A novel route to 6-substituted and 5,6-disubstituted 2-pyrones

Article abstract of DOI:10.1016/S0040-4039(01)00290-8

6-Alkyl- and 6-(1-alkenyl)-5-iodo-2-pyrones, which are available as major products by reaction of the corresponding (Z)-2-en-4-ynoic acids with iodine and NaHCO₃ in CH₃CN, undergo insertion of activated zinc metal into their carbon-iodine bond to provide the corresponding 5-(iodozinc)-2-pyrones. Hydrolysis of these organometallics gives 6-substituted 2-pyrones in satisfactory yields including two natural products. On the other hand, the Pd-catalyzed reaction of the organozincs either with an activated alkenyl halide or with activated and deactivated (hetero)aryl halides provides 5,6-disubstituted 2-pyrones in fair to good yields.

Full text of DOI:10.1016/S0040-4039(01)00290-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2859–2863
A novel route to 6-substituted and 5,6-disubstituted 2-pyrones
Fabio Bellina, Matteo Biagetti, Adriano Carpita and Renzo Rossi*
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via Risorgimento 35, I-56126 Pisa, Italy
Received 8 February 2001; accepted 20 February 2001
Abstract—6-Alkyl- and 6-(1-alkenyl)-5-iodo-2-pyrones, which are available as major products by reaction of the corresponding
(
Z)-2-en-4-ynoic acids with iodine and NaHCO in CH CN, undergo insertion of activated zinc metal into their carbonꢀiodine
3
3
bond to provide the corresponding 5-(iodozinc)-2-pyrones. Hydrolysis of these organometallics gives 6-substituted 2-pyrones in
satisfactory yields including two natural products. On the other hand, the Pd-catalyzed reaction of the organozincs either with an
activated alkenyl halide or with activated and deactivated (hetero)aryl halides provides 5,6-disubstituted 2-pyrones in fair to good
yields. © 2001 Elsevier Science Ltd. All rights reserved.
In recent years considerable efforts have been directed
towards the synthesis of 2-pyrone derivatives either by
Even though the results of this procedure were satisfac-
tory, we decided to search for a new alternative and
practical synthetic route to unsymmetrically 5,6-disub-
stituted 2-pyrones, which was based on the use of
compounds 3, but did not involve the utilization and
manipulation of toxic organotin compounds and their
byproducts and was also amenable for the preparation
1
traditional approaches or by processes involving tran-
2
sition metal-catalyzed reactions. In fact, 2-pyrones are
3
useful synthetic intermediates and occur as structural
subunits in a wide variety of biologically active natural
4
products.
6
-substituted 2-pyrones. Thus, we examined the possi-
Recently, in the context of a research program aimed at
the synthesis of natural and unnatural oxygen-contain-
ing heterocycles by approaches which involve transition
bility of converting iodides 3 into the corresponding
5-(iodozinc)-2-pyrones 5 and to use these organometal-
lics in Pd-catalyzed reactions with electrophiles such as
alkenyl and (hetero)aryl halides. On the other hand,
hydrolysis of the metalꢀcarbon bond of compounds 5
could allow a facile synthesis of 6-substituted 2-pyrones
5
metal-catalyzed reactions, we developed a two-step
protocol for the synthesis of 5,6-disubstituted 2-pyrones
6
4
(Scheme 1).
I
O
O
R1
1
(
E)-2 : R = aryl, alkyl, alkenyl
a)
COOH
+
R2
I
R1
1
b)
1
: R = aryl, alkyl,
alkenyl
R1
R
1
1
O
O
O
O
1
3
: R = aryl, alkyl
alkenyl
4 : R = aryl, alkyl, alkenyl
2
R = aryl, Me, 1-alkynyl, alkenyl
2
Scheme 1. (a) I (3 equiv.), NaHCO (3 equiv.), CH CN, 1.5 h, rt; (b) R -SnR , Pd cat.
2
3
3
3
IZn
Y
R1
R1
O
O
R
1
1
O
O
O
O
1
1
5
: R = aryl, alkyl,
alkenyl
6 : R = aryl, alkyl,
7 : R = alkyl, alkenyl
alkenyl
Y = (hetero)aryl, alkenyl
*
0
Corresponding author. Tel.: +39 50918214; fax: +39 50918260; e-mail: rossi@dcci.unipi.it
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00290-8

2
860
F. Bellina et al. / Tetrahedron Letters 42 (2001) 2859–2863
6
for which no general synthetic procedure has been
reported so far in the literature.
