Synthesis of 2,5-disubstituted furans via palladium-catalyzed annulation of alkyl 3-oxo-6-heptynoates

Article abstract of DOI:10.1021/jo962386v

The reaction of the readily available alkyl 3-oxo-6-heptynoates with aryl halides in the presence of K₂CO₃ and catalytic amounts of Pd(PPh₃)₄ at 100 °C provides a valuable new route to 2,5-disubstituted furans 3. Most probably, the furan ring is generated through an annulation reaction promoted by δ-arylpalladium complexes generated in situ and involving the nucleophilic attack of the ketonic oxygen across the carbon-carbon triple bond coordinated to palladium, followed by the base-catalyzed isomerization of the resultant stereoisomeric 2,5-dialkylidenetetrahydrofuran intermediates 4 and 5. The reaction is highly chemoselective. No evidence was obtained of carboannulation products. The reaction temperature has proven to be crucial for the success of the methodology. The K₂CO₃:alkyne ratio also affects the reaction outcome. The highest yields of furan derivatives have been obtained with aryl halides containing electron-withdrawing substituents, very likely because the higher acidity of the methylene protons of 4 and 5 favors the isomerization step. Extension of the methodology to methyl 3-oxo-7- substituted-6-heptynoates leads to the formation of 2,5-disubstituted furans containing a branched side chain. The presence of an alkyl substituent on the C-2 of the staring alkyne, however, seems to prevent the isomerization step. Treatment of ethyl 2-methyl-3-oxo-6-heptynoate under our standard conditions produced in fact the 2,5-dialkylidene derivative 5p in 42% yield, and no evidence of the corresponding furan derivative was attained.

Full text of DOI:10.1021/jo962386v

J . Org. Chem. 1997, 62, 5327-5332
5327
Syn th esis of 2,5-Disu bstitu ted F u r a n s via P a lla d iu m -Ca ta lyzed
An n u la tion of Alk yl 3-Oxo-6-h ep tyn oa tes
Sandro Cacchi,* Giancarlo Fabrizi, and Leonardo Moro
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
Universita` La Sapienza, P.le A. Moro 5, I-00185 Roma, Italy
Received December 20, 1996X
The reaction of the readily available alkyl 3-oxo-6-heptynoates with aryl halides in the presence of
K2CO3 and catalytic amounts of Pd(PPh3)4 at 100 °C provides a valuable new route to 2,5-
disubstituted furans 3. Most probably, the furan ring is generated through an annulation reaction
promoted by σ-arylpalladium complexes generated in situ and involving the nucleophilic attack of
the ketonic oxygen across the carbon-carbon triple bond coordinated to palladium, followed by the
base-catalyzed isomerization of the resultant stereoisomeric 2,5-dialkylidenetetrahydrofuran
intermediates 4 and 5. The reaction is highly chemoselective. No evidence was obtained of
carboannulation products. The reaction temperature has proven to be crucial for the success of
the methodology. The K2CO3:alkyne ratio also affects the reaction outcome. The highest yields of
furan derivatives have been obtained with aryl halides containing electron-withdrawing substit-
uents, very likely because the higher acidity of the methylene protons of 4 and 5 favors the
isomerization step. Extension of the methodology to methyl 3-oxo-7-substituted-6-heptynoates leads
to the formation of 2,5-disubstituted furans containing a branched side chain. The presence of an
alkyl substituent on the C-2 of the staring alkyne, however, seems to prevent the isomerization
step. Treatment of ethyl 2-methyl-3-oxo-6-heptynoate under our standard conditions produced in
fact the 2,5-dialkylidene derivative 5p in 42% yield, and no evidence of the corresponding furan
derivative was attained.
In tr od u ction
alkynes promoted by PdII species not containing σ-carbon-
palladium bonds (typically palladium dichloride or diace-
tate),9 provides a straightforward approach to the con-
struction of ring systems through the regio- and stereo-
selective addition of a nucleophile and of a vinyl, aryl, or
alkynyl unit across the carbon-carbon triple bond (eqs
1a and 1b). One of its most remarkable features is that
it enables the annulation process to combine with a rapid
increase in molecular complexity. In this respect, the
annulation carried out in the presence of carbon monox-
ide (leading to the addition of a nucleophile and of an
acyl unit across the carbon-carbon triple bond)6-8 takes
on particular significance (eq 1c).
The annulation of alkynes containing nucleophiles
close to the carbon-carbon triple bond, promoted by
σ-vinyl-, σ-aryl-, and σ-alkynylpalladium complexes gen-
erated in situ from unsaturated triflates or halides, is
emerging as a unique, powerful tool for the preparation
of functionalized carbo-1 and heterocycles.2-8 This reac-
tion, in fact, unlike from most nucleopalladations of
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) Fournet, G.; Balme, G.; Van Hemelryck, B.; Gore, J . Tetrahedron
Lett. 1990, 31, 5147; Fournet, G.; Balme, G.; Gore, J . Tetrahedron 1991,
47, 6293. Bouyssi, D.; Balme, G.; Gore, J . Tetrahedron Lett. 1991, 32,
6541; Balme, G.; Bouyssi, D. Tetrahedron 1994, 50, 403.
(2) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.;
Pietroni, B. R. J . Org. Chem. 1992, 57, 976.
(3) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33,
3915.
(4) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F. Tetraherdon
Lett. 1993, 34, 2813.
(5) Inoue, Y.; Itoh, Y.; Imaizumi, Y.; Imaizumi, S. J . Mol. Cat. 1990,
60, L1-L3. Bouyssi, D.; Gore, J .; Balme, G. Tetrahedron Lett. 1992,
33, 2811. Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1992, 33, 6835.
Luo, F.-T.; Schreuder, I.; Wang, R.-T. J . Org. Chem. 1992, 57, 2213.
