparation and use of
3,6-disubstituted 5-iodo-2(2H)-pyranones 17.
Scheme 4. Alternative retrosynthetic analysis of compounds 7
Scheme 2. Synthesis of 6-substituted and 5,6-disubstituted 2(2H)-
pyranones; reagents: a) activated zinc dust (3 equiv.), THF, room
temp., 3Ϫ3.5 h; b) 5% HCl, 0 °C; c) R2X (X ϭ Br, I) (0.83Ϫ1.43
equiv.), Pd2(dba)3 (2 mol %), PPh3 (8 mol %), THF, 20Ϫ70 °C;
15Ϫ63 h
We now wish to describe and comment on the results of
these studies. In particular, we show that compounds 11
were useful intermediates for the selective synthesis of com-
tuted 2(2H)-pyranones 6, including two natural products, pounds 8, characterized by an alkyl or an aryl group at C-
in satisfactory yields (Scheme 2).[15]
6. We also report that, whereas compounds of general for-
More recently, we examined the possibility of accessing mula 7, characterized by an alkyl group at C-6, could be
3,6-disubstituted and 3,5,6-trisubstituted 2(2H)-pyranones selectively synthesized in satisfactory yields by a reaction
of general formula 7 and 8, respectively, through chemistry sequence involving the preparation and use of a 6-alkyl-3-
similar to that successfully used to prepare compounds 4 bromo-5-iodo-2(2H)-pyranone 11 (R1 ϭ alkyl), a similar
and 6. In particular, we speculated that carboxylic acids 10, reaction sequence involving stereodefined 6-(alkenyl)-3-
corresponding to the readily available methyl esters 9,[16] bromo-5-iodo-2(2H)-pyranones 11 [R1 ϭ (Z)- or (E)-alk-
might be regioselectively converted into 3-bromo-5-iodo- enyl] was not suitable for the synthesis of two stereoiso-
2(2H)-pyranones 11 and that these dihalogen derivatives merically pure 3,6-disubstituted 2(2H)-pyranones isolated
might be useful starting materials to prepare compounds 7 from fungi: 6-[(Z)-2-butenyl]-3-methyl-2(2H)-pyranone (fu-
if it was possible to reduce compounds 11 selectively to the salanipyrone, 7a)[3a] and 6-[(E)-2-butenyl]-3-methyl-2(2H)-
corresponding 3-bromo derivatives 12 and then to perform pyranone (gibepyrone A, 7b)[3b] (Figure 1). Finally, we re-
a transition metal-catalysed methylation reaction on these port that these naturally occurring compounds could be re-
last compounds, as illustrated in the retrosynthetic analysis gioselectively synthesized in stereoisomerically pure form
shown in Scheme 3. The trisubstituted 2(2H)-pyranones 8, and in satisfactory overall yields by seven-step reaction se-
on the other hand, we imagined might be prepared from quences based on the retrosynthetic analysis depicted in
11, if it was possible to achieve a regioselective Pd-catalysed Scheme 4.
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Eur. J. Org. Chem. 2002, 1063Ϫ1076

Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
FULL PAPER
In particular, a mixture of 20a and 0.47 equiv. of bis(tri-
butyltin) oxide in dry THF was treated with 0.02 equiv. of
TBAF and the resulting mixture was heated to 65 °C for
2.5 h. The volatiles were then removed under reduced pres-
sure to give a quantitative yield of crude 14a with 97% ste-
reoisomeric purity and a chemical purity higher than 92%.
A similar reaction sequence was then used to prepare 14b
from 18b in 74% overall yield (Scheme 5). Compound 14b
was stereoisomerically pure and had a chemical purity
higher than 95%.
The subsequent regioselective and stereospecific reactions
between 15 and 1.1 equiv. of the organotin derivatives
14aϪd, in N-methylpyrrolidinone (NMP) at room temper-
ature in the presence of 5 mol % PdCl2(PhCN)2 and 10
mol % AsPh3, allowed stereoisomerically pure compounds
9a, 9b, 9c, and 9d to be prepared in 66, 54, 67, and 69%
yields, respectively (Scheme 6).
Figure 1. Chemical structures of compounds 7a and 7b
Results and Discussion
6-Substituted 3-Bromo-5-iodo-2(2H)-pyranones and
6-Substituted 5-Iodo-3-methyl-2(2H)-pyranones
The starting materials for the synthesis of the possible
precursors to 6-substituted 3-methyl-2(2H)-pyranones 7
and 5,6-disubstituted 3-methyl-2(2H)-pyranones 8, com-
pounds 11 and 17, were methyl (E)-2,3-dibromopropenoate
(15)[17] and the organotin derivatives 14 (Scheme 4).
Whereas one of these organometallics Ϫ phenylethynyltribu-
tyltin (14d) Ϫ was commercially available, and 1-hexynyltri-
butyltin (14c) could be prepared according to the literat-
ure,[18] (Z)- and (E)-3-methyl-3-penten-1-ynyltributyltin
(14a and 14b) were synthesized by a two-step reaction se-
quence that did not involve the use of the corresponding
volatile enynes (Scheme 5). The first step of this sequence
used to prepare 14a, involved treatment of stereoiso-
merically pure (Z)-2-bromo-2-butene (18a) with a THF so-
lution of 1.25 equiv. of 19 in the presence of 5 mol %
Pd(PPh3)4. This reaction furnished 95% stereoisomerically
pure 20a in 51% yield after 6 d at 65 °C. However, when
the coupling was performed at 60 °C for 24 h in a 1:1 mix-
ture of THF and DMF in the presence of 5 mol %
Pd(PPh3)4, it provided 97% stereoisomerically pure 20a in
71% yield. In the second step of the reaction sequence, 20a
was converted into the corresponding tributyltin derivative
14a by means of a catalytic method for the conversion of
1-alkynylsilanes into the corresponding tributylstannanes
(Scheme 5).[19]
Scheme 6. Synthesis of 5-substituted (E)-2-bromo-2-en-4-ynoic ac-
ids 10 and their iodolactonization; reagents: a) 14 (1.1 equiv.),
PdCl2(PhCN)2 (5 mol %), AsPh3 (10 mol %), NMP, room temp.,
20Ϫ24 h; b) 8  aq. KF, Et2O; c) MPLC on silica gel; d) for com-
pounds 9a,c,d: 1  LiOH, THF, 24 h, then 10% H2SO4, 0 °C; e)
Method A: I2 (3.0 equiv.), NaHCO3 (3.0 equiv.), MeCN, room
temp., 1 h; f) Method B: ICl (1.0 equiv.), CH2Cl2, 0 °C, 1 h; g)
Method C: NIS (1.1 equiv.), KHCO3 (1.0 equiv.), MeCN, room
temp., 1 h
We then examined the possibility of preparing the 6-sub-
stituted 3-bromo-5-iodo-2(2H)-pyranones 11a, 11c, and 11d
by conversion of 9a, 9c, and 9d, respectively, into the corres-
ponding carboxylic acids 10, followed by iodolactonization
of these compounds by one of the procedures that we had
previously employed to prepare 5-iodo-2(2H)-pyranones 3
from the corresponding acids 1.[14] Thus, THF solutions of
9a, 9c, and 9d were treated with molar excesses of 1  LiOH
solutions for 24Ϫ36 h, followed by acidification at 0 °C to
give the corresponding carboxylic acids 10a, 10c, and 10d
in 80, 100, and 73% yields, respectively. Three procedures
for iodolactonization of these carboxylic acids were then
investigated (Scheme 6 and Table 1). The first of these
(Method A) involved treatment of the carboxylic acid with
3.0 equiv. of iodine and 3.0 equiv. of NaHCO3 in CH3CN
at room temperature for 1 h. The second procedure
(Method B) consisted of treatment of the carboxylic acid
with 1.0 equiv. of ICl in CH2Cl2 at 0 °C, while the last
procedure (Method C) involved treatment of the carboxylic
acid with 1.1 equiv. of N-iodosuccinimide (NIS) and 1.0
equiv. of KHCO3 in CH3CN at room temperature for 1 h.
Scheme 5. Synthesis of (Z)- and (E)-(3-methyl-3-penten-1-ynyl)tri-
butyltin (14a) and (14b); reagents: a) 19 (1.25 equiv.), Pd(PPh3)4 (5
mol %), THF, 65 °C, 6 days; b) 19 (1.25 equiv.), Pd(PPh3)4 (5
mol %), THF and DMF (1:1), 60 °C, 24 h (for 18a) and 3 h (for
18b); c) (Bu3Sn)2O (0.47 equiv.), TBAF (0.02 equiv.), THF, 65 °C,
2.5 h
Eur. J. Org. Chem. 2002, 1063Ϫ1076
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M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
Table 1. Synthesis of 6-substituted 3-bromo-5-iodo-2(2H)-pyranones 11 and the corresponding (E)-3-bromo-5-(1-iodoylidene)-2(5H)-
furanones 21
Entry
Carboxylic
acid
10
Method for iodo
lactonization[a]
Products
11/21 molar ratio[b]
11 ϩ 21
Yield of 11
Yield of 21
1
2
3
4
5
6
7
8
9
10a
10a
10a
10c
10c
10c
10d
10d
10d
A
B
C
A
B
C
A
B
C
11a ϩ 21a
11a ϩ 21a
11a ϩ 21a
11c ϩ 21c
11c ϩ 21c
11c ϩ 21c
11d ϩ 21d
11d ϩ 21d
21d
97.5:2.5
Ͼ 99.0:Ͻ 1.0
53.0:47.0
40.0:60.0
57.0:43.0
1.5:98.5
49.0:51.0
92.8:7.2
0:100
75
52
38
30
n.d.
n.d.
40
70
n.d.
n.d
n.d.
40[c]
50[d]
n.d.
n.d.
43
7
n.d.
[a] Methods A, B, and C were used for iodolactonization of compounds 10. [b] Molar ratio in the crude reaction mixture. [c] This compound
was isolated as a mixture of four stereoisomers. [d] Compound 21c was contaminated with ca. 30% of the corresponding (Z) stereoisomer.
