Synthesis of 2(3H)-furanones via electrophilic cyclization

Article abstract of DOI:10.1021/jo702666j

(Chemical Equation Presented) A variety of highly substituted 2(3H)-furanones are readily prepared from 3-alkynoate esters and the corresponding acids via electrophilic cyclization. Successful electrophiles in this process include I₂, ICl, and

Full text of DOI:10.1021/jo702666j

Synthesis of 2(3H)-Furanones via Electrophilic Cyclization
Ziwei W. Just and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed December 14, 2007
A variety of highly substituted 2(3H)-furanones are readily prepared from 3-alkynoate esters and the
corresponding acids via electrophilic cyclization. Successful electrophiles in this process include I2, ICl,
and PhSeCl. This highly efficient process proceeds under mild conditions, tolerates various functional
groups, and generally provides substituted 2(3H)-furanones in good to excellent yields.
SCHEME 1
Introduction
2(3H)-Furanone derivatives1 constitute an important group
of natural products and possess a wide range of biological
activities. For example, the dihydro-2(3H)-furanone moiety is
abundant in a large variety of natural and synthetic compounds
used as agrochemicals, pharmaceuticals, and in the food
industry.2 Recently, several highly substituted, unsaturated
2(3H)-furanones have been discovered, attracting great interest
due to their biological activities. For example, the naturally
occurring compound Spirovibsanin A (I) has been isolated from
the plant Viburnum awabuki.3 Some other highly substituted
2(3H)-furanones, such as spiro[butenolide]pyrrolidines (II), have
been studied for their antibacterial and antifungal activity against
human pathogenic bacteria and dermatophytic fungi (Scheme
1).4
azoles,7 isoindolin-1-ones,8 benzo[b]thiophenes,9 bicyclic â-lac-
tams,10 indoles,11 chromones,12 pyrilium salts and isoch-
romenes,13 2-naphthols,14 benzofurans,15 cyclic carbonates,16
(7) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (b) Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643.
(8) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432.
(9) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.;
Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(10) Ren, X.-F.; Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.;
Gonza´lez, J.; Turos, E. J. Org. Chem. 1998, 63, 8898.
The electrophilic cyclization of functionally substituted
alkynes has attracted much attention due to its wide utility in
the preparation of a range of useful, functionally substituted
heterocycles and carbocycles,5 including quinolines,6 isox-
(11) (a) Barluenga, J.; Trincado, M.; Rublio, E.; Gonza´lez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406. (b) Muhammad, A.; Knight, D. W.
Tetrahedron Lett. 2004, 45, 539. (c) Yue, D.; Larock, R. C. Org. Lett. 2004,
6, 1037. (d) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62.
(e) Yue, D.; Yao, T.; Larock, R. C. J. Comb. Chem. 2005, 7, 809.
(12) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006,
71, 1626.
(13) (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonza´lez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (b) Yue, D.; Della Ca´, N.; Larock,
R. C. Org. Lett. 2004, 6, 1581. (c) Yue, D.; Della Ca´, N.; Larock, R. C. J.
Org. Chem. 2006, 71, 3381.
(1) (a) Yao, Y. S. Chem. ReV. 1964, 64, 353. (b) Yao, Y. S. Chem. ReV.
1976, 76, 625.
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(b) Hislop, J.-A.; Hunt, M. B.; Fielder, S.; Rowan, D. D. J. Agric. Food
Chem. 2004, 52, 7075. (c) Frediani, P.; Rosi, L.; Frediani, M.; Bartolucci,
C.; Bambagiotti-Alberti, M. J. Agric. Food Chem. 2007, 55, 3877.
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(5) For a review, see: Larock, R. C. In Acetylene Chemistry. Chemistry,
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7, 763.
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1999, 1432. (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
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10.1021/jo702666j CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/06/2008
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J. Org. Chem. 2008, 73, 2662-2667

2(3H)-Furanones Via Electrophilic Cyclization
pyrroles,17 furans,18 isocoumarins and R-pyrones,19 isoquinolines
and naphthyridines,20 polycyclic aromatics,14,21 benzo[b]sele-
nophenes,22 and furopyridines.23 Herein, we report an efficient
approach to various highly substituted 2(3H)-furanones by the
electrophilic cyclization of 3-alkynoate esters and acids. The
resulting iodine-containing products can be further elaborated
to a wide range of functionally substituted furanones using
subsequent palladium-catalyzed processes.