Bouyssi, D.; Gore, J .; Balme, G.; Louis, D.; Wallach, J . Tetrahedron
Lett. 1993, 34, 3129. Saulnier, M. G.; Frennesson, D. B.; Deshpande,
M. S.; Vyas, D. M. Tetrahedron Lett. 1995, 36, 7841. Cavicchioli, M.;
Bouyssi, D.; Gore, J .; Balme, G. Tetrahedron Lett. 1996, 37, 1429.
(6) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437.
(7) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F.
J . Org. Chem. 1996, 61, 9280.
Our success in the utilization of this chemistry with
acetylenic building blocks such as pentynoic acids,2
o-alkynyltrifluoroacetanilides,3,6 2-propargyl-1,3-dicarbo-
nyl compounds,4 and o-alkynylphenols7 encouraged us to
investigate a possible extension to alkyl 3-oxo-6-hep-
tynoates 1 in order to develop a new synthesis of 2,5-
disubstituted furans 3 (eq 2). On the other hand, furan
derivatives constitute one of the most important classes
of heteroaromatic compounds. They are widely diffused
among natural substances10 and important pharmaceu-
(8) Arcadi, A.; Rossi, E. Tetrahedron Lett. 1996, 37, 6811.
(9) See for example: Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron
Lett. 1981, 22, 4277. Utimoto, K. Pure Appl. Chem. 1983, 55, 1845.
Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 5323. Wakaba-
yashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. Tetra-
hedron 1985, 41, 3655. Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.
Tetrahedron Lett. 1985, 26, 5963. Iritani, K.; Matsubara, S.; Utimoto,
K. Tetrahedron Lett. 1988, 29, 1799. Arcadi, A.; Cacchi, S.; Marinelli,
F. Tetrahedron Lett. 1989, 30, 2581. Kondo, Y. K.; Sakamoto, T.;
Yamanaka, H. Heterocycles 1989, 29, 1013. Rudisill, D. E.; Stille, J .
K. J . Org. Chem. 1989, 54, 5856. Fukuda, Y.; Shiragami, H.; Utimoto,
K.; Nozaki; H. J . Org. Chem. 1991, 56, 5816. Lambert, C.; Fukuda,
Y.; Matsubara, S.; Utimoto, K. J . Org. Chem. 1991, 56, 5812.
S0022-3263(96)02386-9 CCC: $14.00 © 1997 American Chemical Society

5328 J . Org. Chem., Vol. 62, No. 16, 1997
Cacchi et al.
Ta ble 1. Solven ts, Rea ction Tim e, a n d Rea ction
Tem p er a tu r e in th e P a lla d iu m -Ca ta lyzed An n u la tion of
Meth yl 3-Oxo-6-h ep tyn oa te (1a ) w ith p-Acetylp h en yl
Iod id e (2a )a
sol-
vent
reaction reaction yield (%) yield (%) yield (%)
entry
temp (°C) time(h)
of 3a b
of 4a b
of 5a b
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
60
60
60
60
60
2
5
15
15
15
15
6.5
3
3
19
66
40
54
40
28
59
67
76
38
20
-
-
9
54
-
-
-
17
6
-
-
-
12
-
-
-
DMFc
DMSOc
MeCNc
DMF
ticals.11 Additionally, polysubstituted furans serve as
useful building blocks in organic synthesis.12 This justi-
fies the continued, considerable effort in the development
of novel approaches to this class of compounds,13 par-
ticularly when they use readily available starting materi-
als, accommodate considerable functionalities, and are
simple to carry out.
60
80
DMF
DMF
100
100d
a
Unless otherwise stated, reactions were carried out under an
argon atmosphere using the following molar ratios: 1a :2a :K2CO3:
b
Pd(PPh3)4 ) 1.2:1.0:5:0.05. Yields are for pure isolated products.
c Anhydrous. 1a :2a :K2CO3:Pd(PPh3)4 ) 1.5:1.0:1.5:0.05.
d
Hereafter we report the result of this study.
rivatives 4a (38%) and 5a (17%) (Table 1, entry 1). The
stereochemistry of 4a and 5a was determined by NOE
difference studies. Some of the significant NOE effects
are quoted in the eq 3. As 4a and 5a were converted
into 3a (50% yield and almost quantitative yield, respec-
tively) on treatment with K2CO3 in DMF at 60 °C for 1 h
in the absence of palladium catalyst, suggesting that 3a
is generated from 4a and 5a through a base-catalyzed
isomerization, the reaction of 1a with 2a was repeated
[Pd(PPh3)4, K2CO3, DMF, 60 °C] prolonging the reaction
time to 5 h as to favor the isomerization step. Although
significant amounts of 4a (20%) and 5a (6%) were still
obtained, the furan derivative 3a was isolated in good
yield (66%) (Table 1, entry 2).
Resu lts a n d Discu ssion
Methyl 2-oxo-6-heptynoate 1a (R ) Me; R1 ) R2 ) H)
was used as the model starting alkyne. It was prepared
in 70% yield through a one-pot procedure based on the
acylation of Meldrum’s acid with 4-pentynoic acid in the
presence of dicyclohexylcarbodiimide (DCC) and 4-(di-
methylamino)pyridine, followed by the methanolysis of
the resultant crude 5-acyl derivative of Meldrum’s acid.
On the basis of the results obtained in our previous work,
we initially examined the reaction of 1a with p-acetyl-
phenyl iodide 2a in the presence of K2CO3 (5 equiv) and
Pd(PPh3)4 (0.05 equiv) in DMF at 60 °C for 2 h (eq 3).
Unfortunately, apart from m-nitrophenyl iodide (Table
2, entry 15), a variety of aryl halides failed to give the
corresponding 2,5-disubstituted furans in satisfactory
yield under these conditions. The intermediates 4 and
5 were always isolated in significant amount or as the
main products (Table 2, entries 3, 9, 11, 13, 21, 23).