As shown in Table 1, where the results of these reactions give stereoisomerically pure 22a and 22b, in 74 and 84%
are summarized, our attempts to prepare 11c with high se- yields, respectively (Scheme 7).
lectivity by Methods A or B met with no success (Entries 4
and 5). In fact, these methods gave 11c and the correspond-
ing isomer 21c in comparable amounts. On the other hand,
Method C furnished a crude reaction mixture in which 21c
was the major product (Entry 6). However, we were able
to obtain isomerically pure 11c in 30% isolated yield by
chromatographic purification of the crude reaction mixture
obtained in Entry 4. This purification also allowed 21c to
be isolated in 50% yield. This latter compound, however,
which had been stereoisomerically pure in the crude reac-
tion mixture, underwent partial stereomutation during the
chromatographic purification and was isolated as a mixture
Scheme 7. Synthesis of 5-substituted (Z)-2-methyl-2-en-4-ynoic ac-
of (E) and (Z) stereoisomers in ca. 70:30 molar ratio.
ids 16 and their iodolactonization; reagents: a) Me4Sn (3.0 equiv.),
PdCl2[P(o-tolyl)3]2 (5 mol %), CuI (10 mol %), NMP, 70 °C, 2.5 h;
b) 1  LiOH, THF, room temp., 24 h, then 10% H2SO4, 0 °C; c)
In contrast, both Methods A and B proved to be suitable
Method A: I2 (3.0 equiv.), NaHCO3 (3.0 equiv.), MeCN, room
for the selective preparation of stereoisomerically pure 11a
temp., 1 h; d) Method B: ICl (1.0 equiv.), CH2Cl2, 0 °C, 1 h
(Entries 1 and 2), although a higher isolated yield of this
compound could be obtained by the first of these proced-
ures (Entry 1). Finally, we found that compound 11d could
Saponification of these esters with 1  LiOH at room
also be regioselectively prepared in satisfactory yield by
temperature, followed by acidification at 0 °C, provided the
iodolactonization of 10d by Method B (Entry 8). In con-
corresponding crude carboxylic acids 16a and 16b in 100
trast, Method A unexpectedly furnished a crude mixture of
and 92% yields, respectively. Interestingly, iodolactonization
11d and 21d in 49:51 molar ratio (Entry 7). It should also
of these carboxylic acids by Method A, which we had used
be noted that, whereas compounds 21c and 21d could be
to prepare the dihalogen derivatives 11, allowed us to ob-
regioselectively obtained by iodolactonization of 10c and
tain mixtures of compounds 23 and the required 6-alkenyl-
10d, respectively, by Method C (Entries 6 and 9, Table 1),
5-iodo-3-methyl-2(2H)-pyranones 17 with these last iodides
a crude mixture of 11a and 21a in 53:47 molar ratio was
as the major products (Scheme 7, Table 2).
unexpectedly obtained when this same method was used for
It should be noted that the regioselectivity of iodolacton-
iodolactonization of 10a (Entry 3, Table 1).
ization of 16a was different from that of the analogous reac-
Next, we completed our studies on the preparation of tion involving 16b. In fact, whereas treatment of 16a with
possible precursors to 6-substituted 3-methyl-2(2H)-pyr- iodine and NaHCO3 in CH3CN gave a crude reaction mix-
anones 7 by investigating the synthesis of two stereodefined ture in which 17a and the corresponding stereoisomerically
6-alkenyl-5-iodo-3-methyl-2(2H)-pyranones:
compounds pure regioisomer 23a were in a ca. 92:8 molar ratio (Entry
17a and 17b. Thus, 9a and 9b were treated with 3.0 equiv. 1, Table 2), iodolactonization of 16b by this procedure af-
of tetramethyltin in the presence of 5 mol % PdCl2[P(o-to- forded a mixture of 17b and stereoisomerically pure 23b in
lyl)3]2 and 10 mol % CuI[20] in NMP at 70 °C for 2.5 h to a ca. 80:20 molar ratio (Entry 3, Table 2). Chromatographic
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Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
FULL PAPER
Table 2. Synthesis of 6-substituted 5-iodo-3-methyl-2(2H)-pyranones 17 and the corresponding (E)-5-(1-iodoylidene)-3-methyl-2(5H)-
furanones 23
Entry
Carboxylic
acid
16
Method for iodo
lactonization[a]
Products
17/23 molar ratio[b]
17 ϩ 23
Yield of 17
Yield of 23
1
2
3
16a
16a
16b
A
B
A
17a ϩ 23a
17a
17b ϩ 23b
92.0:8.0
Ͼ 99.0:Ͻ 1.0
80.0:20.0
78
88
59
7[c]
Ϫ
17[d]
[a]
[b]
[c]
Methods A and B were used for iodolactonization of compounds 16. Molar ratio in the crude reaction mixture. 23a underwent
[d]
stereomutation during purification by MPLC on silica gel to give a mixture of (5E)- and (5Z)-23a in a ca. 70:30 molar ratio.
underwent isomerization during the purification by MPLC on silica gel to give a complex mixture of compounds.
23b
purification of the crude reaction mixture deriving from 16a
furnished regio- and stereoisomerically pure 17a and 23a
in 78 and 7% yields, respectively. During this purification,
however, 23a underwent partial stereomutation and the
isolated product proved to consist of a mixture of two ste-
reoisomers in ca. 70:30 molar ratio. On the other hand,
chromatographic purification of the crude reaction mixture
derived from 16b allowed us to isolate regio- and stereoiso-
merically pure 17b and a complex mixture of stereoisomers
of the corresponding 5-[(E)-1-iodoylidene]-3-methyl-2(5H)-
furanone, in which the major component was presumably
23b, in 59 and 17% yields, respectively.
Finally, it is worth mentioning that iodolactonization of
16a with ICl in CH2Cl2 at room temperature for 2 h fur-
nished stereoisomerically pure 17a in 88% isolated yield
with complete regioselectivity (Entry 2, Table 2).
Scheme 8. Synthesis of 5,6-disubstituted 3-bromo-2(2H)-pyranones
13, 5,6-disubstituted 3-methyl-2(2H)-pyranones 8, 6-substituted 3-
bromo-2(2H)-pyranones 12 and 6-substituted 3-methyl-2(2H)-pyr-
anones 7; reagents: a) for 11c: 4-MeOC6H4SnBu3 (24) (1.1 equiv.),
PdCl2(PhCN)2 (5 mol %), CuI (10 mol %), AsPh3 (10 mol %),
NMP, 23 h, 45 °C; b) for 11d: 14c (1.1 equiv.), PdCl2(PPh3)2 (3
mol %), THF, 22 h, 20 °C, then 44 h, 45 °C; c) Me4Sn (3.0 equiv.),
PdCl2[P(o-tolyl)3]2 (5 mol %), CuI (10 mol %), NMP, 80 °C, 22 h;
d) for 11a: Pd(OAc)2 (2 mol %), Et3N (3.0 equiv.), PPh3 (4 mol %),
HCOOH (1.5 equiv.), DMF, 60 °C, 5 h; e) activated zinc dust (5.0
equiv.), THF, 2.5Ϫ13.5 h, then H3Oϩ; f) Me4Sn (3.0 equiv.),
PdCl2[P(o-tolyl)3]2 (5 mol %), CuI (10 mol %), NMP, 80 °C, 22 h
5,6-Disubstituted and 6-Substituted 3-Methyl-2(2H)-
pyranones
Encouraged by the successful outcome of the reaction
sequences affording 6-substituted 3-bromo-5-iodo-2(2H)-
pyranones 11 and 6-substituted 5-iodo-3-methyl-2(2H)-pyr-
anones 17, we first of all decided to investigate the use of
compounds 11 in the selective synthesis of 5,6-disubstituted
On the other hand, the cross-coupling reaction between
3-methyl-2(2H)-pyranones 8. Our attempt to synthesize 13c and 3 equiv. of tetramethyltin in NMP at 80 °C for
these compounds through preparation of 5,6-disubstituted 22 h, in the presence of catalytic amounts of PdCl2[P(o-to-
3-bromo-2(2H)-pyranones 13 by selective Stille-type reac- lyl)3]2 and CuI, gave 8c in 94% yield (Scheme 8). Similarly,
tions involving the dihalogen derivatives 11 was based on treatment of 11d with 1.1 equiv. of 14c in THF, in the pres-
the assumptions that: (i) oxidative addition of compounds ence of 3 mol % PdCl2(PPh3)2, proved to be highly selective
11 to Pd0 would be the selectivity-determining step, and (ii) and furnished 13d in 74% yield. This last compound then
the reactivity for this oxidative addition of the underwent a Pd-catalysed reaction with tetramethyltin to
carbonϪiodine bond at C-5 of 11 would be higher than that give 8d in 83% yield (Scheme 8).
of the carbonϪbromine bond at C-3 of these derivatives.
We next examined the possibility of using compounds 11
Indeed, we were gratified to find that treatment of 11c with as precursors to 6-substituted 3-methyl-2(2H)-pyranones 7.
1.1 equiv. of 4-methoxyphenyltributyltin in NMP at 45 °C In particular, we investigated a reaction sequence involving
for 23 h, in the presence of 5 mol % PdCl2(PhCN)2, 10 the selective reduction of 11 to the corresponding 3-bromo
mol % AsPh3 and 10 mol % CuI,[20] was highly selective and derivatives 12 and the Pd/Cu-catalysed methylation of these
gave the required cross-coupled product 13c in 89% yield compounds. The procedure initially used to reduce 11 was
(Scheme 8).
similar to that that we had recently developed to prepare 6-
Eur. J. Org. Chem. 2002, 1063Ϫ1076
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M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
substituted 2(2H)-pyranones from the corresponding 5- curred during the chromatographic purification of crude
iodo derivatives, and involved the formation of 5-(iodo- 12a. In fact, this compound was isolated in 34% yield as a
zinc)-2(2H)-pyranones.[15] Thus, we found that 11c was se- mixture of 12a and 12b, in which the 12a:12b ratio was
lectively converted into 12c in 74% yield by treatment with 38:62.
a large molar excess of activated zinc dust,[21] followed by
acidic hydrolysis of the obtained organometallic. Com-
pound 12c then underwent a Pd/Cu-catalysed reaction with
tetramethyltin to give 6-butyl-3-methyl-2(2H)-pyranone
(7c) in 91% yield (Scheme 8).
Interestingly, we observed that the reaction between 11a
and activated zinc dust was slower than that for insertion
of activated zinc metal into the carbonϪiodine bond of 11c
Figure 2. Chemical structures of compounds 27 and 28
(13.5 h instead of 2.5 h) and provided a crude reaction
product consisting of stereoisomerically pure 12a and 10a
in a ca. 1:2.5 molar ratio. However, 12a underwent stereo-
mutation during its isolation by MPLC on silica gel. In fact,
chromatographic purification of the crude reaction product
furnished a stereoisomeric mixture of 12b and 12a in a ca.
83:17 molar ratio, in 36% yield.
Despite these unsatisfactory results, however, we at-
tempted to prepare fusalanipyrone (7a) and gibepyrone A
(7b) from a stereoisomeric mixture of 12a and 12b. Thus,
we performed a Pd/Cu-catalysed reaction between tetra-
methyltin and a 46:54 mixture of 12a and 12b (Scheme 8).
This reaction proved to be stereospecific and provided a
A possible explanation for the formation of 10a and the
mixture of 7a and 7b in quantitative yield. Unfortunately,
mixture of 12a and 12b is summarized in Scheme 9.
the chromatographic separation of these compounds was
difficult, and 7a and 7b isolated in this way were in fact
judged by GLC analysis to be only 85% stereoisomerically
pure.
Nevertheless, we succeeded in preparing stereoiso-
merically pure 7a and 7b cleanly in 87 and 81% yields, re-
spectively, by Pd-catalysed triethylammonium formate re-
duction of 17a and 17b, respectively (Scheme 10).
Scheme 9. Possible explanation for the formation of compounds
10a, 12a, and 12b in the reaction between 11a and activated zinc
dust, followed by acidic hydrolysis
Scheme 10. Synthesis of stereoisomerically pure 7a and 7b; re-
agents: a) Pd(OAc)2 (2 mol %), Et3N (3.0 equiv.), PPh3 (4 mol %),
HCOOH (1.5 equiv.), DMF, 55Ϫ60 °C, 2Ϫ3 h
This proposal involves: (i) partial conversion of the or-
ganozinc derivative 25a, which derives from insertion of ac-
1
The H NMR parameters of 7a, with the exception of
the chemical shift of the olefinic proton 6b-H were in agree-
ment with those reported for naturally occurring fusalani-
pyrone.[3a] It should also be noted that, whereas gibepyrone
A was reported to be an oil,[3b] our sample of stereoiso-
merically pure 7b proved to be a colourless solid with m.p.