All of the 3-alkynoic acids were prepared from the corre-
sponding esters by alkaline hydrolysis (eq 4).27 The detailed
syntheses of all of the starting materials are provided in the
experimental section.
To examine the reactivity of the 3-alkynoate esters, we first
explored the reaction of the 3-alkynoate ester 1 with 1.5 equiv
of I2 in dichloromethane under our previously established
reaction conditions for the synthesis of benzo[b]thiophenes9b
and indoles.11d The reaction proceeded smoothly and reached
completion in 1.5 h, affording an 87% yield of the iodolactone
2 (Table 1, entry 1). We have also examined the reaction of
ester 1 with the readily available electrophiles ICl and PhSeCl.
ICl gave the fastest reaction and reached completion in 1 h
(Table 1, entry 2). However, ICl afforded a 1:1 inseparable
mixture of the corresponding 4-iodo- and 4-chloro-2(3H)-
furanones in a 70% total yield. PhSeCl has also been success-
fully employed in this electrophilic cyclization, providing a 70%
yield of the desired selenium cyclization product 4 in 1 h (Table
1, entry 3).
Results and Discussion
The 3-alkynoate esters required for our studies have typically
been prepared in two or three steps. The 4-aryl-2,2-dialkylbut-
3-ynoates have been synthesized by the reaction of alkyl-
substituted ester enolates with the corresponding 2-aryl-1-
chloroethynes at -78 °C (eq 1).24
The 2,2-dialkyl-3-hexynoate esters have been synthesized by
a one-pot reaction of ethyl 2-hexynoate with excess LDA at
-98 °C, followed by the addition of an excess of the appropriate
alkyl bromide (eq 2).25
We next employed this chemistry on various substituted
3-alkynyl esters (Table 1, entries 4-37). 4-Aryl-2,2-dimethyl-
but-3-ynoate esters bearing an electron-rich aromatic ring, such
as 5, and an electron-deficient aromatic ring, such as 8, reacted
smoothly with I2, affording the corresponding lactones 6 and 9
in 78% (Table 1, entry 4) and 67% (Table 1, entry 8) yields,
respectively. However, when ICl was used in place of I2, these
esters afforded mixtures of the 4-iodo- and 4-chloro-2(3H)-
furanones. The ratio of these two products depends on the
amount of ICl employed. When we utilized 1.1 equiv of ICl in
the cyclization of 5, the iodo-substituted product 6 was
dominant. Lactones 6 and 7 were formed in an 11:1 ratio (Table
1, entry 5). As we increased the amount of ICl to 1.5 equiv, the
ratio of the iodo-substituted product 6 to the chloro-substituted
product 7 decreased to 2:1 (Table 1, entry 6). When we
employed 3.0 equiv of ICl in the reaction of 5, the ratio of 6 to
7 changed to 1:3 and the overall yield dropped to 40% (Table
1, entry 7). Furthermore, when ICl was allowed to react directly
with the pure iodo-substituted product 6, a mixture of 6 and 7
was obtained after 24 h (eq 5). For substrate 8, cyclization using
1.5 equiv of ICl also gave a mixture of the iodo-substituted
lactone 9 and the chloro-substituted lactone 10 in a 1:1 ratio
(Table 1, entry 9). Although it is very interesting that two
different halogenated products can be obtained in this process,
the mechanism for this formation is unclear.
Various methods have been utilized to prepare the remaining
esters. For example, the 2-alkyl-4-aryl-2-hydroxybut-3-ynoate
esters were prepared by reacting a terminal aryl acetylene with
EtMgBr, followed by the appropiate ethyl 2-oxoalkanoate ester
(eq 3).26
(17) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Chem.
Commun. 1998, 2207.
(18) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996,
1007. (b) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (c)
Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (d)
Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (e)
Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679. (f) Liu,
Y.; Zhou, S. Org. Lett. 2005, 7, 4609.
(19) (a) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401. (b)
Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Oliver, M. A.;
Gandour, R. D. J. Org. Chem. 1984, 49, 558. (d) Biagetti, M.; Bellina, F.;
Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023. (e) Rossi,
R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59,
2067.
(20) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437.
(21) (a) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
(b) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511.
(22) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307.
(23) Arcadi, A.; Cacchi, S.; Di, Giuseppe, S.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2002, 4, 2409.
(24) Kende, A. S.; Fludzinski, P.; Hill, J. H.; Swenson, W.; Clardy, J. J.