Further extension of the reaction time (to 15 h) to bring
the isomerization process to an end resulted in the
isolation of 3a in lower yield (Table 1, entry 3), most
probably because of the instability of the furan derivative.
This view seems to be supported by the recovery of 3a in
only 36% yield when it was subjected to reaction condi-
tions in the absence of the palladium catalyst for 7.5 h.
The use of anhydrous DMF, DMSO, and MeCN did not
produce better results (Table 1, entries 4, 5, and 6).
A simple solution to the problem was found by increas-
ing the reaction temperature to 100 °C and decreasing
(13) For recent approaches to the construction of the furan ring, see
for example: Padwa, A.; Ishida, M.; Muller, C. L.; Murphree, S. S. J .
Org. Chem. 1992, 57, 1170. Dulce`re, J .-P.; Faure, R.; Rodriguez, J .
Synlett 1992, 737. Marshall, J . A.; DuBay, W. J . J . Am. Chem. Soc.
1992, 114, 1450. Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J .
Org. Chem. 1992, 57, 4754. Kataoka, Y.; Tezuka, M.; Takai, K.;
Utimoto, K. Tetrahedron Lett. 1992, 48, 3495. Yang, Y.; Wong, H. N.
C. J . Chem. Soc., Chem. Commun. 1992, 656. Song, Z. Z.; Zhou, Z. Y.;
Mak, T. C. W.; Wong, H. N. C. Angew. Chem., Int. Ed. Engl. 1993, 32,
432. J i, J .; Lu, X. J . Chem. Soc., Chem. Commun. 1993, 764. Aso, M.;
Ojida, A.; Yang, G.; Cha, O.-J .; Osawa, E.; Kanematsu, K. J . Org.
Chem. 1993, 58, 3960. Marshall, J . A.; DuBay, W. J . J . Org. Chem.
1993, 58, 3435. Katritzky, A. R.; Li, J .; Gordeev, M. F. J . Org. Chem.
1993, 58, 3038. Frey, H. Synlett 1993, 905. Marshall, J . A.; DuBay,
W. J . J . Org. Chem. 1993, 58, 3602. Shishido, K;; Umimoto, K.; Ouchi,
M.; Irie, O.; Omodani, T.; Takata, T.; Shibuya, M. J . Chem. Res. 1993,
58; Marson, C. M.; Harper, S.; Wrigglesworth, R. J . Chem. Soc., Chem.
Commun. 1994, 1879. Song, Z. Z.; Wong, H. N. C. J . Org. Chem. 1994,
59, 33. Marshall, J . A.; Bartley, G. S. J . Org. Chem. 1994, 59, 7169.
Antonioletti, R.; Cecchini, C.; Cianni, B.; Magnanti, S. Tetrahedron
Lett. 1995, 36, 9019. Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl.
1995, 34, 1581. Trost, B. M.; McIntosh, M. C. J . Am. Chem Soc. 1995,
117, 7255. Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995,
51, 13089. Bew, S. P.; Knight, D. W. Chem. Commun. 1996, 1007.
Under these conditions the 2,5-disubstituted furan de-
rivative 3a was isolated in a sparing 19% yield along with
the stereoisomeric 2,5-dialkylidenetetrahydrofuran de-
(10) Donnelly, D. M. X.; Meegan, M. J . In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press:
New York, 1984; Vol. 3, pp 657-712.
(11) Nakanishi, K. In Natural Products Chemistry; Kodansha,
Ltd.: Tokyo, 1974.
(12) Lipshutz,B. H. Chem. Rev. 1986, 86, 795; Pelter, A.; Rowlands,
M. Tetrahedron Lett. 1987, 28, 1203; Tanis, S. T.; Robinson, E. D.;
McMills, M. C.; Watt, W. J . Am. Chem. Soc. 1992, 112, 8349.

Synthesis of 2,5-Disubstituted Furans
J . Org. Chem., Vol. 62, No. 16, 1997 5329
Ta ble 2. P a lla d iu m -Ca ta lyzed An n u la tion of Ar yl Ha lid es 2 w ith Meth yl 3-Oxo-6-h ep tyn oa te (1a )a
reaction
temp (°C)
reaction
time (h)
yield (%)
yield (%)
yield (%)
entry
aryl halide 2
of 3b
of 4b
of 5b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
m-F3C-C6H4-I (2b)
m-F3C-C6H4-I (2b)
m-F3C-C6H4-I (2b)
p-OHC-C6H4-Br (2c)
p-OHC-C6H4-Br (2c)
m-OHC-C6H4-Br (2d )
m-OHC-C6H4-Br (2d )
m-MeCO-C6H4-Br (2e)
m-MeCO-C6H4-Br (2e)
p-MeOOC-C6H4-I (2f)
p-MeOOC-C6H4-I (2f)
m-MeOOC-C6H4-I (2g)
m-MeOOC-C6H4-I (2g)
m-O2N-C6H4-I (2h )
m-O2N-C6H4-I (2h )
p-O2N-C6H4-Br (2i)
N
100c
80c
5.5
20
87
76
47
57
38
43
-
-
-
6
-
-
60d
5.0
1.75
5.5
5.0
2.5
3.5
4.5
5.0
7.0
5.0
7.0
1.75
5.0
2.5
6.0
21
-
100c
60d
-
-
-
-
-
22
-
-
-
25
-
-
-
-
-
100c
60d
-
-
100c
60d
89
8
-
49
-
100c
60d
80
29
77
6
82
66
50
73
10
-
100c
60d
45
-
100c
60d
-
100c
100c
-
-
Br (2j)
S
18
19
20
21
22
23
m-F-C6H4-I (2k )
p-F-C6H4-I (2l)
PhI (2m )
PhI (2m )
p-MeO-C6H4-I (2n )
p-MeO-C6H4-I (2n )
100c
100c
100c
60d
5.0
5.0
3.0
7.0
6.0
17
39
12
9
-
-
-
14
49
-
30
25
19
-
-
21
51
-
100c
60d
57
a
b
Reactions were carried out in DMF under an argon atmosphere. Yields are for pure isolated products. c 1a :2:K2CO3:Pd(PPh3)4
)
d
1.5:1.0:1.5:0.05. 1a :2:K2CO3:Pd(PPh3)4 ) 1.2:1.0:5:0.05.