39Ϫ41 °C.
tivated zinc metal into the carbonϪiodine bond of 11a, into
the iodozinc carboxylate 26a,[22] and (ii) room-temperature
stereomutation of compound 12a, derived from acidic hy-
drolysis of 25a.
A similar explanation could be put forward to explain
the previously observed formation of a mixture of (Z)-5-
phenyl-2-buten-4-ynoic acid and 6-phenyl-2(2H)-pyranone
in the reaction between 5-iodo-6-phenyl-2(2H)-pyranone
and activated zinc dust, followed by acidic hydrolysis.[15]
It should also be noted that we were unsuccessful in pre- Conclusion
paring stereoisomerically pure 12a by Pd-catalysed triethyl-
ammonium formate reduction[23] of 11a (Scheme 8). In fact,
In this study we have demonstrated that: (i) iodolactoniz-
the crude product of this reaction consisted of a mixture ation of carboxylic acids 10 affords mixtures of the required
of 93% stereoisomerically pure 12a and two other major 3-bromo-5-iodo-2(2H)-pyranones 11 and the corresponding
components, which Ϫ on the basis of their MS spectra Ϫ 3-bromo-5-[(E)-1-iodoylidene]-2(5H)-furanones 21, and (ii)
presumably corresponded to the overreduction product 27 the selectivity of this reaction is dependent either on the
and 28 (Figure 2). Moreover, significant stereomutation oc- nature of the substituent present at C-5 of 10 or on the
1068
Eur. J. Org. Chem. 2002, 1063Ϫ1076

Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
FULL PAPER
eronuclear Multiple Quantum Coherence) and HMBC (Heteronu-
clear Multiple Bond Correlation). All reactions of air- and water-
sensitive materials were performed in flame-dried glassware under
argon or nitrogen, by standard syringe, cannula and septa tech-
niques. The following compounds were prepared by published pro-
cedures: Pd(PPh3)4,[24] PdCl2(PhCN)2,[25] methyl (E)-2,3-dibromop-
ropenoate (15),[17] tributyl(1-hexynyl)tin (14c)[18] and tributyl(4-me-
thoxyphenyl)tin (24).[26]
procedure used for iodolactonization (Methods A, B, or C).
We also showed that compounds 11 are useful synthetic in-
termediates. In fact, they proved to be able to undergo se-
lective Stille-type reactions to give, in satisfactory yields,
5,6-disubstituted 3-bromo-2(2H)-pyranones 13, which are
direct precursors to 5,6-disubstituted 3-methyl-2(2H)-pyr-
anones 8.
Compounds 11 could also be selectively reduced to the
corresponding 3-bromo derivatives 12, and these last com-
pounds proved to be useful precursors for 6-substituted 3-
methyl-2(2H)-pyranones 7. However, a serious disadvant-
age of this procedure was that it was not suitable for the
preparation of stereoisomerically pure fusalanipyrone (7a).
(Z)-Trimethyl(3-methyl-3-penten-1-ynyl)silane (20a)
First Procedure: Trimethylsilylacetylene (8.65 g, 88.1 mmol) was ad-
ded dropwise to
a
solution of ethylmagnesium bromide
(88.1 mmol) in THF (100 mL), and the mixture was heated under
reflux for 1 h. The resulting solution was then cooled to 20 °C
In fact, reduction of 11a by Pd-catalysed triethylammonium and slowly added with stirring to a slurry of dry ZnCl2 (15.60 g,
114.5 mmol) in THF (150 mL), cooled to 0 °C. The resulting mix-
ture was maintained at room temperature for 0.5 h. Pd(PPh3)4
(4.07 g, 3.52 mmol) and (Z)-2-bromo-2-butene (18a) (9.55 g,
70.5 mmol) were then added sequentially, and the mixture, which
was periodically monitored by GLC analysis of samples hydrolysed
with aqueous NH4Cl solution, was heated under reflux for 6 d. It
was then cooled to room temperature, poured into a saturated
aqueous NH4Cl solution (300 mL) and extracted with diethyl ether
(4 ϫ 100 mL). The extracts were washed with brine (100 mL),
dried, and concentrated. The residue was diluted with pentane (250
formate or by treatment with a large excess of activated
zinc dust in THF followed by acidic hydrolysis provided a
stereoisomeric mixture of 12a and 12b. Moreover, the chro-
matographic separation of 7a and 7b, prepared by means of
a Pd-catalysed reaction between a mixture of 12a and 12b
and tetramethyltin, proved to be difficult and these natural
products were isolated only in 85% stereoisomerically pure
form.
Nevertheless, we then succeeded in preparing stereoiso-
merically pure 7a in 26% overall yield from (Z)-2-bromo-2- mL), filtered through Celite and concentrated. Fractional distilla-
tion of the residue gave 20a (5.47 g, 51%) as a colourless liquid.
butene (18a) by a seven-step reaction sequence involving the
highly regioselective iodolactonization of carboxylic acid
16a, followed by the Pd-catalysed triethylammonium form-
ate reduction of the obtained compound 17a. An analogous
reaction sequence involving carboxylic acid 16b and the de-
rived iodolactone 17b was then used to synthesize stereoiso-
merically pure 7b in 15% overall yield starting from 18b.
Studies on the use of some of these compounds as inter-
mediates for the synthesis of some natural product hybrids,
B.p. 77Ϫ79 °C/99 mbar. MS: m/z (%) ϭ 152 (28) [Mϩ], 138 (14),
˜
137 (100), 109 (10), 97 (8), 83 (16), 59 (16). IR (film): ν ϭ 2135
cmϪ1, 1340, 1251, 1042, 961, 864, 843, 760, 633. 1H NMR
(600 MHz, CDCl3): δ ϭ 5.76 (m, 1 H, 4-H), 1.82 (m, 3 H, 3a-H),
1.81 (m, 3 H, 5-H), 0.20 (s, 9 H, SiMe3). 13C NMR (150 MHz,
CDCl3): δ ϭ 133.91, 118.78, 104.62, 97.73, 22.75, 16.29, 0.15. An
NOESY experiment showed the presence of a cross-peak between
the resonances of protons 4-H and 3a-H. C9H16Si (152.31): calcd.
C 70.97, H 10.59; found C 71.19, H 10.75. 1H NMR and GLC
which are characterized by two different pharmacophoric analyses showed that 20a had 95% stereoisomeric purity.
subunits and are pharmacologically and/or agrochemically
Second Procedure: A solution of trimethylsilylethynylmagnesium
important, are in progress.
bromide (44.2 mmol) in THF (50 mL), prepared according to the
procedure described above, was added at 0 °C to a slurry of dry
ZnCl2 (7.83 g, 57.5 mmol) in THF (40 mL), and the mixture was
stirred at 20 °C for 0.5 h. Pd(PPh3)4 (2.00 g, 1.77 mmol) and a solu-
Experimental Section
tion of 18a (4.77 g, 35.4 mmol) in DMF (90 mL) were then added
General Remarks: Melting points and boiling points are uncorrec-
sequentially and the resulting mixture was stirred at 60 °C for 24 h.
ted. Precoated Merck 60 F254 aluminium silica gel sheets were used
After this period of time, the reaction was complete, and so it was
for TLC analyses. GLC analyses were performed with a Dani GC
worked up as usual. The crude reaction product was diluted with
1000 instrument with a PTV injector, which was equipped with a
pentane (150 mL) and filtered through Celite. Fractional distilla-
Dani 86.01 data station. Two types of capillary columns were used:
tion of the filtrate gave 20a (3.82 g, 71%) as a colourless liquid. 1H
an Alltech AT-1 bonded FSOT column (30 m ϫ 0.25 mm i.d.) and
NMR and GLC analyses showed that 20a had stereoisomeric pur-
an Alltech AT-35 bonded FSOT column (30 m ϫ 0.25 mm i.d.).
ity higher than 97%.
Purifications by MPLC on silica gel (Merck 60 silica gel, particle
size 0.015Ϫ0.040 mm) were performed with a Büchi B-680 system
(E)-Trimethyl(3-methyl-3-penten-1-ynyl)silane (20b): (E)-2-Bromo-
with a Knauer K-2400 differential refractometer as detector. GLC/ 2-butene (18b, 5.18 g, 38.4 mmol) was converted into 20b (4.32 g,
MS analyses were performed with a Q-mass 910 spectrometer, in- 74%) by the second procedure used for the synthesis of 20a. Inter-
terfaced with a PerkinϪElmer 8500 gas chromatograph or an HP estingly, the Pd-catalysed reaction between 18b and trimethylsilyle-
6890 Plus GC system equipped with a mass-selective detector HP thynylzinc chloride 19 was complete after 3 h at 60 °C. GLC ana-
5973. IR spectra were recorded with a PerkinϪElmer 1725 FT-
IR spectrophotometer. NMR spectra were recorded with a Varian
Gemini 200 MHz spectrometer or a Bruker AMX 600 spectro-
meter, with TMS and CDCl3, respectively, as internal standards.
The structures of compounds 20a, 20b, 11a, 22a, 22b, 7a, and 7b
were assigned by a combination of NMR techniques, which in-
cluded 11H COSY, NOESY (mixing time: 400 ms), HMQC (Het-
lysis showed that 20b, which was obtained as a pale yellow liquid,
was stereoisomerically pure. B.p. 91Ϫ92 °C/100 mbar (ref.[27] b.p.
56 °C/20 mbar). MS: m/z (%) ϭ 152 (23) [Mϩ], 138 (45), 137 (100),
109 (6), 97 (7), 83 (12), 59 (8). IR (film): ν ϭ 2144 cmϪ1, 1250,
˜
1
1220, 1094, 960, 842, 760, 698, 643. H NMR (600 MHz, CDCl3):
δ ϭ 6.00 (qq, J ϭ 7.0, 1.2 Hz, 1 H, 4-H), 1.77 (quint, J ϭ 1.2 Hz,
3 H, 5-H), 1.67 (dq, J ϭ 7.0, 1.2 Hz, 3 H, 3a-H), 0.17 (s, 9 H,
Eur. J. Org. Chem. 2002, 1063Ϫ1076
1069

M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
SiMe3). 13C NMR (150 MHz, CDCl3): δ ϭ 133.91, 118.76, 108.73,
δ ϭ 6.85 (s, 1 H, 3-H), 5.89Ϫ5.69 (m, 1 H, 7-H), 3.86 (s, 3 H,
97.73, 16.77, 14.12, 0.11. The spectral properties of this compound OCH3), 1.89 (br s, 3 H, 6a-H), 1.92Ϫ1.85 (m, 3 H, 8-H).
were in satisfactory agreement with those previously reported.[27]
C10H11BrO2 (243.10): calcd. C 49.40, H 4.56; found C 49.65, H
4.61. GLC and 1H NMR analyses showed that 9a was stereoiso-
merically pure.