Purification of these hydrolyzed reaction mixtures by
9a 9a
MPLC on silica gel allowed the isolation of 6a, 6b
9b 10
and 6c in 78, 88 and 52% yields, respectively.
We now wish to describe the synthesis of the organo-
zincs 5 from iodides 3 and the use of these organometal-
lics for the efficient preparation either of 6-alkyl- and
Compound 6a, which possesses a characteristic coconut
1
1
odour, is a fungal metabolite of Trichoderma viride
and has been shown to possess significant antifungal
6
-(1-alkenyl)-2-pyrones 6 including two natural prod-
4d
ucts, or of 5,6-disubstituted 2-pyrones of general for-
mula 7, which are characterized by a (hetero)aryl or an
alkenyl group in their 5-position. Moreover, we will
report the preparation of a naturally-occurring 6-aryl-2-
pyrone by Pd-catalyzed hydrogenolysis of the corre-
sponding 6-aryl-5-iodo derivative.
activity. Compound 6c has been isolated from a strain
9b
of Trichoderma viride and has been shown to display
12
antifungal properties similar to those of 6a.
1
On the other hand, GLC/MS and H NMR analyses of
the reaction mixture which was obtained by acidic
hydrolysis of the product derived from insertion of
activated zinc metal into the carbon iodine bond of 3d,
showed the presence of two compounds in a ca. 22:78
molar ratio. They were identified as 6d and 1d, respec-
tively (Scheme 3). It must also be noted that attempts
to obtain 6d selectively by a modification of this proce-
dure, i.e. by using 5 equiv. of activated zinc dust or
performing the insertion reaction in the presence of 1–3
equiv. of N,N,N%,N%-tetramethylenediamine, gave
unsatisfactory results. Nevertheless, we succeeded in
Iodides 3a–d, which we used as starting materials for
the synthesis of compounds 6 and 7, were prepared in
6
5, 65, 72 and 59% yields by reaction of carboxylic
6
acids 1a–d, respectively, with 3.0 equiv. of iodine and
3.0 equiv. of NaHCO in CH CN at 20°C for 1.5 h,
3
3
followed by a Na S O quench and purification of the
2
2
3
6
resulting reaction mixtures by MPLC on silica gel.
I
COOH
13
cleanly synthesizing naturally occurring 6d, using a
R1
R1
O
O
protocol very similar to that previously employed to
1
4
1
1
convert aryl triflates into the corresponding arenes. In
fact, treatment of 3d with 2 equiv. of formic acid, 3
equiv. of Et N, 2 mol% Pd(OAc) and 4 mol% PPh in
1
1
1
1
a : R = C H
3a : R = C H
5 11
5
11
1
1
b : R = C H
3b : R = C H
6 13
6
13
1
1
c : R = (E)-C H -CH=CH
3c : R = (E)-C H -CH=CH
3 7
3
7
3
2
3
1
1
d : R = C H
3d : R = C H
6 5
6
5
DMF at 60°C for 3 h gave 6d in an 83% isolated yield
Scheme 3).
(
These iodides proved to undergo insertion of zinc metal
into their carbonꢀiodine bond provided that the metal
was first activated with 1,2-dibromoethane and then
Finally, we found that, in contrast to that reported for
the Pd-catalyzed reaction of 2-iodo-1-[2-(trimethylsi-
lyl)ethoxymethyl]indole with the organozinc bromide
derived from 5-bromo-2-pyrone, which proved to be
7
,8
with Me SiCl. In fact, GLC and GLC/MS analyses
3
of the products, which were obtained by acidic hydroly-
sis of the reaction mixtures prepared by stirring THF
solutions of compounds 3a–d with 3–5 equiv. of acti-
vated zinc dust at 20°C for 3–3.5 h, showed that these
iodides had been completely consumed. Moreover, in
the case of the reaction mixtures which were obtained
by treatment of 3 equiv. of zinc metal with 3a–c fol-
lowed by acidic hydrolysis, these GLC and GLC/MS
analyses also showed the presence of a major product
which was subsequently isolated and identified as the
compound derived from hydrolysis of the organozinc
iodides 5a–5c, i.e. as 6a–6c, respectively (Scheme 2).