the base:alkyne ratio from 5:1 to 1.5:1. Under these
conditions the starting alkyne disappears very quickly,
and the isomerization of the addition intermediates 4 and
5 to 3 is faster than the decomposition of the furan
derivative. The yield of 3a increased to 76% in 3 h, and
only trace amounts if any of 4a and 5a were detected
into the reaction mixture (Table 1, entry 7). Entries 7
and 8 (Table 1) illustrate the dominant effect on the
reaction outcome of the temperature increase, and entries
8 and 9 (Table 1) illustrate the effect of decreasing the
base:alkyne ratio. The study was next extended to
include some other aryl halides. The preparative results
are summarized in Table 2 (entries 1, 4, 8, 10, 12, 14,
16, 17, 18). The best results have been obtained with
aryl halides bearing electron-withdrawing substituents,
maybe because the higher acidity of the methylene
protons of the 2,5-dialkylidenetetrahydrofuran interme-
diates favors the isomerization step. In the presence of
electron-donating substituents in the aromatic ring, 4
and 5 showed a strong inertness to isomerize, even at
100 °C (Table 2, entries 22 and 23). The employment of
stronger bases resulted in the formation of decomposition
products. For example, treatment of 5n with MeONa in
an anhydrous 1:2 MeOH/THF mixture at 25 °C for 24 h
produced 6n as the main reaction product (eq 4) and none
of the furan derivative was isolated. In the presence of
KOBu-t (HOBu-t/THF 1:6; 60 °C; 3 h) a complex reaction
mixture was obtained that was not investigated.
disubstituted-furans containing a branched side chain.
As an example, exposure of 1b, readily prepared from
1a through the palladium-catalyzed coupling with p-
acetylphenyl iodide, to m-carbethoxylphenyl iodide under
usual conditions produced the corresponding furan de-
rivative 3o in high yield (eq 5). The presence of a
substituent on the C-2 in the starting alkyne, however,
appears to prevent the isomerization step. At least, this
is the result we obtained with ethyl 2-methyl-3-oxo-6-
heptynoate 1c14 (eq 6).
Mechanistically, the present reaction may proceed
through the following basic steps (illustrated by 1a in
eq 7): (a) formation of the η2-palladium complex 7, (b)
generation of the σ-vinylpalladium complex 8 via regio-
selective trans addition of the oxygen and palladium
across the carbon-carbon triple bond (no evidence was
attained of annulation products arising from the nucleo-
philic attack of the carbon terminus of the putative
enolate intermediate), (c) reductive elimination of Pd0
species to give the stereoisomers 4 and 5, and (d)
It may be worth mentioning that the organopalladium-
promoted annulation has always been found to be fast
and efficient, independently of the nature of the aryl
halide. The low yields of 4 and 5 reported in Table 2 in
the reactions run at 60 °C reflect our efforts to favor the
isomerization step by prolonging reaction times. 4 and
5 can be isolated in high yields interrupting the reaction
as soon as the annulation step is completed. For ex-
ample, 4n and 5n were isolated in an overall 81% yield
after 7 h (Table 2, entry 21), when 3n was completely,
or near, absent from the reaction mixture.
(14) 1c was prepared through a malonate method involving the
preparation of a magnesium-malonate complex from the potassium salt
of the malonate monoethyl ester, followed by its reaction with the
imidazolide of 4-pentynoic acid prepared in situ from pentynoic acid
and carbonyl diimidazolide: Clay, R. C.; Collom, T. A.; Karrick, G. L.;
Wemple, J . Synthesis 1993, 290.
The extension of the procedure to alkyl 3-oxo-7-
substituted-6-heptynoates provides an entry into 2,5-

5330 J . Org. Chem., Vol. 62, No. 16, 1997
Cacchi et al.
arise from the base-catalyzed annulation of the coupling
intermediate possibly generated from the η2-acetylene-
palladium complex 7 (eq 9a). This pathway, however,
seems to be flawed by the absence of the arylalkyne 1b
as intermediate in the palladium-catalyzed reaction of
1a with 2a (none of 1b was in fact discernible monitoring
the reaction) and by the lower reaction rate for the base-
catalyzed annulation of 1b (compare eq 8a with Table 1,
entry 9). In addition, no cyclization derivative (3, 4, or
5) was isolated when methyl 3-oxo-7-(p-methoxyphenyl)-
6-heptynoate (1d ) was treated with K2CO3 in the absence
isomerization of 4 and 5 to 3 (very likely through a base-
catalyzed process; 4a was recovered essentially un-
changed when warmed at 60 °C in DMF for 6 h in the
absence of base).
of palladium. The main reaction product was the ketone
14 (51% yield) resulting from the decarboxylation of 1d .
The starting alkyne was recovered in 25% yield (eq 8b).
These results suggest that the efficiency of the base-
catalyzed annulation depends strongly on the nature of
the substituent on the aromatic ring. Conversely, an-
nulation promoted by σ-arylpalladium complexes is a
very efficient reaction, both with electron-donating and
electron-withdrawing substituents. The formation of 3o
in the reaction of m-carbethoxyphenyl iodide with 1b, in
which the absence of a Csp-H bond prevents any coupling
reaction (eq 5), also argues in favor of an annulation
reaction promoted by σ-arylpalladium complexes.