(Z)-Tributyl(3-methyl-3-penten-1-ynyl)tin (14a): A flame-dried reac-
tion vessel, maintained under argon, was charged with a deaerated
solution of 20a (5.20 g, 34.1 mmol) in THF (60 mL) and bis(tribu-
tyltin) oxide (9.50 g, 15.9 mmol). A THF solution of TBAF (1 ,
0.68 mL, 0.68 mmol) was added, and the mixture was stirred at 65
°C for 2.5 h, after which the volatiles were removed under reduced
pressure to give 14a (11.77 g, 100%) as an orange liquid. MS: m/z
(%) ϭ 313 (100), 311 (77), 257 (41), 255 (33), 199 (63), 177 (7), 121
(17). 1H NMR (200 MHz, CDCl3): δ ϭ 5.74 (m, 1 H, 4-H),
1.84Ϫ1.80 (m, 6 H, 5-H and 3a-H), 1.63Ϫ1.25 (m, 12 H,
SnϪCH2ϪCH2), 1.00 (t, J ϭ 7.8 Hz, 6 H, SnϪCH2), 0.90 (t, J ϭ
7.1 Hz, 9 H, SnϪCϪCϪCϪCH3). GLC and GLC/MS analyses
showed that 14a had 97% stereoisomeric purity and a chemical
purity higher than 92%. This crude product was used in the next
step without any further purification and characterization.
Methyl (2E,6E)-2-Bromo-6-methylocta-2,6-dien-4-ynoate (9b): The
crude reaction product obtained by the Pd-catalysed reaction be-
tween 15 and 14b (22 h at room temperature) was purified by
MPLC on silica gel, with a mixture of petroleum ether and toluene
(60:40) as eluent, to give 9b (3.68 g, 54%) as a pale yellow liquid.
MS: m/z (%) ϭ 244 (43) [Mϩ], 242 (43) [Mϩ], 163 (100), 131 (81),
120 (39), 103 (80), 91 (51). IR (film): ν ϭ 1724 cmϪ1, 1568, 1435,
˜
1342, 1330, 1221, 1031, 881, 762. 1H NMR (200 MHz, CDCl3):
δ ϭ 6.85 (s, 1 H, 3-H), 6.11 (qq, J ϭ 7.3, 1.5 Hz, 1 H, 7-H), 3.86
(s, 3 H, OCH3), 1.93 (pseudo-quint, J ϭ 1.5 Hz, 3 H, 6a-H), 1.73
(dq, J ϭ 7.3, 1.1 Hz, 3 H, 8-H). C10H11BrO2 (243.10): calcd. C
49.40, H 4.56; found C 49.55, H 4.69. GLC and 1H NMR analyses
showed that 9b was stereoisomerically pure.
Methyl (E)-2-Bromonon-2-en-4-ynoate (9c): The crude reaction
product obtained by the Pd-catalysed reaction between 15 and 14c
(24 h at room temperature) was purified by MPLC on silica gel,
with a mixture of petroleum ether and toluene (70:30) as eluent, to
yield 9c (4.60 g, 67%) as an orange liquid. MS: m/z (%) ϭ 246 (1)
[Mϩ], 244 (1) [Mϩ], 189 (9), 105 (11), 63 (16), 51 (37), 41 (100). IR
(E)-Tributyl(3-methyl-3-penten-1-ynyl)tin (14b): Compound 20b
(4.20 g, 27.6 mmol) was converted into crude 14b (9.50 g, 100%) by
the procedure used to prepare the corresponding stereoisomer.
GLC analysis showed that crude 14b, which was an orange liquid,
was stereoisomerically pure and had a chemical purity higher than
95%. MS: m/z (%) ϭ 313 (100), 311 (77), 257 (43), 255 (34), 199
(71), 197 (51), 121 (14). 1H NMR (200 MHz, CDCl3): δ ϭ 5.93
(qq, J ϭ 7.3, 1.5 Hz, 1 H, 4-H), 1.77 (pseudo-quint, J ϭ 1.1 Hz, 3
H, 3a-H), 1.66 (dq, J ϭ 7.3, 1.1 Hz, 3 H, 5-H), 1.61Ϫ0.90 (m, 27
H, SnBu3). This crude product was used in the next step without
any further purification and characterization.
(film): ν ϭ 2213 cmϪ1, 1727, 1435, 1337, 1223, 1168, 1031, 1010,
˜
1
763. H NMR (200 MHz, CDCl3): δ ϭ 6.66 (t, J ϭ 2.6 Hz, 1 H,
3-H), 3.85 (s, 3 H, OCH3), 2.39 (dt, J ϭ 6.8, 2.6 Hz, 2 H, 6-H),
1.65Ϫ1.39 (m, 4 H, 7-H and 8-H), 0.93 (t, J ϭ 7.2 Hz, 3 H, 9-H).
C10H13BrO2 (245.11): calcd. C 49.00, H 5.34; found C 49.22, H
5.16. GLC and 1H NMR analyses showed that 9c was stereoiso-
merically pure.
General Procedure for the Pd-Catalysed Cross-Coupling Reactions
between 15 and Tributyl(1-ynyl)tin Derivatives of General Formula
14: A flame-dried reaction vessel, flushed with argon, was charged
with PdCl2(PhCN)2 (0.54 g, 1.4 mmol), AsPh3 (0.86 g, 2.8 mmol),
15 (6.83 g, 28.0 mmol), and NMP (25 mL). A deaerated solution
of a tributyl(1-ynyl)tin derivative 14 in NMP (25 mL) was then
added and the mixture was stirred at room temperature until the
reaction was complete (18Ϫ24 h). Reactions involving 14a and 14c
were carried out with a 1:1 molar ratio between the organometallics
and 15, but coupling reactions involving 14b and 14d were per-
formed with 1.10:1 and 1.05:1 molar ratios, respectively, between
the organometallics and 15. After completion of the reaction,
which was periodically monitored by GLC, the reaction mixture
was poured into a saturated aqueous NH4Cl solution (200 mL) and
extracted with diethyl ether (4 ϫ 60 mL). The organic extract was
then stirred for 3 h with aqueous KF (8 , 120 mL) and filtered
through Celite, and the filtrate was extracted with diethyl ether (4
ϫ 50 mL). The organic extract was washed with brine (50 mL),
dried, filtered, and concentrated under reduced pressure, and the
residue was analysed by GLC/MS and TLC. It was then diluted
with the solvent used for TLC analysis (200 mL) and filtered. The
filtrate was concentrated under reduced pressure and the residue
was purified by MPLC on silica gel. Compounds 9aϪd were pre-
pared by this procedure.
Methyl (E)-2-Bromo-5-phenylpent-2-en-4-ynoate (9d): The crude re-
action product obtained from the Pd-catalysed reaction between 15
and 14d (18 h at room temperature) was purified by MPLC on
silica gel, with a mixture of petroleum ether and toluene (60:40) as
eluent, to give 9d (5.12 g, 69%) as an orange liquid. MS: m/z (%) ϭ
266 (21) [Mϩ], 264 (22) [Mϩ], 195 (9), 185 (100), 153 (42), 74 (13),
63 (16). IR (film): ν ϭ 2194 cmϪ1, 1723, 1490, 1435, 1336, 1224,
˜
1
1049, 758, 690. H NMR (200 MHz, CDCl3): δ ϭ 7.51Ϫ7.20 (m,
5 H, Harom.), 6.87 (s, 1 H, 3-H), 3.89 (s, 3 H, OCH3). C12H9BrO2
(265.11): calcd. C 54.37, H 3.42; found C 54.56, H 3.68. GLC and
1H NMR analyses showed that 9d was stereoisomerically pure.
(2E,6Z)-2-Bromo-6-methylocta-2,6-dien-4-ynoic Acid (10a): An
aqueous LiOH solution (1 , 55.5 mL, 55.5 mmol) was added to a
solution of 9a (4.50 g, 18.5 mmol) in THF (115 mL), and the re-
sulting mixture was stirred at room temperature for 24 h. It was
then diluted with water (100 mL) and extracted with diethyl ether
(3 ϫ 50 mL). The aqueous phase was cooled to 0 °C, acidified with
cold 10% H2SO4 and extracted with diethyl ether (3 ϫ 50 mL). The
organic extract was dried and concentrated under reduced pressure
to give crude 10a (3.39 g, 80%) as a pale yellow solid. M.p. 57Ϫ60
°C. 1H NMR (200 MHz, CDCl3): δ ϭ 9.40 (br s, 1 H, COOH),
6.97 (s, 1 H, 3-H), 5.90 (qq, J ϭ 6.0, 1.1 Hz, 1 H, 7-H), 1.87 (br s,
3 H, 6a-H), 1.88Ϫ1.81 (m, 3 H, 8-H). This crude product was used
in the next step without any further purification and characteriza-
tion.
Methyl (2E,6Z)-2-Bromo-6-methylocta-2,6-dien-4-ynoate (9a): The
crude reaction product obtained by the Pd-catalysed reaction be-
tween 15 and 14a (20 h at room temperature) was purified by
MPLC on silica gel, with a mixture of petroleum ether and toluene
(E)-2-Bromonon-2-en-4-ynoic Acid (10c): Compound 9c (4.95 g,
(60:40) as eluent, to give 9a (4.49 g, 66%) as a pale yellow liquid. 20.2 mmol) was converted into crude 10c (4.66 g, 100%) by the
MS: m/z (%) ϭ 244 (42) [Mϩ], 242 (44) [Mϩ], 163 (100), 131 (78), same procedure as employed to prepare 10a. Crude 10c was a col-
1
120 (40), 103 (76), 91 (49). IR (film): ν˜ ϭ 2175 cmϪ1, 1724, 1570, ourless solid. M.p. 56Ϫ60 °C. H NMR (200 MHz, CDCl3): δ ϭ
1435, 1329, 1218, 1037, 882, 762. 1H NMR (200 MHz, CDCl3):
8.55 (br s, 1 H, COOH), 6.79 (t, J ϭ 2.7 Hz, 1 H, 3-H), 2.40 (dt,
1070
Eur. J. Org. Chem. 2002, 1063Ϫ1076

Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
J ϭ 6.8, 2.7 Hz, 2 H, 6-H), 1.63Ϫ1.34 (m, 4 H, 7-H and 8-H), 0.95 3-Bromo-6-[(Z)-2-butenyl]-5-iodo-2(2H)-pyranone (11a): GLC ana-
FULL PAPER
(t, J ϭ 7.0 Hz, 3 H, 9-H). This crude product was used in the next
step without any further purification and characterization.
lysis of the crude reaction mixture obtained by iodolactonization
of 10a by Method A showed the presence of two isomeric com-
pounds in a 97.5:2.5 molar ratio (Entry 1, Table 1). The major
product was subsequently identified as 11a. The structure of 5-
[(5E,7Z)-1-iodo-2-methylbutylidene]-2(5H)-furanone (21a), on the
other hand, was tentatively assigned to the minor product. The
mixture was purified by MPLC on silica gel, with toluene as eluent.
Concentration of the intermediate chromatographic fractions al-
lowed pure 11a (3.87 g, 75%) to be isolated as a colourless solid.