3c
low yielding, the reactions of the organozinc iodides
a–c with organic electrophiles such as alkenyl or (het-
5
ero)aryl halides in THF solution, in the presence of a
catalyst precursor constituted of 2 mol% Pd (dba) and
2
3
8 mol% PPh , gave the desired 5,6-disubstituted 2-
3
pyrones 7 in fair to good yields. As shown in Table 1,
where the results of some of these Pd-catalyzed cross-
coupling reactions are summarized, compounds 5a and
5b could be reacted with typical activated alkenyl
halides such as ethyl (E)-3-iodopropenoate (8a) (entry
1), with activated (hetero)aryl halides such as 2-bromo-
I
IZn
R1
a)
b)
R1
R1
O
O
O
O
O
O
1
1
1
3
3
3
a : R = C H
b : R = C H
c : R = (E)-C H -CH=CH
5a : R = C H
5b : R = C H
5c : R = (E)-C H -CH=CH
6a : R = C H
5 11
6b : R = C H
6c : R = (E)-C H -CH=CH
5
11
5
11
1
1
1
6
13
6
13
6 13
1
1
1
3
7
3
7
3
7
Scheme 2. (a) Activated zinc dust (3 equiv.), THF, rt, 3–3.5 h; (b) 5% HCl, 0°C.
I
a), b)
c)
+
1d
6d
C H
O
O
C H
6 5
O
O
6
5
6d
3d
Scheme 3. (a) Activated zinc dust (3 equiv.), THF, rt, 3 h; (b) 5% HCl, 0°C; (c) Et N (3 equiv.), HCOOH (2 equiv.), Pd(OAc)2
3
(
2 mol%), PPh (4 mol%), DMF, 60°C, 3 h.
3

F. Bellina et al. / Tetrahedron Letters 42 (2001) 2859–2863
2861
a
Table 1. Palladium-catalyzed reactions of 5-(iodozinc)-2-pyrones 5 with organic electrophiles 8
IZn
R1
Y
Pd (dba) , PPh
2
3
3
+
Y-X
THF
R1
O
O
O
O
5
8
7
Entry
5
Organozinc iodideb
Electrophile
5/8 molar ratio
1.20
Reaction conditions
Product
Yield (%)
R1
C H
8
Y
X
h/°C
7
1
2
5a
8a
I
18/20
7a
79
5
11
EtOOC
c
5b
5b
5b
5b
5b
5a
C H
8b
8c
8c
8d
8e
8f
Br
0.71
0.71
1.20
1.20
0.71
1.20
39/20 then 5/70
15/20 then 48/70d
37/70
7b
7c
7c
7d
7e
7f
60
6
13
H C
3
N
3d
c
C H
Br
Br
I
65
33
68
64
72
6
13
13
13
13
11
COOCH3
4
C H
6
COOCH3
5
C H
15/70
6
H CO
3
c
6
C H
Br
Br
15/20 then 48/70
6
N
7
C H
44/20
5
N
N
a
Unless otherwise noted all the reactions were performed in the presence of 2 mol% Pd (dba) and 8 mol% PPh3.
Unless otherwise noted the organozinc iodides were prepared by treatment of iodides 3 with 3 equiv. of activated zinc dust in THF.
This organozinc derivative was prepared by reaction of 3b with 5 equiv. of activated zinc dust in THF.
2
3
b
c
d
This reaction was performed for 15 h at 20°C and for 24 h at 70°C in the presence of Pd (dba) (2 mol%) and PPh (8 mol%). After this period
2
3
3
Pd (dba)3 (2 mol%) and PPh3 (8 mol%) were added and the reaction mixture was stirred at 70°C for 24 h.
2
5
-methylpyridine (8b), methyl 2-bromobenzoate (8c),
-bromoquinoline (8e) and 5-bromopyrimidine (8f)
formed using a 5b/8c molar ratio of 0.71; 5b was
prepared by treatment of 3b with 5 equiv. of activated
zinc dust (entry 3). On the basis of this result, we
thought it right to prepare compounds 7b and 7e using
a protocol very similar to that employed in entry 3
(entries 2 and 6, respectively).