In effect, the isolation of the furan derivative 3a in 51%
yield upon treatment of 1b under our standard condi-
tions, omitting the aryl halide and the palladium catalyst
(eq 8a), appears to suggest that an alternative mecha-
nism might be operating. Compound 3a could in fact

Synthesis of 2,5-Disubstituted Furans
J . Org. Chem., Vol. 62, No. 16, 1997 5331
4-(N,N-dimethylamino)pyridine (1.870 g, 15.28 mmol) in CH2Cl2
(5 mL). The reaction mixture was stirred at room temperature
for 24 h. Then the reaction mixture was filtered and washed
five times with 30 mL of CH2Cl2. The organic phase was
exctracted with 2 N HCl, washed with water, dried over
Na2SO4, and evaporated under reduced pressure. The residue
was diluted with 15 mL of methanol and refluxed overnight.
The solution was concentrated under reduced pressure, and
the residue was chromatographed on silica gel, eluting with
n-hexane/EtOAc (80/20 v/v) to afford 1a (1.099 g, 70% yield):
mp oil; IR (liquid film) 3288, 2123, 1745, 1721 cm-1; 1H NMR
δ 3.75 (s, 3H), 3.50 (s, 2H), 2.82 (t, J ) 6.9 Hz, 2H), 2.47 (dt,
J ) 6.9 Hz, J ) 2.6 Hz, 2H), 1.99 (t, J ) 2.6 Hz, 1H); 13C NMR
δ 200.52, 167.35, 82.50, 69.04, 52.40, 48.88, 41.57, 12.76; MS
(CI) m/e (relative intensity): 155 (M+ + 1, 100). Anal. Calcd
for C8H10O3: C, 62.31; H, 6.54. Found: C, 62.44; H, 6.55.
Typ ica l P r oced u r e for th e P r ep a r a tion of 2,5-Disu b-
stitu ted F u r a n s 3 fr om Meth yl 3-Oxo-6-h ep tyn oa te (1a ).
2-(Ca r b om et h oxym et h yl)-5-((p -a cet ylp h en yl)m et h yl)-
fu r a n (3a ). To a stirred solution of methyl 3-oxo-6-heptynoate
(1a ) (0.113 g, 0.73 mmol) and p-acetylphenyl iodide (2a ) (0.120
g, 0.49 mmol) in DMF (3 mL) were added K2CO3 (0.101 g, 0.73
mmol) and Pd(PPh3)4 (0.028 g, 0.02 mmol). The reaction
mixture was stirred at 100 °C for 3 h under argon. After
cooling the mixture, ethyl acetate was added, and the organic
layer was washed with water, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was chromato-
graphed on silica gel, eluting with n-hexane/EtOAc (85/15 v/v)
to afford 3a (0.151 g, 76% yield): mp oil; IR (liquid film) 1743,
The most convincing evidence confirming the validity
of a mechanism producing the furan ring without requir-
ing the cleavage of the Csp-H bond (eq 7) and ruling out
the possible formation of 3 through a coupling/cyclization
sequence (eq 9a) is the isolation of the deuterio derivative
3q from the reaction of methyl 3-oxo-7-deuterio-6-hep-
tynoate 1e with p-acetylphenyl iodide (eq 10).
Another possible mechanism for the generation of 3,
which would meet the requirement of producing the furan
ring without involving the Csp-H bond, might be con-
sidered (eq 9b). This involves the (a) syn addition of the
σ-arylpalladium complex to the carbon-carbon triple
bond to give the σ-vinylpalladium complex 10, (b) nu-
cleophilic attack of the oxygen on the palladium atom to
give the six-membered ring, oxygen-containing pallada-
cycle 11, (c) reductive elimination of Pd0 species, and (d)
base-catalyzed isomerization of the stereoisomeric alkyli-
dene furan derivatives 12 and 13. This mechanism,
however, may be safely excluded because it predicts the
wrong stereochemistry for the carbon-carbon double
bond bearing the added aryl unit in the intermediates
12 and 13.
In conclusion, we have shown that the present syn-
thesis of 2,5-disubstituted furans from readily available
alkyl 3-oxo-6-heptynoates and 3-oxo-7-substituted-6-hep-
tynoates is quite efficient with aryl halides bearing
electron-withdrawing substituents. The poor results
achieved with aryl halides bearing electron-donating
substituents depends on the requirements of the base-
catalyzed isomerization step (the annulation step pro-
duces good results with aryl halides bearing both electron-
withdrawing and electron-donating substituents). In
spite of this limitation, the reaction can accommodate a
variety of considerable functionalities, amenable of fur-
ther functionalization, and may represent a useful method
for the preparation of this class of compounds.
1
1684 cm-1; H NMR δ 7.91 (d, J ) 8.0 Hz, 2H), 7.36 (d, J )
8.0 Hz, 2H), 6.14 (d, J ) 3.1 Hz, 1H), 5.96 (d, J ) 3.1 Hz, 1H),
4.00 (s, 2H), 3.72 (s, 3H), 3.64 (s, 2H), 2.59 (s, 3H); 13C NMR
δ 197.83, 169.95, 152.89, 146.79, 143.70, 135.51, 128.87,
128.61, 108.84, 107.71, 52.24, 34.39, 33.90, 26.61; MS m/e
(relative intensity) 272 (M+, 53), 213 (100), 147 (63). Anal.
Calcd for C16H16O4: C, 70.56; H, 5.93. Found: C, 70.65; H,
5.91.
2(Z)-(C a r b o m e t h o x y m e t h y lid e n e )-5(E )-((p -a c e t y l-
p h en yl)m eth ylid en e)-3,4-tetr a h yd r ofu r a n (4a ): mp 178-
180 °C; IR (KBr) 1708, 1683 cm-1; 1H NMR δ 7.84 (d, J ) 10.0
Hz, 2H), 7.22 (d, J ) 10.0 Hz, 2H), 6.34 (bs, 1H), 4.90 (t, J )
1.8 Hz), 3.67 (s, 3H), 2.91 (bs, 4H), 2.53 (s, 3H); 13C NMR δ
197.26, 166.90, 165.15, 158.93, 140.25, 134.39, 128.57, 127.22,
104.75, 90.75, 50.90, 29.81, 26.39, 25.12; MS m/e (relative
intensity) 272 (M+, 100), 257 (61), 213 (69). Anal. Calcd for
C16H16O4: C, 70.56; H, 5.93. Found: C, 70.66; H, 5.95.