M.p. 102Ϫ104 °C. MS: m/z (%) ϭ 356 (97) [Mϩ], 354 (100) [Mϩ],
(E)-2-Bromo-5-phenylpent-2-en-4-ynoic (10d): Compound 9d
(7.27 g, 27.4 mmol) was converted into crude 10d (5.02 g, 73%) by
the same procedure as used to prepare 10a. Crude 10d was a col-
1
ourless solid. M.p. 87Ϫ90 °C. H NMR (200 MHz, CDCl3): δ ϭ
8.35 (br s, 1 H, COOH), 7.51Ϫ7.25 (m, 5 H, Harom.), 7.02 (s, 1 H,
3-H). This crude product was used in the next step without any
further purification and characterization.
˜
201 (20), 199 (21), 173 (33), 171 (34), 91 (74). IR (KBr): ν ϭ 1718
General Procedures for the Iodolactonization of Carboxylic Acids 10
cmϪ1, 1594, 1530, 1196, 1009, 950, 909, 742, 712. 1H NMR
(200 MHz, CDCl3): δ ϭ 7.88 (s, 1 H, 4-H), 5.70 (qq, J ϭ 7.0,
1.5 Hz, 1 H, 6b-H), 1.93 (pseudo-quint, J ϭ 1.5 Hz, 3 H, 6aЈ-H),
1.64 (dq, J ϭ 7.0, 1.5 Hz, 3 H, 6c-H). 13C NMR (50 MHz, CDCl3):
δ ϭ 162.41, 157.98, 151.84, 130.53, 129.69, 110.56, 67.29, 20.84,
15.72. C9H8BrIO2 (354.97): calcd. C 30.45, H 2.27; found C 30.78,
H 2.45. The MS spectrum of 21a was as follows. MS: m/z (%) ϭ
356 (100) [Mϩ], 354 (100) [Mϩ], 201 (26), 199 (29), 173 (53), 171
(49), 92 (84). Purification of the crude reaction mixtures obtained
by iodolactonization of 10a by Methods B and C provided 11a in
52 and 38% isolated yields, respectively (Entries 2 and 3, Table 1).
GLC analysis showed that the crude reaction mixture obtained in
Entry 3 contained stereoisomerically pure 21a and 11a in a
47.0:53.0 molar ratio. Nevertheless, 21a underwent significant ste-
reomutation during its isolation by MPLC on silica gel, with a
mixture of toluene and petroleum ether (50:50) as eluent. The IR
spectrum of the stereoisomeric mixture derived from 21a was as
Synthesis of 6-Substituted 3-Bromo-5-iodo-2(2H)-pyranones 11 and
the Corresponding 3-Bromo-5-[(E)-1-iodoylidene]-2(5H)-furanones
21: The iodolactonization of carboxylic acids 10 was performed by
three different procedures (Methods AϪC).
Method A: A solution of the carboxylic acid 10 (14.54 mmol) in
CH3CN (40 mL) and iodine (11.07 g, 43.6 mmol) were added se-
quentially to a suspension of NaHCO3 (3.66 g, 43.6 mmol) in
CH3CN (60 mL), and the mixture was stirred in the dark under
nitrogen at room temperature for 1 h, at which point the reaction
was complete by TLC and GLC analyses. The reaction mixture was
then diluted with EtOAc (200 mL) and washed with a 10% aqueous
Na2S2O3 solution (50 mL) and water (50 mL). The organic phase
was dried and concentrated under reduced pressure to give a mix-
ture of a 6-substituted 3-bromo-5-iodo-2(2H)-pyranone 11 and the
corresponding 5-[(E)-1-iodoylidene]-2(5H)-furanone 21. Com-
pounds 11 and 21 were separated by MPLC on silica gel. In all
cases examined, the more rapidly eluting regioisomers were com-
pounds 21. This procedure was employed for iodolactonization of
10a, 10c, and 10d. Table 1 summarizes the 11/21 molar ratio found
in the crude reaction mixtures obtained from these reactions and
the isolated yields of compounds 11a, 11c, 11d, 21c, and 21d pre-
pared by this procedure (Entries 1, 4, and 7). It must be noted that
compound 21c underwent partial stereomutation during its isola-
tion.
follows. IR (film): ν ϭ 1777 cmϪ1, 1623, 1552, 1246, 1110, 969,
˜
848, 749, 728. C9H8BrIO2 (354.97): calcd. C 30.45, H 2.27; found
C 30.65, H 2.38.
3-Bromo-6-butyl-5-iodo-2(2H)-pyranone (11c) and 3-Bromo-5-[(E)-
1-iodopentylidene]-2(5H)-furanone (21c): GLC analysis of the crude
reaction mixture obtained by iodolactonization of 10c by Method
A showed the presence of two compounds in a 40.0:60.0 molar
ratio (Entry 4, Table 1). This mixture was purified by MPLC on
silica gel, with a mixture of petroleum ether and toluene (70:30) as
eluent. Concentration of the first eluted chromatographic fractions
allowed 21c (2.59 g, 50%) to be isolated as an orange liquid. MS:
m/z (%) ϭ 358 (1) [Mϩ], 356 (3) [Mϩ], 285 (2), 173 (3), 119 (3), 43
Method B: This procedure was used for iodolactonization of 10a,
10c, and 10d (Entries 2, 5, and 8, Table 1). A solution of ICl
(177 mg, 1.1 mmol) in CH2Cl2 (2 mL) was added to a deaerated
solution of a carboxylic acid 10 (1.1 mmol) in CH2Cl2 (5 mL), and
the mixture was stirred in the dark at 0 °C for 1 h. It was then
poured into an aqueous NaHCO3 solution (10%, 15 mL) and ex-
tracted with EtOAc (3 ϫ 10 mL). The organic extract was washed
with a 10% aqueous Na2S2O3 solution (10 mL) and water (15 mL),
dried, and analysed by GLC, with biphenyl as an internal standard.
Compounds 11a, 11d, and 21d were isolated by chromatographic
purification of the crude reaction mixtures derived from 10a and
10d, respectively, according to this procedure (Entries 2 and 8,
Table 1). However, no attempt was made to isolate the iodolacton-
ization products derived from 10c (Entry 5, Table 1).
(37), 41 (100). IR (film): ν ϭ 1782 cmϪ1, 1556, 1464, 1113, 1072,
˜
980, 906, 870, 749. 1H NMR (600 MHz, CDCl3): δ ϭ 7.76 (s, 1 H,
4-H), 2.78 (t, J ϭ 7.3 Hz, 2 H, 7-H), 1.55 (m, 2 H, 8-H), 1.34 (sext,
J ϭ 7.4 Hz, 2 H, 9-H), 0.93 (t, J ϭ 7.4 Hz, 3 H, 10-H). 13C NMR
(150 MHz, CDCl3): δ ϭ 165.33, 148.27, 142.91, 115.75, 96.46,
37.60, 31.26, 21.36, 13.76. NMR analysis showed that 21c was con-
taminated by ca. 30% of the corresponding (Z) stereoisomer. The
NMR parameters of the (Z) stereoisomer were as follows. 1H NMR
(600 MHz, CDCl3): δ ϭ 7.71 (s, 1 H, 4-H), 2.67 (t, J ϭ 7.3 Hz, 2
H, 7-H), 1.59 (m, 2 H, 8-H), 1.35 (m, 2 H, 9-H), 0.93 (m, 3 H, 10-
H). 13C NMR (150 MHz, CDCl3): δ ϭ 164.48, 150.05, 135.29,
114.42, 94.82, 37.90, 32.05, 21.58, 13.78. A NOESY experiment
showed the presence of a cross-peak between the resonances of the
4-H and 7-H protons and those of the 4-H and 8-H protons. These
Method C: N-Iodosuccinimide (246 mg, 1.2 mmol) was added to
stirred mixture of a carboxylic acid 10 (1.1 mmol) and KHCO3
(108 mg, 1.1 mmol) in CH3CN (5 mL), and the mixture was stirred cross-peaks were not observed for 21c. C9H10BrIO2 (356.98): calcd.
in the dark at room temperature for 1 h. It was then poured into C 30.28, H 2.82; found C 30.35, H 3.04. On the other hand, concen-
an aqueous Na2S2O3 solution (10%, 15 mL) and extracted with
tration of the last eluted chromatographic fractions allowed pure
EtOAc (3 ϫ 8 mL). The organic extract was washed with water (5
11c (1.56 g, 30%) to be isolated as an orange solid. M.p. 42Ϫ44 °C.
mL), dried, and analysed by GLC, with biphenyl as an internal MS: m/z (%) ϭ 358(3) [Mϩ], 356 (2) [Mϩ], 189 (13), 187 (18), 55
(19), 53 (38), 41 (100). IR (KBr): ν ϭ 1719 cmϪ1, 1599, 1527, 1294,
˜
standard. This method for used for iodolactonization of 10a, 10c
and 10d (Entries 3, 6, 9, Table 1). However, no attempt was made
to isolate the products of iodolactonization of 10c and 10d.
1
1087, 1016, 967, 802, 743. H NMR (600 MHz, CDCl3): δ ϭ 7.81
(s, 1 H, 4-H), 2.71 (t, J ϭ 7.7 Hz, 2 H, 6a-H), 1.66 (m, 2 H, 6b-
Eur. J. Org. Chem. 2002, 1063Ϫ1076
1071

M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
H), 1.40 (sext, J ϭ 7.4 Hz, 2 H, 6c-H), 0.95 (t, J ϭ 7.4 Hz, 3 H, 14.22. C11H14O2 (178.23): calcd. C 74.13, H 7.92; found C 74.27,
6d-H). 13C NMR (150 MHz, CDCl3): δ ϭ 165.28, 158.14, 151.99,
109.47, 66.41, 35.98, 29.04, 22.17, 13.70. C9H10BrIO2 (356.98):
calcd. C 30.28, H 2.82; found C 30.45, H 2.99.
H 8.06.
(2Z,6Z)-2,6-Dimethylocta-2,6-dien-4-ynoic Acid (16a): By the same
procedure as was used to prepare 10a from 9a, saponification of
22a (1.54 g, 8.6 mmol) followed by acidification gave crude 16a
(1.41 g, 100%) as a pale yellow solid. M.p. 36 °C. 1H NMR
(200 MHz, CDCl3): δ ϭ 10.61 (br s, 1 H, COOH), 6.25 (q, J ϭ
1.5 Hz, 1 H, 3-H), 5.87Ϫ5.75 (m, 1 H, 7-H), 2.02 (d, J ϭ 1.5 Hz,
3 H, 2Ј-H), 1.85 (br s, 3 H, 6Ј-H), 1.85Ϫ1.78 (m, 3 H, 8-H). This
crude product was used in the next step without any further puri-
fication and characterization.
3-Bromo-5-iodo-6-phenyl-2(2H)-pyranone (11d) and 3-Bromo-5-[(E)-
1-iodobenzylidene]-2(5H)-furanone (21d): GLC analysis of the crude
reaction mixture obtained by iodolactonization of 11d by Method
A (Entry 7, Table 1) showed the presence of two compounds in a
49.0:51.0 molar ratio. This mixture was purified by MPLC on silica
gel, with toluene as eluent. Concentration of the first eluted chro-
matographic fractions allowed 21d (2.36 g, 43%) to be isolated as
an orange solid. M.p. 108Ϫ111 °C. MS: m/z (%) ϭ 378 (64) [Mϩ],
376 (66) [Mϩ], 251 (85), 249 (87), 196 (98), 193 (100), 142 (40), 114
(2Z,6E)-2,6-Dimethylocta-2,6-dien-4-ynoic Acid (16b): By the same
procedure as was used to prepare 10a from 9b, saponification of
22b (1.48 g, 8.3 mmol) followed by acidification gave crude 16b
(1.25 g, 92%) as a pale yellow solid. M.p. 70 °C. 1H NMR
(200 MHz, CDCl3): δ ϭ 8.73 (br s, 1 H, COOH), 6.22 (q, J ϭ
1.4 Hz, 1 H, 3-H), 6.04 (qq, J ϭ 7.0, 1.4 Hz, 1 H, 7-H), 2.03 (d,
J ϭ 1.4 Hz, 3 H, 2Ј-H), 1.82 (pseudo-quint, J ϭ 1.4 Hz, 3 H, 6Ј-
H), 1.75Ϫ1.70 (m, 3 H, 8-H). This crude product was used in the
next step without any further purification and characterization.