3
(
entries 2–6), as well as with a typical deactivated aryl
15
halide such as 4-iodoanisole (8d) (entry 7). Table 1
also shows that, when 5b was coupled with 8c using the
experimental conditions employed for the synthesis of
compounds 7a, 7d and 7f, i.e. preparing 5b by treat-
ment of 3b with 3 equiv. of activated zinc dust and
using a 5b/8c molar ratio of 1.20, the yield of the
desired cross-coupled product 7c was rather low (entry
In conclusion, we have shown that easily available
6-substituted 5-(iodozinc)-2-pyrones 5 are synthetically
useful organometallic reagents. In fact, they can be
conveniently employed for the efficient and selective
preparation either of 6-substituted 2-pyrones, which
include some natural products, or a large variety of
unsymmetrically 5,6-disubstituted 2-pyrones of general
4).
Nevertheless, we found that this yield could be signifi-
cantly improved when this coupling reaction was per-

2
862
F. Bellina et al. / Tetrahedron Letters 42 (2001) 2859–2863
formula 7. The synthesis of compounds 7 from the
organozinc iodides 5 complements a procedure recently
8. A similar reaction has been recently employed for the
synthesis of the organozinc bromide corresponding to
5-bromo-2-pyrone: Ref. 3c.
6
developed in our laboratory.
9
. The spectral properties of 6a–c were in agreement with
those previously reported. See: (a) Pittet, A. O.; Klaiber,
E. M. J. Agric. Food Chem. 1975, 23, 1189–1195 (for 6a
and 6b); (b) Moss, M. O.; Jackson, R. M.; Rogers, D.
Phytochemistry 1975, 14, 2706–2708 (for 6c).
Acknowledgements
1
0. Compounds 6a–c were prepared according to the follow-
This work was supported by the Ministero dell’Univer-
sit a` e della Ricerca Scientifica e Tecnologica (MURST)
and the University of Pisa.
ing procedure. A mixture of zinc dust (Aldrich, 325 mesh,
1.21 g, 18.48 mmol) and THF (5 ml) containing 1,2-
dibromoethane (0.123 g, 0.65 mmol) was stirred under
argon at 65°C for 1 min and then it was allowed to cool
to 20°C. Chlorotrimethylsilane (0.66 ml, 0.52 mmol) was
added and after 20 min at 20°C a solution of a 5-iodo-2-
pyrone 3 (6.16 mmol) in THF (15 ml) was added drop-
wise. The mixture was stirred at 20°C for 3–3.5 h and
then it was allowed to settle. The clear solution of the
organozinc derivative 5 so obtained was transferred via
syringe to a new reaction flask, hydrolyzed at 0°C with
References
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15. All new compounds were obtained in analytically pure
form. Selected spectral properties of compounds 7a–f are
as follows. Compound 7a: mp 35°C. MS, m/z (%): 264
(8), 219 (11), 162 (100), 137 (41), 121 (98), 107 (36), 93
(38). IR (KBr): 1750, 1719, 1638, 1551, 1304, 1181, 834
−
1 1
cm . H NMR (CDCl ): l 7.59 (1H, d, J=15.7 Hz), 7.53
3
(1H, d, J=9.8 Hz), 6.26 (1H, d, J=9.8 Hz), 6.15 (1H, d,
J=15.7 Hz), 4.26 (2H, q, J=7.5 Hz), 2.70 (3H, t, J=7.8
Hz), 1.72 (2H, t, J=7.8 Hz), 1.38–1.29 (3H, m), 1.33 (3H,
t, J=7.5 Hz), 0.90 ppm (3H, t, J=7.0 Hz). Compound
7b: MS, m/z (%): 271 (7), 215 (22), 214 (29), 201 (100),
186 (25), 158 (18), 130 (23). IR (film): 1736, 1633, 1551,
1
3022; (c) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.;
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−
1
1
1487, 1067, 1014, 823 cm . H NMR (CDCl ): l 8.49
3
(1H, d, J=2.6 Hz), 7.59–7.53 (1H, m), 7.56 (1H, d,
J=9.6 Hz), 7.21 (1H, d, J=8.4 Hz), 6.25 (1H, d, J=9.6
Hz), 2.66 (2H, t, J=7.7 Hz), 2.39 (3H, s), 1.80–1.64 (2H,
m), 1.32–1.18 (6H, m), 0.85 ppm (3H, t, J=6.6 Hz).