Am. Chem. Soc. 1984, 106, 3551.
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4704161 A, 1986. (b) Meyer, A.; Flammang, M.; Wermuth, C. G. Synthesis
1976, 832.
J. Org. Chem, Vol. 73, No. 7, 2008 2663

Just and Larock
TABLE 1. Synthesis of Substituted 2(3H)-Furanones by the Electrophilic Cyclization of 3-Alkynoate Estersa
a All reactions were conducted on a 0.25 mmol scale using 1.5 equiv of electrophile in 4 mL of CH2Cl2 at room temperature unless otherwise indicated.
b All yields are isolated yields. c Yield is the combined yields of the iodo-substituted and chloro-substituted products. The ratio of these products, as determined
by 1H NMR spectroscopy, is reported in parentheses. d Employing 1.1 equiv of ICl. e Employing 3.0 equiv of ICl. f Only the product of addition of the
electrophile across the carbon-carbon triple bond was obtained. Some addition product was not stable and reverted to the starting material upon column
chromatography. g Only unidentified products, which are not 2-furanones, were obtained. h An inseparable mixture was obtained.
When there is a six-membered ring present next to the ester
moiety, the reaction proceeds more slowly than the 2,2-dimethyl
counterpart. Cyclization of the 3-alkynoate ester 11 with I2
reached completion in 24 h and resulted in an 89% yield (Table
1, entry 10). The reaction of 11 with ICl and PhSeCl gave the
desired 2-furanone products in 89% and 73% yields, respectively
(Table 1, entries 11 and 12). The chloro-substituted product was
not observed in the ICl cyclization of 11. The I2 cyclization of
2664 J. Org. Chem., Vol. 73, No. 7, 2008

2(3H)-Furanones Via Electrophilic Cyclization
the 3-alkynoate ester 14 bearing â-ketoester functionality
proceeded smoothly and resulted in an 80% yield of the
spirocyclic product 15 (Table 1, entry 13). Although the oxygens
of both of the carbonyl groups could potentially attack the
presumed iodonium intermediate (see the later mechanistic
discussion), only the ester oxygen reacted to give the lactone
15 as the exclusive product. Previous work on the electrophilic
cyclization of acetylenic ketones and aldehydes has been
reported by others and our group.13,18 This chemoselectivity may
be explained by the closer proximity of the ester oxygen to the
hypothetical iodonium intermediate.
When we introduced an alkyl group instead of an aryl group
into the 4-position of the 3-alkynoate ester, the reaction was
somewhat faster (Table 1, entries 14-20). The cyclization of
3-alkynoate ester 16 proceeded cleanly in 1 h using I2 and
afforded an 86% yield of the iodolactone 17 (Table 1, entry
14). The yield for the analogous ICl cyclization was significantly
lower (Table 1, entry 15). However, none of the corresponding
chlorolactone was observed. For the 3-alkynoate ester 18 bearing
a cyclohexane moiety, the reaction proceeded more slowly than
that of 16, when employing I2 (Table 1, entry 16). However,
we still obtained a 78% yield of the corresponding iodolactone
19. Here ICl cyclization of 18 gave exclusively iodolactone 19
in 1 h, but in only a 60% yield (Table 1, entry 17). When we
employed I2 in the cyclization of the 2,2-diallyl-3-alkynoate ester
20, the reaction proceeded smoothly affording an 84% yield of
iodolactone 21 (Table 1, entry 18). Thus, neighboring carbon-
carbon double bonds are not problem. However, the terminal
double bonds of 20 were vulnerable to ICl and the reaction with
this reagent was messy. In the case of the cyclopentane-
containing ester 22, the yield of the corresponding iodolactone
23 was almost quantitative when using I2 (Table 1, entry 19).
The ICl cyclization of 22 gave exclusively iodolactone 23 in
only 0.5 h in an 86% yield (Table 1, entry 20).
We next considered the possibility of preparing 2-furanones
by the cyclization of 3-alkynoate esters bearing one or no
R-substituents. Since mono-R-substituted alkynoate esters are
not very stable and can be easily isomerized to the corresponding
allenic esters in the presence of a base,28 we chose to explore
instead the cyclization of the allenic ester 24, rather than a
monosubstituted 3-alkynoate ester. This cyclization resulted in
a 96% yield of the lactone 25, bearing the more stable
conjugated 2-furanone ring (Table 1, entry 21). Similar allenic
ester and acid electrophilic cyclizations with different electro-
philes have been explored by others under different reaction
conditions.29 Thus, we chose not to examine any additional
allenic esters.