(57), 89 (91). IR (KBr): ν ϭ 1784 cmϪ1, 1772, 1441, 1108, 984, 942,
˜
1
866, 762, 722. H NMR (200 MHz, CDCl3): δ ϭ 8.00 (s, 1 H, 4-
H), 7.66Ϫ7.34 (m, 5 H, Harom.). 13C NMR (50 MHz, CDCl3): δ ϭ
165.70, 147.68, 144.39, 136.84, 130.79, 130.04, 128.33, 115.85,
89.65. C11H6BrO2 (376.97): calcd. C 35.04, H 1.60; found C 35.39,
H 1.97. Concentration of the last eluted chromatographic fractions
allowed 11d (2.19 g, 40%) to be isolated as a pale yellow solid. M.p.
117Ϫ119 °C. MS: m/z (%) ϭ 378 (49) [Mϩ], 376 (51) [Mϩ], 350
(27), 348 (28), 241 (18), 195 (40), 193 (41), 105 (100), 77 (95). IR
6-[(Z)-2-Butenyl]-5-iodo-3-methyl-2(2H)-pyranone (17a) and 5-[(5Z/
E,7Z)-1-Iodo-2-methylbutylidene]-3-methyl-2(5H)-furanone
(KBr): ν ϭ 1727 cmϪ1, 1601, 1198, 1050, 981, 906, 769, 744, 706.
[(5Z/
˜
1H NMR (200 MHz, CDCl3): δ ϭ 8.02 (s, 1 H, 4-H), 7.76Ϫ7.71
(m, 2 H, Harom.), 7.51Ϫ7.45 (m, 3 H, Harom.). 13C NMR (50 MHz,
CDCl3): δ ϭ 160.12, 157.50, 153.14, 132.49, 131.07, 129.16, 128.28,
110.70, 65.27. C11H6BrO2 (376.97): calcd. C 35.04, H 1.60; found
C 35.38, H 1.87.
E)-23a]: GLC analysis of the crude reaction mixture obtained by
iodolactonization of 16a (1.05 g, 6.4 mmol) by the procedure used
to prepare 11a and 21a from 10a (Method A) showed the presence
of two compounds in a 92.0:8.0 molar ratio (Entry 1, Table 2).
During the purification of this mixture by MPLC on silica gel, with
toluene as eluent, the minor component of this mixture underwent
partial isomerization to give a mixture of two compounds in a ca.
70:30 molar ratio. The structures (5E)-23a and (5Z)-23a were tent-
atively assigned to these compounds. Concentration of the first
eluted chromatographic fractions allowed this mixture of stereoiso-
mers (0.13 g, 7%) to be obtained as a red solid. M.p. 30 °C. The
MS and 1H NMR parameters of the minor component of this mix-
ture were as follows. MS: m/z (%) ϭ 290 (100) [Mϩ], 262 (79), 247
(15), 163 (21), 135 (30), 107 (25), 91 (62). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.33 (q, J ϭ 1.4 Hz, 1 H, 4-H), 5.50 (dq, J ϭ 7.0,
1.4 Hz, 1 H, 8-H), 1.98 (d, J ϭ 1.4 Hz, 3 H, 3a-H), 1.84 (pseudo-
quint, J ϭ 1.4 Hz, 3 H, 7a-H), 1.71 (dq, J ϭ 7.0, 1.4 Hz, 3 H, 9-
Methyl (2Z,6Z)-2,6-Dimethylocta-2,6-dien-4-ynoate (22a): A flame-
dried reaction vessel was charged with PdCl2[P(o-tolyl)3]2 (524 mg,
0.7 mmol) and CuI (253 mg, 1.3 mmol) and flushed with argon. A
deaerated solution of 9a (3.23 g, 13.3 mmol) in dry NMP (60 mL)
and deaerated tetramethyltin (7.13 g, 39.8 mmol) were then added
sequentially, and the mixture was stirred at 70 °C for 2.5 h. After
this period of time, the reaction was complete. The mixture was
cooled to room temperature, poured into a saturated aqueous
NH4Cl solution (200 mL) and extracted with EtOAc (4 ϫ 50 mL).
The organic extract was washed with brine (2 ϫ 30 mL), dried, and
concentrated under reduced pressure. The residue was purified by
MPLC on silica gel, with a mixture of petroleum ether and toluene
(70:30) as eluent, to give chemically and stereoisomerically pure
22a (1.75 g, 74%) as a pale yellow liquid. MS: m/z (%) ϭ178 (79)
[Mϩ], 146 (45), 135 (48), 117 (54), 107 (58), 91 (100), 77 (55). IR
1
H). The MS and H NMR parameters of the major component of
this mixture were as follows. MS: m/z (%) ϭ 290 (100) [Mϩ], 262
(72), 247 (13), 163 (19), 135 (29), 107 (25), 91 (62). 1H NMR
(200 MHz, CDCl3): δ ϭ 6.95 (q, J ϭ 1.4 Hz, 1 H, 4-H), 5.57 (dq,
J ϭ 7.0, 1.4 Hz, 1 H, 8-H), 1.90 (d, J ϭ 1.4 Hz, 3 H, 3a-H), 1.86
(pseudo-quint, J ϭ 1.4 Hz, 3 H, 7a-H), 1.47 (dq, J ϭ 7.0, 1.4 Hz,
(KBr): ν ϭ 2179 cmϪ1, 1709, 1605, 1434, 1343, 1224, 1134, 1069,
˜
1
771. H NMR (200 MHz, CDCl3): δ ϭ 6.16 (q, J ϭ 1.8 Hz, 1 H,
3-H), 5.86Ϫ5.75 (m, 1 H, 7-H), 3.78 (s, 3 H, OCH3), 2.02 (d, J ϭ
1.8 Hz, 3 H, 2Ј-H), 1.91Ϫ1.84 (m, 6 H, 6Ј-H and 8-H). 13C NMR
(50 MHz, CDCl3): δ ϭ 166.66, 136.23, 134.10, 118.74, 117.93,
97.10, 90.56, 51.49, 22.61, 19.96, 16.27. C11H14O2 (178.23): calcd.
C 74.13, H 7.92; found C 74.15, H 7.98.
3 H, 9-H). The IR parameters of the stereoisomeric mixture of
Ϫ1
˜
(5E)-23a and (5Z)-23a were as follows. IR (film): ν ϭ 1769 cm
,
1629, 1447, 1376, 1048, 1001, 943, 850, 753. C10H11IO2 (290.10):
calcd. C 41.40, H 3.82; found C 41.65, H 3.95. Concentration of
the last eluted chromatographic fractions allowed 17a (1.44 g, 78%)
to be isolated as a colourless solid. M.p. 41Ϫ43 °C. MS: m/z (%) ϭ
290 (100) [Mϩ], 262 (32), 247 (17), 179 (11), 135 (20), 107 (35), 91
Methyl (2Z,6E)-2,6-Dimethylocta-2,6-dien-4-ynoate (22b): Com-
pound 9b (2.70 g, 11.1 mmol) was converted into pure 22b (1.66 g,
84%) by the same procedure as used to prepare 22a from 9a. Com-
pound 22b, which was a pale yellow liquid, had the following spec-
(31). IR (KBr): ν ϭ 1709 cmϪ1, 1614, 1559, 1165, 1056, 971, 899,
˜
833, 752. 1H NMR (200 MHz, CDCl3): δ ϭ 7.33 (q, J ϭ 1.5 Hz, 1
H, 4-H), 5.64 (qq, J ϭ 7.0, 1.5 Hz, 1 H, 6b-H), 2.08 (d, J ϭ 1.5 Hz,
3 H, 3a-H), 1.91 (pseudo-quint, J ϭ 1.5 Hz, 3 H, 6aЈ-H), 1.61 (dq,
J ϭ 7.0, 1.5 Hz, 3 H, 6c-H). 13C NMR (50 MHz, CDCl3): δ ϭ
162.54, 160.18, 147.24, 130.40, 129.45, 125.19, 68.64, 20.92, 16.24,
15.48. C10H11IO2 (290.10): calcd. C 41.40, H 3.82; found C 41.59,
H 4.01.
tral properties. MS: m/z (%) ϭ178 (68) [Mϩ], 146 (39), 135 (44),
Ϫ1
˜
117 (51), 107 (54), 91 (100), 77 (57). IR (KBr): ν ϭ 2184 cm
,
1709, 1603, 1434, 1250, 1224, 1134, 836, 770. 1H NMR (200 MHz,
CDCl3): δ ϭ 6.04 (q, J ϭ 1.4 Hz, 1 H, 3-H), 5.98 (qq, J ϭ 7.0,
1.4 Hz, 1 H, 7-H), 3.74 (s, 3 H, OCH3), 1.95 (d, J ϭ 1.4 Hz, 3 H,
2Ј-H), 1.78 (pseudo-quint, J ϭ 1.2 Hz, 3 H, 6Ј-H), 1.68 (dq, J ϭ
7.0, 1.4 Hz, 3 H, 8-H). 13C NMR (50 MHz, CDCl3): δ ϭ 166.67,
6-[(E)-2-Butenyl]-5-iodo-3-methyl-2(2H)-pyranone (17b) and 5-
136.08, 134.28, 118.71, 118.33, 101.21, 83.63, 51.46, 19.85, 16.57, [(5E,7E)-1-Iodo-2-methylbutylidene]-3-methyl-2(5H)-furanone
1072 Eur. J. Org. Chem. 2002, 1063Ϫ1076

Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
FULL PAPER
(23b): GLC analysis of the crude reaction mixture obtained by
iodolactonization of 16b (1.14 g, 6.9 mmol) by Method A (Entry 3,
Table 2) showed the presence of two compounds in a ca. 80:20
NMR (200 MHz, CDCl3): δ ϭ 7.14 (d, J ϭ 8.9 Hz, 2 H, Harom.),
7.10 (q, J ϭ 1.1 Hz, 1 H, 4-H), 6.93 (d, J ϭ 8.9 Hz, 2 H, Harom.),
3.84 (s, 3 H, OCH3), 2.47 (t, J ϭ 7.7 Hz, 2 H, 6a-H), 2.10 (d, J ϭ
molar ratio. During the purification of this mixture by MPLC on 1.1 Hz, 3 H, 3a-H), 1.72Ϫ1.57 (m, 2 H, 6b-H), 1.27 (sext, J ϭ
silica gel, with toluene as eluent, the minor component of this mix-
7.4 Hz, 2 H, 6c-H), 0.84 (t, J ϭ 7.4 Hz, 3 H, 6d-H). 13C NMR
ture underwent partial stereomutation to give a complex mixture of (50 MHz, CDCl3): δ ϭ 163.75, 159.76, 158.95, 143.30, 129.82,
compounds. We tentatively assigned the structure 23b to the major
component of this stereoisomeric mixture. Concentration of the
first eluted chromatographic fractions allowed this mixture of ste-
reoisomers (0.34 g, 17%) to be obtained as a yellow liquid. IR
128.32, 121.97, 117.39, 113.94, 55.20, 30.74, 29.80, 22.21, 16.64,
16.32 Ϫ C17H20O3 (272.34): calcd. C 74.97, H 7.40; found C 75.01,
H 7.38.