2(E )-(C a r b o m e t h ox ym e t h y lid e n e )-5(E )-((p -a c e t y l-
p h en yl)m eth ylid en e)-3,4-tetr a h yd r ofu r a n (5a ): mp 153-
155 °C; IR (KBr) 1708, 1679 cm-1; 1H NMR δ 7.94 (d, J ) 12.0
Hz, 2H), 7.27 (d, J ) 12.0 Hz, 2H), 6.27 (t, J ) 1.8 Hz, 1H),
5.56 (t, J ) 1.8 Hz, 1H), 3.74 (s, 3H), 3.41 (td, J ) 7.5 Hz, J )
1.8 Hz, 2H), 3.06 (td, J ) 7.5 Hz, J ) 1.8 Hz, 2H), 2.61 (s,
3H); 13C NMR δ 197.43, 172.28, 168.20, 158.15, 140.49, 134.59,
128.80, 127.30, 104.15, 92.52, 51.11, 28.87, 26.55, 26.19; MS
m/e (relative intensity) 272 (M+, 100), 257 (79), 213 (33). Anal.
Calcd for C16H16O4: C, 70.56; H, 5.93. Found: C, 70.47; H,
5.91.
2(E)-(Ca r b om et h oxym et h ylid en e)-5(E)-((p -m et h oxy-
p h en yl)m eth ylid en e)-3,4-tetr a h yd r ofu r a n (5n ): mp 128-
1
131 °C; IR (KBr) 1700 cm-1; H NMR δ 7.14 (d, J ) 8.8 Hz,
Exp er im en ta l Section
2H), 6.87 (d, J ) 8.8 Hz, 2H), 6.17 (t, J ) 1.7 Hz, 1H), 5.50 (t,
J ) 1.7 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.28 (td, J ) 8.1
Melting points were determined with a Bu¨chi apparatus and
are uncorrected. All of the starting materials, catalysts,
ligands, bases, and solvents (anhydrous solvents included) are
commercially available and were used as purchased, without
further purification. Reaction products were purified on
axially compressed columns (packed with SiO2, 25-40 nm,
Macherey Nagel) connected to a Gilson solvent delivery system
and to a Gilson refractive index detector and eluting with
n-hexane/EtOAc mixtures. 1H NMR spectra (CDCl3, unless
otherwise stated; TMS as internal standard) were recorded
at 200 MHz. 13C NMR spectra were recorded at 50.3 MHz.
On e-F la sk P r ep a r a tion of Meth yl 3-Oxo-6-h ep tyn oa te
(1a ) fr om 4-P en tyn oic Acid . A solution of dicyclohexylcar-
bodiimide (2.518 g, 12.23 mmol in 5 mL of CH2Cl2) was added
dropwise, at 0 °C, to a solution of 4-pentynoic acid (1.000 g,
10.19 mmol), Meldrum’s acid (2.203 g, 15.28 mmol), and
Hz, J ) 1.7 Hz, 2H), 2.94 (td, J ) 8.1 Hz, J ) 1.7 Hz, 2H); 13
C
NMR δ 172.93, 168.39, 158.01, 154.39, 128.56, 127.77, 114.11,
104.09, 91.47, 55.28, 50.90, 29.13, 25.42; MS m/e (relative
intensity) 260 (M+, 100), 221 (21), 121 (17). Anal. Calcd for
C15H16O4: C, 69.20; H, 6.20. Found: C, 69.31; H, 6.21.
Meth yl 3-Meth oxy-6-oxo-7-(p-m eth oxyp h en yl)-2-h ep -
ten oa te (6n ). A solution of sodium methoxide (0.019 g, 0.35
mmol) in anhydrous MeOH (1 mL) was added at room
temperature to a stirred solution of 5n (0.060 g, 0.23 mmol)
in anhydrous THF (1.5 mL). The reaction mixture was stirred
at room temperature for 24 h. After cooling the mixture, ethyl
acetate was added, and the organic layer was washed with
water, dried over Na2SO4, and concentrated under reduced
pressure. The residue was chromatographed on silica gel,
eluting with n-hexane/EtOAc (80/20 v/v) to afford 6n (0.020

5332 J . Org. Chem., Vol. 62, No. 16, 1997
Cacchi et al.
1
g, 30% yield): mp oil; IR (liquid film) 1710 cm-1; H NMR δ
7.12 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6Hz, 2H), 4.98 (s, 1H),
3.79 (s, 3H), 3.65 (s, 3H), 3.64 (s, 2H), 3.02 (t, J ) 8.2 Hz, 2H),
2.67 (t, J ) 8.2 Hz, 2H); 13C NMR δ 207.24, 174.92, 167.86,
158.69, 130.52, 126.38, 114.18, 90.73, 55.61, 55.33, 50.91,
48.95, 38.91, 26.64; MS m/e (relative intensity) 292 (M+, 8),
143 (30), 121 (100). Anal. Calcd for C16H20O5: C, 66.03; H,
6.94. Found: C, 66.17; H, 6.93.
added to a solution of 4-pentynoic acid (0.500 g, 5.10 mmol) in
anhydrous CH3CN (5 mL). The reaction mixture was stirred
at room temperature until the end of CO2 development.