When we explored the R-unsubstituted 3-alkynoate ester 26,
extensive isomerization occurred, affording the conjugated
2-furanone 27 in a 62% yield (Table 1, entry 22). Substrate 28
with a terminal alkyne failed to give the desired cyclization
product 29 even after 2 days (Table 1, entry 23). Some starting
material reacted with I2 to form a product resulting from addition
of the I2 across the acetylene moiety. Introducing two methyl
groups in the 2 position did nothing to improve the situation
(Table 1, entry 24). Introduction of a trimethylsilyl group on
the acetylene failed to afford any of the desired lactone using
either I2 or ICl (Table 1, entry 25). This ester only gave products
of addition of the I2 across the carbon-carbon triple bond, which
decomposed back to the starting material 32 upon column
chromatography. The R-unsubstituted substrate 34 also failed
to provide any iodolactone; only starting material was recovered
after aqueous work up and neither the desired conjugated
cyclization product 35 nor the corresponding 2(3H)-furanone
was observed (Table 1, entry 26). Comparing entries 1 and 26,
the Thorpe-Ingold effect of the gem-dimethyl group clearly
benefits the cyclization.30 When we attempted to cyclize the
R-hydroxy substrate 36, where the oxygen from the OH group
and the oxygen of the carbonyl group can both serve as
nucleophiles, we obtained an unidentified compound, which was
not the desired lactone (Table 1, entries 27 and 28). Even after
we protected the OH group with a TBS group, the desired I2
cyclization product was not formed (Table 1, entry 29).
Surprisingly, however, the TMS-protected compound 40 af-
forded the desired 2-furanone 41 in a 66% yield (Table 1, entry
30). However, the ICl cyclization of 40 did not give the desired
product (Table 1, entry 31). We also examined substrate 42,
which has an sp2 carbon center in the R position. No reaction
took place using I2. With ICl, we obtained a mixture of the
desired cyclization product and an acetylene addition product,
which were hard to separate (Table 1, entry 33). When we
introduced a carbonyl group into the R position (44), we only
observed acetylene addition products when employing either I2
or ICl (Table 1, entries 34 and 35).
In conclusion, the substitution and the hybridization of the R
position of the 3-alkynoate ester are crucial for the electrophilic
cyclization to take place successfully. If there is an sp2 carbon
center present on the R carbon, cyclization is difficult, apparently
due to the wider angle between the alkyne and the ester groups.
The nucleophilic oxygen of the ester group is apparently simply
too far away for the iodonium intermediate to undergo cycliza-
tion. For similar reasons, the 3-alkynoate ester bearing a
cyclopropane ring in the R position also failed to cyclize when
allowed to react with I2 and only the product of addition to the
alkyne was observed (Table 1, entry 36). The addition product
was not stable and quickly reverted back to starting material
upon aqueous work up. Due to the strained, rather reactive
cyclopropane ring system, a ring opened product was observed
in the crude 1H NMR spectrum of the corresponding ICl reaction
(Table 1, entry 37).
In an attempt to overcome some of the limitations encountered
in the electrophilic cyclization of the 3-alkynoate esters, we have
examined the cyclization of the corresponding alkynoic acids.
We hydrolyzed our previous best substrate 22 to the corre-
sponding 3-alkynoic acid 48. This 3-alkynoic acid reacted with
both I2 and ICl in the presence of 3 equiv of NaHCO3 in CH3-
CN in slightly better yields than the corresponding ester (Table
2, entries 1 and 2), suggesting that an acid group or rather the
corresponding carboxylate is a better nucleophile than the ester
in these cyclization reactions. PhSeCl was also a good electro-
phile and gave the desired product 49 in an 85% yield (Table
2, entry 3). Next, we transformed an unsuccessful 3-alkynoate
ester 46 to the corresponding acid 50 and conducted the same
cyclization reaction. As we desired, the acid 50 gave the
cyclization product 47 using either I2 or ICl (Table 2, entries 4
and 5). Under the basic conditions, the acidic hydrogen is
removed and the anionic carboxylate becomes a better nucleo-
(27) (a) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini, P.
Tetrahedron 1998, 54, 135. (b) Chui, C. C.; Jordan, F. J. J. Org. Chem.
1994, 59, 5763.