3-Bromo-5-(1-hexynyl)-6-phenyl-2(2H)-pyranone (13d):
A flame-
(film): ν ϭ 1768 cmϪ1, 1627, 1611, 1438, 1046, 992, 922, 795, 753.
˜
dried reaction vessel, flushed with argon, was charged with
PdCl2(PPh3)2 (50.0 mg, 0.07 mmol), 11d (0.90 g, 2.84 mmol) and
THF (10 mL). A deaerated solution of 14c (1.10 g, 2.9 mmol) in
THF (10 mL) was then added, and the mixture was stirred for 22 h
at room temperature and for 44 h at 45 °C. After this period of
time, GLC analysis showed that 11d had reacted completely. The
reaction mixture was then cooled to 20 °C, poured into a saturated
aqueous NH4Cl solution (100 mL), and extracted with diethyl ether
(4 ϫ 50 mL). The organic extract was then stirred for 3 h with an
aqueous KF solution (8 , 80 mL) and filtered through Celite, and
the filtrate was extracted with diethyl ether (4 ϫ 50 mL). The or-
ganic extract was washed with brine (50 mL), dried, filtered, and
concentrated under reduced pressure, and the residue was purified
by MPLC on silica gel, with a mixture of CH2Cl2 and petroleum
ether (50:50) as eluent, to give 13d (0.58 g,74%) as a yellow solid.
M.p. 68Ϫ70 °C. MS, m/z (%) ϭ 332 (33) [Mϩ], 330 (34) [Mϩ], 290
The MS and 1H NMR parameters of the major component of this
mixture were as follows. MS: m/z (%) ϭ 290 (100) [Mϩ], 262 (71),
1
163 (19), 135 (27), 107 (24), 91 (42), 67 (39). H NMR (200 MHz,
CDCl3): δ ϭ 7.20 (q, J ϭ 1.4 Hz, 1 H, 4-H), 5.67 (qq, J ϭ 7.0,
1.4 Hz, 1 H, 5c-H), 1.95 (d, J ϭ 1.4 Hz, 3 H, 3a-H), 1.87 (pseudo-
quint, J ϭ 1.4 Hz, 3 H, 7a-H), 1.76 (dq, J ϭ 7.0, 1.2 Hz, 3 H, 9-
H). C10H11IO2 (290.10): calcd. C 41.40, H 3.82; found C 41.60, H
4.02. Concentration of the last eluted chromatographic fractions
allowed 17b (1.19 g, 59%) to be isolated as a pale yellow liquid.
MS: m/z (%) ϭ 290 (100) [Mϩ], 262 (31), 135 (25), 107 (49), 91
(44). 83 (27), 55 (55) Ϫ IR (film): ν˜ ϭ 1720 cmϪ1, 1613, 1551, 1444,
1218, 1169, 1049, 969, 754. 1H NMR (200 MHz, CDCl3): δ ϭ 7.37
(q, J ϭ 1.3 Hz, 1 H, 4-H), 6.04 (qq, J ϭ 6.9, 1.5 Hz, 1 H, 6b-H),
2.07 (d, J ϭ 1.0 Hz, 3 H, 3a-H), 1.91 (pseudo-quint, J ϭ 1.0 Hz, 3
H, 6aЈ-H), 1.79 (dq, J ϭ 6.9, 1.0 Hz, 3 H, 6c-H). 13C NMR
(50 MHz, CDCl3): δ ϭ 162.28, 161.53, 148.52, 133.14, 130.02,
124.55, 65.69, 16.10, 14.22, 13.69. C10H11IO2 (290.10): calcd. C
41.40, H 3.82; found C 41.62, H 4.03.
˜
(25), 288 (24), 152 (49), 105 (84), 77 (100). IR (KBr): ν ϭ 2229
cmϪ1, 1736, 1607, 1442, 1325, 1180, 920, 907, 688. 1H NMR
(200 MHz, CDCl3): δ ϭ 8.16Ϫ8.11 (m, 2 H, Harom.), 7.76 (s, 1 H,
4-H), 7.49Ϫ7.38 (m, 3 H, Harom.), 2.41 (t, J ϭ 6.7 Hz, 2 H, 5c-H),
1.69Ϫ1.25 (m, 4 H, 5d-H and 5e-H), 0.94 (t, J ϭ 7.0 Hz, 3 H, 5f-
H). C17H15BrO2 (331.21): calcd. C 61.65, H 4.56; found C 61.78,
H 4.76.
3-Bromo-6-butyl-5-(4-methoxyphenyl)-2(2H)-pyranone (13c):
A
flame-dried reaction vessel, flushed with argon, was charged with
PdCl2(PhCN)2 (37.6 mg, 0.1 mmol), AsPh3 (60.0 mg, 0.2 mmol),
CuI (37.3 mg, 0.2 mmol), compound 11c (0.70 g, 2.0 mmol), and
deaerated NMP (5 mL). A deaerated solution of 24 (0.86 g,
2.2 mmol) in NMP (15 mL) was then added, and the mixture was
stirred at 45 °C for 23 h. It was then cooled to 20 °C, poured into
a saturated aqueous NH4Cl solution (100 mL) and extracted with
EtOAc (4 ϫ 30 mL). The organic extract was stirred for 4 h at 20
°C with an aqueous KF solution (8 , 200 mL) and the reaction
mixture was filtered through Celite. The filtrate was extracted with
EtOAc (4 ϫ 30 mL) and the organic extract was dried, filtered,
and concentrated under reduced pressure. The residue was purified
by MPLC on silica gel, with benzene as eluent, to give 13c (0.59 g,
89%) as a pale yellow liquid. MS, m/z (%) ϭ 338 (41) [Mϩ], 336
(49) [Mϩ], 280 (65), 278 (64), 115 (44), 57 (79), 41 (100). IR (film):
5-(1-Hexynyl)-3-methyl-6-phenyl-2(2H)-pyranone (8d): Compound
13d (0.46 g, 1.4 mmol) was treated with tetramethyltin (0.74 g,
4.3 mmol) in NMP (20 mL) in the presence of PdCl2[P(o-tolyl)3]2
(54 mg, 0.07 mmol) and CuI (26 mg, 0.14 mmol) at 80 °C for 20 h,
by the same procedure as used to prepare 22a from 9a. After the
usual workup, the crude reaction product was purified by MPLC
on silica gel, with benzene as eluent, to give 8d (0.30 g, 83%) as a
yellow solid. M.p. 50Ϫ52 °C. MS: m/z (%) ϭ 266 (100) [Mϩ], 224
˜
(62), 223 (63), 165 (36), 152 (28), 105 (64), 77 (66). IR (KBr): ν ϭ
1
1723 cmϪ1, 1546, 1180, 1056, 1000, 914, 775, 754, 695. H NMR
(200 MHz, CDCl3): δ ϭ 8.15Ϫ8.11 (m, 2 H, Harom.), 7.44Ϫ7.37 (m,
3 H, Harom.), 7.18 (q, J ϭ 1.0 Hz, 1 H, 4-H), 2.39 (t, J ϭ 7.0 Hz,
2 H, 5c-H), 2.11 (d, J ϭ 1.0 Hz, 3 H, 3a-H), 1.63Ϫ1.34 (m, 4 H,
5d-H and 5e-H), 0.93 (t, J ϭ 7.0 Hz, 3 H, 5f-H). 13C NMR
(50 MHz, CDCl3): δ ϭ 161.89, 159.24, 144.08, 131.62, 130.18,
127.97, 127.58, 123.11, 100.54, 95.85, 75.55, 30.30, 21.96, 19.25,
16.20, 13.52. C18H18O2 (266.34): calcd. C 45.10, H 6.81; found C
45.24, H 6.89.
1
ν˜ ϭ 1737 cmϪ1, 1628, 1513, 1281, 1249, 1179, 1035, 967, 835. H
NMR (200 MHz, CDCl3): δ ϭ 7.66 (s, 1 H, 4-H), 7.17 (d, J ϭ
8.8 Hz, 2 H, Harom.), 6.95 (d, J ϭ 8.8 Hz, 2 H, Harom.), 3.85 (s, 3
H, OCH3), 2.48 (t, J ϭ 7.7 Hz, 2 H, 6a-H), 1.72Ϫ1.57 (m, 2 H,
6b-H), 1.28 (sext, J ϭ 7.3 Hz, 2 H, 6c-H), 0.82 (t, J ϭ 7.3 Hz, 3
H, 6d-H). C16H17BrO3 (337.21): calcd. C 56.99, H 5.08; found C
57.12, H 5.16.
General Procedure for the Synthesis of 6-Substituted 3-Bromo-
6-Butyl-5-(4-methoxyphenyl)-3-methyl-2(2H)-pyranone (8c): Com-
2(2H)-pyranones 12: A mixture of zinc dust (Aldrich, 325 mesh,
pound 13c (0.50 g, 1.5 mmol) was treated with tetramethyltin 1.25 g, 19.1 mmol) and THF (30 mL) containing 1,2-dibromoe-
(0.79 g, 4.4 mmol) in NMP (20 mL) in the presence of PdCl2[P(o- thane (35 µL, 0.4 mmol) was stirred under argon at 65 °C for 1 min
tolyl)3]2 (58.8 mg, 0.07 mmol) and CuI (28.1 mg, 0.15 mmol) at 80 and was then allowed to cool to 20 °C. Chlorotrimethylsilane (44
°C for 22 h, by the same procedure as employed to prepare 22a
from 9a. After the usual workup, the crude reaction product was
purified by MPLC on silica gel, with benzene as eluent, to give 8c
µL, 0.34 mmol) was added, and after this had stirred at 20 °C for
20 min, a solution of a compound 11 (3.81 mmol) in THF (10 mL)
was added dropwise. The mixture was stirred at 20 °C until GLC
(0.38 g, 94%) as a pale yellow liquid. MS, m/z (%) ϭ 272 (52) [Mϩ], analysis of a sample of the reaction mixture, hydrolysed with di-
230 (7), 215 (100), 201 (32), 188 (13), 159 (38), 115 (17). IR (film): luted H2SO4, showed that compound 11 had been completely con-
ν ϭ 1719 cmϪ1, 1514, 1464, 1287, 1248, 1176, 981, 836, 763. 1H sumed (2.5Ϫ13.5 h). The reaction mixture was then allowed to
˜
Eur. J. Org. Chem. 2002, 1063Ϫ1076
1073

M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R. Rossi
FULL PAPER
settle. The clear solution of the obtained organozinc compound
ticular, crude 12a proved to be contaminated with ca. 7% of 12b.
was transferred by syringe to a new reaction flask, hydrolysed at 0 The dried organic extract was concentrated under reduced pressure
°C with 10% H2SO4 and extracted with diethyl ether (4 ϫ 15 mL).
and the residue was purified by MPLC on silica gel, with benzene
The dried organic extract was concentrated under reduced pressure as eluent, to give a mixture of 12a and 12b (0.11 g, 34%) as a col-
and the residue, which was analysed by GLC or 1H NMR spectro-
ourless solid. M.p. 75Ϫ90 °C. GLC analysis showed that 12a and
scopy, was purified by MPLC on silica gel. This procedure was 12b were in a 38:62 molar ratio. The spectral properties of this
used to prepare a stereoisomeric mixture of 12a and 12b as well as
compound 12c.
stereoisomeric mixture were in agreement with those of the mixture
of 12a and 12b prepared by insertion of activated zinc metal into
the carbonϪiodine bond of 11a, followed by acidic hydrolysis.