Solution B: Et3N (2.4 mL) and MgCl2 (1.214 g, 12.76 mmol)
were added to a solution of ethyl 2-methylmalonate potassium
salt (1.939 g, 10.71 mmol) in anhydrous MeCN (5 mL). The
reaction mixture was stirred at room temperature for 2 h. The
solution A was added dropwise to the solution B maintained
under stirring at room temperature. The reaction mixture was
stirred overnight. Then, 6 N HCl (20 mL) was added and the
reaction mixture was stirred for 1 h. Ethyl acetate and
saturated NaHCO3 were added, and the organic layer was
washed with water, dried over Na2SO4, and concentrated
under reduced pressure. The residue was chromatographed
on silica gel, eluting with n-hexane/EtOAc (70/30 v/v) to afford
1c (0.740 g, 80% yield): mp oil; IR (liquid film) 3279, 2123,
P r ep a r a t ion of Met h yl 3-Oxo-7-(p -a cet ylp h en yl)-6-
h ep tyn oa te (1b). To a stirred solution of 1a (0.400 g, 2.60
mmol) and Et2NH (2.7 mL) in DMF (4 mL) were added
p-acetylphenyl iodide (0.765 g, 3.11 mmol), Pd(OAc)2(PPh3)2
(0.039 g, 0.05 mmol), and CuI (0.020 g, 0.10 mmol). The
reaction mixture was stirred at room temperature overnight
under argon. Ethyl acetate and 2 N HCl were added, and the
organic layer was separated, neutralized with a saturated
NaHCO3 solution, washed with water, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by chromatography (silica gel, n-hexane/EtOAc 60/40 v/v)
to give 1b (0.403 g, 57% yield): mp oil; IR (liquid film) 2221,
1737, 1712 cm-1; 1H NMR δ 7.87 (d, J ) 8.5 Hz, 2H), 7.45 (d,
J ) 8.5 Hz, 2H), 3.77 (s, 3H), 3.52 (s, 2H), 2.91 (dt, J ) 7.2
Hz, J ) 1.5 Hz, 2H), 2.72 (dt, J ) 7.2 Hz, J ) 1.5 Hz, 2H),
2.58 (s, 3H); 13C NMR δ 197.43, 168.39, 135.96, 131.74, 128.47,
128.21, 91.78, 80.67, 52.52, 49.00, 41.68, 27.82, 26.65, 13.94;
MS m/e (relative intensity) 272 (M+, 24), 213 (26), 199 (100).
Anal. Calcd for C16H16O4: C, 70.56; H, 5.93. Found: C, 70.66;
H, 5.95.
Meth yl 3-Oxo-7-(p-m eth oxyp h en yl)-6-h ep tyn oa te (1d ):
mp oil; IR (liquid film) 1745, 1721 cm-1; 1H NMR δ 7.31 (d, J
) 8.9 Hz, 2H), 6.80 (d, J ) 8.9 Hz, 2H), 3.79 (s, 3H), 3.74 (s,
3H), 3.51 (s, 2H), 2.86 (dt, J ) 6.6 Hz, J ) 1.1 Hz, 2H), 2.67
(dt, J ) 6.6 Hz, J ) 1.1 Hz, 2H); 13C NMR δ 201.01, 167.54,
159.33, 133.03, 115.64, 113.95, 86.44, 81.11, 55.36, 52.55,
49.12, 42.15, 14.01; MS m/e (relative intensity) 260 (M+, 23),
187 (100), 145 (75). Anal. Calcd for C15H16O4: C, 69.20; H,
6.20. Found: C, 69.31; H, 6.18.
P r ep a r a tion of 2-(Ca r bom eth oxym eth yl)-5-(p-a cetyl-
p h en yl)-5-((m -ca r beth oxyp h en yl)m eth yl)fu r a n (3o). To
a stirred solution of 1b (0.177 g, 0.65 mmol) and m-carbethoxy-
phenyl iodide (0.120 g, 0.43 mmol) in DMF (3 mL) were added
K2CO3 (0.090 g, 0.65 mmol) and Pd(PPh3)4 (0.025 g, 0.02
mmol). The reaction mixture was stirred at 100 °C for 4 h
under argon. After cooling the mixture, ethyl acetate was
added, and the organic layer was washed with water, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was chromatographed on silica gel, eluting with
n-hexane/EtOAc (60/40 v/v) to afford 3o (0.151 g, 83% yield):
mp oil; IR (liquid film) 1745, 1720 cm-1; 1H NMR δ 8.00-7.87
(m, 4H), 7.36 (d, J ) 7.6 Hz, 2H), 7.25 (d, J ) 7.6 Hz, 2H),
6.15 (d, J ) 3.1 Hz, 1H), 5.83 (d, J ) 3.1 Hz, 1H), 5.51 (s, 1H),
4.34 (q, J ) 7.1 Hz, 2H), 3.69 (s, 3H), 3.64 (s, 2H), 2.57 (s,
3H), 1.36 (t, J ) 7.1 Hz, 3H); 13C NMR δ 197.80, 169.85, 166.43,
154.60, 147.65, 146.68, 161.33, 135.89, 133.15, 130.93, 129.95,
129.02, 128.78, 128.70, 128.35, 109.99, 108.81, 61.12, 52.28,
50.60, 33.98, 26.66, 14.34; MS m/e (relative intensity) 420 (M+,
22), 388 (100), 361 (38), 271 (36). Anal. Calcd for C25H24O6:
C, 71.40; H, 5.76. Found: C, 71.31; H, 5.78.
Ba se-Ca t a lyzed An n u la t ion of Met h yl 3-Oxo-7-(p -
a cetylp h en yl)-6-h ep tyn oa te (1b). To a stirred solution of
1b (0.100 g, 0.37 mmol) in DMF (3 mL) was added K2CO3
(0.051 g, 0.37 mmol). The reaction mixture was stirred at 100
°C for 3 h under argon. After cooling the mixture, ethyl acetate
was added, and the organic layer was washed with water, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was chromatographed on silica gel, eluting with
n-hexane/ethyl acetate (85/15 v/v) to afford 3a (0.051 g, 51%
yield).