(28) Sleeman, M. J.; Meehan, G. V. Tetrahedron 1989, 30, 3345.
(29) (a) Fu, C.; Ma, S. Eur. J. Org. Chem. 2005, 3942. (b) Ma, S.; Wu,
S. Tetrahedron Lett. 2001, 42, 4075. (c) Ma, S.; Pan, F.; Hao, X.; Huang,
X. Synlett 2004, 85.
(30) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735.
J. Org. Chem, Vol. 73, No. 7, 2008 2665

Just and Larock
TABLE 2. Synthesis of Substituted 2(3H)-Furanones by the
SCHEME 2. Mechanism of the Electrophilic Cyclization of
3-Alkynoate Esters
Electrophilic Cyclization of Alkynoic Acidsa
SCHEME 3. Mechanism of the Electrophilic Cyclization of
3-Alkynoic Acids
the 3-alkynoic acids, the acidic hydrogen is removed under the
basic reaction conditions and the anionic oxygen of the
carboxylate serves as a better nucleophile. In this case, after
the electrophile coordinates to the carbon-carbon triple bond,
the anionic oxygen attacks the intermediate to form the 4-iodo-
2(3H)-furanone directly (Scheme 3). For both the 3-alkynoate
esters and the 3-alkynoic acids, the hybridization of the carbon
in the R position is crucial for the cyclization to take place.
The presence of an sp2 carbon center in the R position of either
the 3-alkynoate ester or the 3-alkynoic acid produced unsuc-
cessful cyclizations. Overall, 3-alkynoic acids provide better
results in these electrophilic cyclizations than the corresponding
3-alkynoate esters.
This approach to 4-iodo-2(3H)-furanones provides a very
useful synthesis of various substituted 2(3H)-furanones via
elaboration of the resulting iodide functionality into other
substituents. For instance, the resulting iodolactones are par-
ticularly useful intermediates in many palladium-catalyzed
processes, such as Sonogashira, Suzuki, and Heck cross-
couplings. For instance, compound 23 can be treated under
standard Heck,31 Sonogashira,32 Suzuki,33 and carbonylation34
conditions, providing the corresponding coupling products 59-
62, respectively (Scheme 4).
a All reactions employing carboxylic acids were conducted on a 0.25
mmol scale, using 1.5 equiv of I2 and 3.0 equiv of NaHCO3 in 4 mL of
CH3CN at room temperature. b All yields are isolated yields. c Only the
product of addition of the electrophile across the carbon-carbon triple bond
was obtained.
phile than the ester group (see the later mechanistic discussion).
Encouraged by these results, we next prepared acid 51 from
the unsuccessful substrate 36. As expected, the desired lactone
37 was obtained upon I2 cyclization (Table 2, entry 6). Reactions
employing ICl and PhSeCl also afforded high yields of the
anticipated products (Table 2, entries 7 and 8). The hydroxy
acid 53 also gave good to excellent yields with all of these
electrophiles (Table 2, entries 9-11). When we introduced a
carbonyl group into the R position, none of the desired furanone
product was observed using either I2 or ICl (Table 2, entry 12).
Thus, the presence of an sp2 carbon in the R position is still a
problem even with carboxylic acid substrates. To solve this
problem, we protected the R carbonyl group as an acetal and
the cyclization of acetal 57 proceeded smoothly using either I2
or ICl to afford 67% and 96% yields of the anticipated lactone
(Table 2, entries 13 and 14).
(31) For leading reviews of the Heck reaction, see: (a) De Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b) Shibasaki,
M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371. (c) Cabri,
W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) Overman, L. E. Pure
Appl. Chem. 1994, 66, 1423.
(32) For reviews, see: (a) Campbell, I. B. The Sonogashira Cu-Pd-
Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Taylor, R.
T. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217-235. (b) Sonogashira,
K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053. (c)
Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-549.
(33) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Suzuki,
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: New York, 1998; Chapter 2.