Compound 7c: MS, m/z (%): 314 (7), 225 (18), 212 (100),
184 (27), 115 (29), 43 (41), 41 (22). IR (film): 1725, 1637,
8
8, 503–513.
5
. (a) Rossi, R.; Bellina, F.; Catanese, A.; Mannina, L.;
Valensin, D. Tetrahedron 2000, 56, 479–487; (b) Bellina,
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6, 2533–2545; (c) Rossi, R.; Bellina, F.; Biagetti, M;
−
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Catanese, A.; Mannina, L. Tetrahedron Lett. 2000, 41,
1549, 1290, 1260, 1087, 768 cm . H NMR (CDCl ): l
3
5
281–5286; (d) Rossi, R.; Bellina, F.; Raugei, E. Synlett
8.04 (1H, dd, J=7.3 and 1.9 Hz), 7.59 (1H, ddd, J=7.5,
7.5 and 1.7 Hz), 7.49 (1H, ddd, J=7.5, 7.5 and 1.7 Hz),
7.23 (1H, dd, J=7.7 and 1.5 Hz), 7.18 (1H, d, J=9.6
Hz), 6.19 (1H, d, J=9.6 Hz), 3.78 (3H, s), 2.26 (2H, t,
J=7.5 Hz), 1.68–1.50 (2H, m), 1.30–1.10 (6H, m), 0.81
ppm (3H, t, J=6.6 Hz). Compound 7d: MS, m/z (%): 286
(35), 215 (13), 187 (39), 145 (100), 115 (15), 102 (31). IR
2
000, 1749–1752; (e) Rossi, R.; Bellina, F.; Biagetti, M.;
Mannina, L. Tetrahedron: Asymmetry 1999, 10, 1163–
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1
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1
998, 39, 7599–7602; (h) Rossi, R.; Bellina, F.; Mannina,
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(film): 1735, 1632, 1610, 1544, 1513, 1248, 825 cm . H
6
7
NMR (CDCl ): l 7.28 (1H, d, J=9.4 Hz), 7.15 (2H, d,
3
J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 6.21 (1H, d, J=9.4
Hz), 3.85 (3H, s), 2.49 (2H, t, J=7.7 Hz), 1.75–1.20 (8H,
m), 0.84 ppm (3H, t, J=6.6 Hz). Compound 7e: MS, m/z

F. Bellina et al. / Tetrahedron Letters 42 (2001) 2859–2863
2863
(
%): 307 (43), 237 (24), 222 (26), 208 (57), 167 (38), 166
(6H, m), 0.81 ppm (3H, t, J=6.6 Hz). Compound 7f:
mp 79–81°C. MS, m/z (%): 244 (11), 188 (14), 173 (19),
160 (32), 159 (62), 117 (100), 63 (45). IR (KBr): 1726,
(100), 140 (20), 43 (24). IR (film): 1736, 1634, 1545,
−
1
1
1
(
464, 1031, 949, 824 cm . H NMR (CDCl ): l 8.81
3
−
1
1
1H, d, J=2.2 Hz), 8.15 (1H, d, J=8.1 Hz), 8.04 (1H,
1628, 1540, 1310, 990, 837, 727 cm .
H NMR
d, J=2.2 Hz), 7.86 (1H, d, J=8.1 Hz), 7.79 (1H, ddd,
J=8.1, 8.1 and 1.7 Hz), 7.62 (1H, dd, J=7.6 and 7.6
Hz), 7.38 (1H, d, J=9.5 Hz), 6.32 (1H, d, J=9.5 Hz),
(CDCl ): l 9.25 (1H, s), 8.68 (2H, s), 7.26 (1H, d,
3
J=9.6 Hz), 6.32 (1H, d, J=9.6 Hz), 2.48 (2H, t, J=7.8
Hz), 1.79–1.60 (2H, m), 1.35–1.15 (4H, m), 0.88 ppm
(3H, m).
2
.54 (2H, t, J=7.7 Hz), 1.75–1.65 (2H, m), 1.29–1.20
.