1
1737, 1721 cm-1; H NMR δ 4.20 (q, J ) 7.3 Hz, 2H), 3.54 (q,
J ) 7.2 Hz, 1H), 2.89 (dt, J ) 17.6 Hz, J ) 6.7 Hz, 1H), 2.76
(dt, J ) 17.6 Hz, J ) 6.7 Hz, 1H), 2.48 (dt, J ) 6.7 Hz, J ) 1.7
Hz, 2H), 1.96 (t, J ) 1.7 Hz, 1H), 1.36 (d, J ) 7.2 Hz, 3H),
1.28 (t, J ) 7.3 Hz, 3H); 13C NMR δ 203.70, 170.31, 82.74,
68.87, 61.51, 52.77, 40.14, 14.11, 12.94, 12.64; MS (CI) m/e
(relative intensity) (183 (M+ + 1, 100). Anal. Calcd for
C10H14O3: C, 65.90; H, 7.75. Found: C, 65.81; H, 7.74.
2(E)-(1-Ca r b et h oxyp r op ylid en e)-5(E)-((m -(t r iflu or o-
m eth yl)p h en yl)m eth ylid en e)-3,4-tetr a h yd r ofu r a n (5p ):
mp 89-91 °C; IR (nujol) 1704 cm-1; 1H NMR δ 7.55-7.30 (m,
4H), 6.27 (t, J ) 2.1 Hz, 1H), 4.19 (q, J ) 7.0 Hz, 2H), 3.29
(tq, J ) 7.0 Hz, J ) 1.6 Hz, 2H), 3.01 (td, J ) 7.0 Hz, J ) 2.1
Hz, 2H), 1.91 (t, J ) 1.6 Hz, 3H), 1.31 (t, J ) 7.0 Hz, 3H); 13
C
NMR δ 160.70, 165.80, 157.62, 136.60, 132.64, 131.22, 130.80
(q, J ) 32.4 Hz), 130.37, 128.94, 124.10 (q, J ) 272.8), 123.72
(q, J ) 3.7 Hz), 122.32 (q, J ) 3.7 Hz),102.75, 100.88, 61.05,
29.37, 26.54, 14.40, 11.53; MS m/e (relative intensity) 326 (M+,
100), 281 (34), 252 (37). Anal. Calcd for C17H17F3O3: C, 62.56;
H, 5.25. Found: C, 62.64; H, 5.23.
P r ep a r a tion of Meth yl 3-Oxo-7-d eu ter io-6-h ep tyn oa te
(1e). To a stirred solution of methyl 3-oxo-6-heptynoate (1a )
(0.500 g, 3.25 mmol) in anhydrous THF (4 mL) at -72 °C was
added dropwise a solution of lithium diisopropylamide (2 M)
in THF (8.1 mL); the reaction mixture was warmed at 0 °C
for 45 min. Then the solution was cooled at -72 °C, and D2O
(2 mL) was added. Then the reaction mixture was warmed
at room temperature for 1 h. Ethyl acetate and 2 N HCl were
added, and the organic layer was washed with water, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was chromatographed on silica gel, eluting with
n-hexane/EtOAc (80/20 v/v) to afford the deuteriated and the
undeuteriated product in 85% yield (0.378 g).
1
The methyl 3-oxo-6-heptynoate % D was determined by H
NMR and MS. From these analyses an abundance of D of
approximately 76% was calculated.
2-(1-Ca r b om e t h oxy-1-d e u t e r iom e t h ylid e n e )-5-((p -
a cetylp h en yl)m eth yl)fu r a n (3q): mp oil; IR (liquid film)
1745, 1678 cm-1; 1H NMR δ 7.85 (d, J ) 8.4 Hz, 2H), 7.26 (d,
J ) 8.4 Hz, 2H), 6.09 (d, J ) 3.1 Hz, 1H), 5.92 (d, J ) 3.1 Hz,
1H), 3.95 (s, 1.25H), 3.66 (s, 3H), 3.60 (s, 2H), 2.53 (s, 3H); 13
C
NMR δ 197.82, 169.96, 152.92, 146.84, 143.73, 135.56, 128.89,
128.63, 108.86, 107.73, 52.26, 33.92, 33.90 (t, J ) 19.6 Hz),
26.62; MS m/e (relative intensity) 273 (M+, 58), 214 (100). Anal.
Calcd for C16H16O4: C, 70.56; H, 5.93. Found: C, 70.41; H,
5.94.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the Consiglio Nazionale delle Ricerche (CNR) and
the Ministero dell’Universita` e della Ricerca Scientifica
(MURST) for financial support of this research. The
authors are also greatly indebted to Dr. Luciana Tur-
chetto of the Istituto Superiore di Sanita` for obtaining
the mass spectra of new products.
6-(p-Meth oxyp h en yl)h ex-5-yn -2-on e (14): mp oil; IR
(Nujol) 1713 cm-1; H NMR δ 7.31 (d, J ) 8.9 Hz, 2H), 6.80
1
(d, J ) 8.9 Hz, 2H), 3.77 (s, 3H), 2.76-2.60 (m, 4H), 2.18 (s,
3H); 13C NMR δ 206.81, 189.14, 132.87, 115.66, 113.79, 86.87,
80.68, 55.20, 42.57, 29.90, 13.97; MS m/e (relative intensity)
202 (M+, 53), 187 (100), 145 (71). Anal. Calcd for C13H14O2:
C, 77.19; H, 6.98. Found: C, 77.30; H, 6.96.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 3b-m (3 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
P r epar ation of Eth yl 2-Meth yl-3-oxo-6-h eptyn oate (1c).
Solution A: 1,1′-carbonyldiimidazole (1.134 g, 10.74 mmol) was
J O962386V