(34) Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.;
Cote, B.; Frenette, R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.;
Laliberte, F.; Lynch, J. J.; Mancini, J.; Martins, E.; Masson, P.; Muise, E.;
Pon, D. J.; Siegl, P. K. S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young,
R. N.; Girard, Y. J. Med. Chem. 2003, 46, 2413.
Mechanistically, we believe that the cyclizations of the
3-alkynoate esters proceed by coordination of the carbon-
carbon triple bond to the electrophile, followed by nucleophilic
attack by the oxygen of the carbonyl group of the ester to
produce an intermediate A, which undergoes removal of the
alkyl group of the ester group via SN2 displacement by
nucleophiles present in the reaction mixture (Scheme 2). For
2666 J. Org. Chem., Vol. 73, No. 7, 2008

2(3H)-Furanones Via Electrophilic Cyclization
SCHEME 4. Pd-Catalyzed Diversification of 4-Iodo-2(3H)-furanone Derivatives
General Procedure for Preparation of 4-Iodo-2(3H)-fura-
Conclusions
nones from Alkynoic Acids (Table 2). To a vial of the corre-
sponding alkynoic acid (0.25 mmol) in 1 mL of CH3CN was added
NaHCO3 (0.75 mmol). The mixture was stirred for 5 min under
Ar. Then I2 or ICl (0.375 mmol) in 3 mL of CH3CN was added
dropwise to the above solution. The reaction was stirred at room
temperature for the indicated time. The mixture was then quenched
with 20 mL of saturated aqueous Na2S2O3 solution and extracted
three times with ethyl ether (20 mL each). The combined organic
layers were dried over anhydrous MgSO4, filtered and evaporated
under reduced pressure. The product was purified by chromatog-
raphy on a silica gel column.
3-Ethyl-4-iodo-2-oxaspiro[4.2]hept-3-en-1-one (47). Light yel-
low solid, mp 29-30 °C; 1H NMR (CDCl3) δ 1.18 (t, J ) 7.5 Hz,
3H), 1.33-1.48 (m, 4H), 2.50 (q, J ) 7.5 Hz, 2H); 13C NMR
(CDCl3) δ 11.2, 17.4, 22.7, 31.2, 68.2, 156.3, 177.6; IR (CH2Cl2)
2977, 2939, 1790, 1650, 1284 cm-1; HRMS (EI) calcd for C8H9O2I
263.9647, found 263.9652.
In conclusion, we have developed a simple, highly efficient
approach to various highly functionalized, unsaturated 2(3H)-
furanones via electrophilic cyclization of acetylenic esters and
acids. We have shown that the electrophiles I2, ICl, and PhSeCl
can be used in this chemistry. In most cases, the I2 cyclization
gave one pure product in a high yield. The use of ICl as an
electrophile occasionally gave more than one product. These
reactions are run under mild conditions, tolerate a number of
functional groups, and generally provide the highly substituted
2(3H)-furanones in good to excellent yields. The resulting
iodolactones are readily elaborated to more complex compounds
by using known organopalladium chemistry.
Experimental Section
General Procedure for Preparation of 4-Iodo-2(3H)-fura-
nones from Alkynoate Esters (Table 1). To a vial of the
corresponding alkynoate ester (0.25 mmol) in 1 mL of CH2Cl2 under
Ar was added dropwise a solution of I2 or ICl (0.375 mmol)
dissolved in 3 mL of CH2Cl2. The reaction was stirred at room
temperature for the indicated time. The reaction mixture was then
quenched with 20 mL of saturated aqueous Na2S2O3 solution and
extracted three times with ethyl ether (20 mL each). The combined
organic layers were dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure. The product was purified by
chromatography on a silica gel column.
Acknowledgment. We gratefully acknowledge the National
Institute of General Medical Sciences (GM070620) and the
National Institutes of Health Kansas University Chemical
Methodologies and Library Development Center of Excellence
(P50 GM069663) for support of this research. Thanks are also
extended to Johnson Matthey, Inc. and Kawaken Fine Chemicals
Co. for donating the Pd catalysts and Frontier Scientific and
Synthonix for donating boronic acids.
3-Ethyl-4-iodo-2-oxaspiro[4.4]non-3-en-1-one (23). Light yel-
low solid, mp 52-53 °C; 1H NMR (CDCl3) δ 1.13 (t, J ) 7.5 Hz,
3H), 1.88-1.93 (m, 8H), 2.40 (q, J ) 7.7 Hz, 2H); 13C NMR
(CDCl3) δ 11.0, 22.4, 26.7, 37.4, 56.7, 76.1, 155.2, 181.4; IR (CH2-
Cl2) 2959, 2871, 1779, 1663, 1460, 1442, 1278 cm-1; HRMS (EI)
calcd for C10H13O2I 292.9960, found 292.9965.
Supporting Information Available: Detailed experimental
procedures and characterization data for all previously unknown
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702666J
J. Org. Chem, Vol. 73, No. 7, 2008 2667