3-Bromo-6-[(Z/E)-2-butenyl]-2(2H)-pyranone (12a؉b): 1H NMR
analysis of the crude reaction product obtained from 11a by the
general procedure described above showed that it consisted of 10a
and a mixture of two compounds, which were subsequently identi-
fied as 12a and 12b. Compound 10a was the major component.
Purification of this crude reaction product by MPLC on silica gel,
with benzene as eluent, allowed a mixture of 12a and 12b (0.31 g,
36%) to be isolated as a colourless solid. GLC analysis showed that
12b and 12a were in a ca. 83:17 molar ratio. The configurations of
these compounds were established on the basis of those of com-
pounds 7b and 7a, subsequently obtained through a stereospecific
6-Butyl-3-methyl-2(2H)-pyranone (7c): Compound 12c (0.85 g,
3.7 mmol) was treated with tetramethyltin (1.97 g, 11.0 mmol) in
the presence of PdCl2[P(o-tolyl)3]2 (0.144 g, 0.2 mmol) and CuI
(70 mg, 0.4 mmol) in NMP (10 mL) at 80 °C for 22 h, by the same
procedure as employed to prepare 22a from 9a. After the usual
workup, the crude reaction product was purified by MPLC on silica
gel, with benzene as eluent, to give 7c (0.56 g, 91%) as a pale yellow
liquid. MS: m/z (%) ϭ 166 (50) [Mϩ], 138 (30), 124 (12), 109 (22),
95 (100), 82 (20), 53 (41). IR (film): ν ϭ 1719 cmϪ1, 1645, 1585,
˜
1433, 1114, 1090, 1044, 815, 762. 1H NMR (200 MHz, CDCl3):
δ ϭ 7.06 (dq, J ϭ 6.6, 1.6 Hz, 1 H, 4-H), 5.90 (d, J ϭ 6.6 Hz, 1 H,
5-H), 2.47 (t, J ϭ 7.5 Hz, 3 H, 6a-H), 2.07 (s, 3 H, 3a-H), 1.72Ϫ1.56
(m, 2 H, 6b-H), 1.46Ϫ1.26 (m, 2 H, 6c-H), 0.93 (t, J ϭ 7.2 Hz, 3
H, 6d-H). 13C NMR (50 MHz, CDCl3): δ ϭ 166.24, 163.61, 139.72,
122.29, 102.62, 33.18, 29.06, 22.08, 16.56, 13.73. C10H14O2
(166.22): calcd. C 72.26, H 8.49; found C 72.45, H 8.61.
Pd-catalysed reaction between a stereoisomeric mixture of 12a and
Ϫ1
˜
,
12b and tetramethyltin. M.p. 75Ϫ90 °C. IR (film): ν ϭ 1714 cm
1637, 1603, 1524, 1341, 1112, 961, 809, 751. The MS and 1H NMR
parameters of 12a were as follows. MS: m/z (%) ϭ 230 (64) [Mϩ],
228 (65) [Mϩ], 202 (35), 200 (36), 121 (38), 93 (100), 77 (56). 1H
NMR (200 MHz, CDCl3): δ ϭ 7.70 (d, J ϭ 7.3 Hz, 1 H, 4-H), 6.05
(d, J ϭ 7.3 Hz, 1 H, 5-H), 5.99Ϫ5.86 (m, 1 H, 6b-H), 1.99Ϫ1.81
1
(m, 6 H, 6aЈ-H and 6c-H). The MS and H NMR parameters of
Palladium-Catalysed Methylation of 3-Bromo-6-[(E/Z)-2-butenyl]-
2(2H)-pyranone (12a؉b): A mixture of 12a and 12b (0.50 g,
2.2 mmol; 12a/12b ϭ 46:54) was treated with tetramethyltin (1.17 g,
6.6 mmol) in the presence of PdCl2[P(o-tolyl)3]2 (86 mg, 0.1 mmol)
and CuI (41 mg, 0.22 mmol) in NMP (10 mL) at 80 °C for 20 h.
GLC analysis of the crude reaction product obtained after the
usual workup showed the presence of two compounds in a ca. 46:54
molar ratio. These were subsequently identified as gibepyrone A
(7b) and fusalanipyrone (7a), respectively. This crude product was
purified by MPLC analysis on silica gel, with a mixture of petro-
leum ether and diethyl ether (75:25) as eluent. Concentration of the
first eluted chromatographic fractions allowed 85% stereoiso-
merically pure 7a (0.17 g, 48%) to be isolated as a colourless liquid.
12b were as follows. MS: m/z (%) ϭ230 (68) [Mϩ], 228 (70) [Mϩ],
202 (35), 200 (36), 121 (36), 93 (100), 77 (50). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.67 (d, J ϭ 7.3 Hz, 1 H, 4-H), 6.71 (q, J ϭ 6.7 Hz,
1 H, 6b-H), 6.05 (d, J ϭ 7.3 Hz, 1 H, 5-H), 1.99Ϫ1.81 (m, 6 H,
6aЈ-H and 6c-H). C9H9BrO2 (229.07): calcd. C 47.19, H 3.96; found
C 47.38, H 4.05.
3-Bromo-6-butyl-2(2H)-pyranone (12c): GLC analysis of the crude
reaction product obtained from 11c according to the general pro-
cedure described above showed the presence of a major product
together with very small amounts of unidentified compounds. Puri-
fication of this crude product by MPLC on silica gel, with benzene
as eluent, allowed pure 12c (0.65 g, 74%) to be isolated as a colour-
less solid. M.p. 30 °C. MS: m/z (%) ϭ 232 (77) [Mϩ], 230 (80), 187
IR (film): ν ϭ 1713 cmϪ1, 1643, 1557, 1381, 1122, 1101, 1040, 831,
˜
1
759. The MS and H NMR parameters of stereoisomerically pure
˜
(100), 176 (79), 174 (82), 132 (71), 123 (78). IR (film): ν ϭ 1729
7a were as follows. MS: m/z (%) ϭ 164 (89) [Mϩ], 136 (61), 121
(100), 109 (21), 93 (31), 91 (23), 53 (52). 1H NMR (600 MHz,
CDCl3): δ ϭ 7.13 (dq, J ϭ 6.9, 1.2 Hz, 1 H, 4-H), 6.03 (d, J ϭ
6.9 Hz, 1 H, 5-H), 5.79 (qq, J ϭ 7.1, 1.4 Hz, 1 H, 6b-H), 2.10 (d,
J ϭ 1.2 Hz, 3 H, 3a-H), 1.95 (m, 3 H, 6aЈ-H), 1.93 (m, 3 H, 6c-H).
13C NMR (150 MHz, CDCl3): δ ϭ 163.54, 159.87, 139.55, 130.26,
127.63, 123.21, 104.36, 21.50, 16.50, 15.70. The 1H NMR para-
cmϪ1, 1635, 1542, 1340, 1090, 985, 957, 922, 753. 1H NMR
(200 MHz, CDCl3): δ ϭ 7.61 (d, J ϭ 6.9 Hz, 1 H, 4-H), 5.91 (d,
J ϭ 6.9 Hz, 1 H, 5-H), 2.48 (t, J ϭ 7.5 Hz, 2 H, 6a-H), 1.64 (quint,
J ϭ 7.5 Hz, 2 H, 6b-H), 1.36 (sext, J ϭ 7.3 Hz, 2 H, 6c-H), 0.93
(t, J ϭ 7.3 Hz, 3 H, 6d-H). C9H11BrO2 (231.09): calcd. C 46.78, H
4.80; found C 47.01, H 5.01.
Palladium-Catalysed Triethylammonium Formate Reduction of 11a: meters of 7a, except for the chemical shift of the olefinic proton
Formic acid (99%, 80 µL, 2.1 mmol) was added to a mixture of 11a
6b-H were in agreement with those reported for the natural prod-
(0.50 g, 1.4 mmol), triethylamine (0.59 mL, 4.2 mmol), Pd(OAc)2 uct.[3a] In fact, a chemical shift of δ ϭ 6.62 was reported for the
(6.3 mg, 0.028 mmol) and triphenylphosphane (14.7 mg, aberrant proton,[3a] whereas our assignment indicated that it should
0.05 mmol) in dry DMF (10 mL), and the mixture was stirred at
be δ ϭ 5.79. Concentration of the last eluted chromatographic frac-
60 °C for 5 h under argon. It was then cooled to 20 °C, diluted
tions allowed 85% stereoisomerically pure 7b (0.19 g, 52%) to be
with water (60 mL), and extracted with diethyl ether (4 ϫ 20 mL). obtained as a colourless liquid. IR (film): ν ϭ 1712 cmϪ1, 1644,
˜
GLC/MS analysis of the organic extract, which was washed with
brine (30 mL) and dried, showed the presence of three major com-
pounds in a ca. 25:20:55 molar ratio. The first two of these, on the
basis of their MS spectra, presumably corresponded to 6-[(Z)-2-
butenyl]-2(2H)-pyranone (27) and 6-[(Z)-2-butenyl]-5-iodo-2(2H)-
pyranone (28), respectively. The last compound was subsequently
identified as 12a. However, all these compounds were contaminated
1561, 1378, 1128, 1108, 1052, 820, 759. The MS and 1H NMR para-
meters of stereoisomerically pure 7b were as follows. MS: m/z (%) ϭ
164 (80) [Mϩ], 136 (56), 121 (100), 109 (21), 93 (29), 91 (23), 53
1
(49). H NMR (600 MHz, CDCl3): δ ϭ 7.11 (dd, J ϭ 7.0, 1.1 Hz,
1 H, 4-H), 6.61 (q, J ϭ 7.1 Hz, 1 H, 6b-H), 6.04 (d, J ϭ 7.0 Hz, 1
H, 5-H), 2.09 (d, J ϭ 1.1 Hz, 3 H, 3a-H), 1.85 (s, 3 H, 6aЈ-H), 1.82
(d, J ϭ 7.1 Hz, 3 H, 6c-H). 13C NMR (150 MHz, CDCl3): δ ϭ
with minor amounts of the corresponding stereoisomers. In par- 163.49, 159.89, 140.05, 128.22, 126.84, 122.99, 100.49, 16.59, 14.10,
1074 Eur. J. Org. Chem. 2002, 1063Ϫ1076

Selective Synthesis of Substituted 3-Methyl-2(2H)-pyranones
FULL PAPER
R. L. Edwards, D. G. Lewis, D. V.
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Received September 28, 2001
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