Synthesis of enol lactones via Cu(I)-catalyzed intramolecular O-vinylation of carboxylic acids

Article abstract of DOI:10.1021/ol9015578

With the catalysis of Cul/trans-W,W-dimethylcyclohexane-1,2-diamine, a number of carboxylic acids underwent efficient intramolecular O-vinylation with vinyl bromides leading to the synthesis of the corresponding five- and six-membered enol lactones. The same catalytic system also led to the efficient cycloisomerization of alkynoic acids.

Full text of DOI:10.1021/ol9015578

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4084-4087
Synthesis of Enol Lactones via
Cu(I)-Catalyzed Intramolecular
O-Vinylation of Carboxylic Acids
Changhui Sun,† Yewen Fang,‡ Shuang Li,† Yue Zhang,‡ Qiwu Zhao,‡ Shana Zhu,‡
and Chaozhong Li*,†,‡
Department of Chemistry, Tongji UniVersity, 1239 Siping Road, Shanghai 200092,
P. R. China, and Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China
clig@mail.sioc.ac.cn
Received July 9, 2009
ABSTRACT
With the catalysis of CuI/trans-N,N′-dimethylcyclohexane-1,2-diamine, a number of carboxylic acids underwent efficient intramolecular O-vinylation
with vinyl bromides leading to the synthesis of the corresponding five- and six-membered enol lactones. The same catalytic system also led
to the efficient cycloisomerization of alkynoic acids.
Enol lactones are structural motifs in many biologically active
natural products such as cyanobacterin1 and eresmofarfugin
A.2 They are also versatile intermediates in organic synthesis.
The preparations of enol lactones have long been an
important target and continue to be actively pursued.
Conventional methods typically involve the halolactonization
of alkynoic acids3 or the halolactonization of alkenoic acids
followed by dehydrohalogenation.4 Recent progress has been
made in the cycloisomerization of alkynoic acids, providing
an atom-economic entry to enol lactones.5 A number of
transition metal complexes have been shown to catalyze these
transformations with variable degrees of regio- and stereo-
selectivity.6 It could be envisioned that transition-metal-
catalyzed intramolecular cross-coupling reactions between
carboxylic acids and alkenyl halides would allow the direct
and stereospecific synthesis of enol lactones. However, this
strategy remains virtually unexplored. Herein we report that
the copper-catalyzed intramolecular O-vinylation of car-
(5) For reviews, see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem.
ReV. 2004, 104, 3079. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004,
104, 2127. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem.,
Int. Ed. 2004, 43, 3368.
† Tongji University.
‡ Chinese Academy of Sciences.
(6) For recent selected examples, see: (a) Mindt, T. L.; Schibli, R. J.
Org. Chem. 2007, 72, 10247. (b) Genin, E.; Toullec, P. Y.; Antoniotti, S.;
Brancour, C.; Genet, J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112.
(c) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2006, 47, 6273.
(d) Imagawa, H.; Fujikawa, Y.; Tsuchihiro, A.; Kinoshita, A.; Yoshinaga,
T.; Takao, H.; Nishizawa, M. Synlett 2006, 639. (e) Takei, I.; Wakebe, Y.;
Suzuki, K.; Enta, Y.; Suzuki, T.; Mizobe, Y.; Hidai, M. Organometallics
2003, 22, 4639. (f) Jimenez-Tenorio, M.; Puerta, M. C.; Valerga, P.;
Moreno-Dorado, F. J.; Guerra, F. M.; Massanet, G. M. Chem. Commun.
2001, 2324.
(1) Mason, C. P.; Edwards, K. R.; Carlson, R. E.; Pignatello, J.; Gleason,
F. K.; Wood, J. M. Science 1982, 215, 400.
(2) Tori, M.; Shiotani, Y.; Tanaka, M.; Nakashima, K.; Sono, M.
Tetrahedron Lett. 2000, 41, 1797.
(3) (a) Sofia, M. J.; Chakravarty, P. K.; Katzenellenbogen, J. A. J. Org.
Chem. 1983, 48, 3318. (b) Krafft, G. A.; Katzenellenbogen, J. A. J. Am.
Chem. Soc. 1981, 103, 5459.
(4) For an example, see: Maddess, M. L.; Lautens, M. Synthesis 2004,
1399.
10.1021/ol9015578 CCC: $40.75
Published on Web 08/18/2009
 2009 American Chemical Society

boxylic acids with alkenyl bromides provides an efficient
and general route to the synthesis of enol lactones.
Table 2. O-Vinylation of Carboxylic Acids 1
The past few years have witnessed a rapid progress in the
formation of aryl (or vinyl) C-X bonds (X ) N, O, S, etc.)
via copper-catalyzed Ullmann coupling between aryl (or vinyl)
halides and heteroatom-centered nucleophiles.7 The high stabil-
ity and low costs of the copper catalysts make these transforma-
tions attractive for industrial applications. By the appropriate
choice of copper source, ligand, base, and solvent, these
reactions have been developed to include a wide range of
substrates under mild conditions. Various O-centered nucleo-
philes such as alcohols and ketone enolates can be successfully
used for the coupling reactions. However, the use of carboxy-
lates as the nucleophiles remains far less explored.8 Thasana
and co-workers recently reported the preparation of benzopy-
ranones via the cyclization of 2′-halobiaryl-2-carboxylic acids
under microwave irradiation using stoichiometric amounts of
Cu(I).8a Their method failed to provide simpler lactones starting
from nonaromatic carboxylic acids; only decarboxylation was
observed. Driven by our interest in Cu(I)-catalyzed intramo-
lecular vinlyation reactions,9 we set out to study the intramo-
lecular O-vinylation of carboxylic acids.
Thus, 4-bromo-2-phenylpent-4-enoic acid (1a) was chosen
as the model substrate. Compound 1a was first subjected to
the following typical Ullmann coupling conditions: CuI (10
mol %), 1,10-phenanthroline (Phen, 20 mol %),10 K2CO3 (2
equiv) in refluxing THF. No reaction occurred within 6 h
(entry 1, Table 1). Switching the ligand to L-proline11 did
not help. To our delight, when N,N,N′,N′-tetramethylethyl-
enediamine (TMEDA)12 was used as the ligand, the expected
product 2a was obtained in 25% yield (entry 3, Table 1).
The best result (87% yield of 2a) was achieved with N,N′-
dimethylcyclohexane-1,2-diamine13 (DMCHDA) as the ligand
a Reaction conditions: 1 (0.3 mmol), CuI (0.03 mmol), DMCHDA (0.06
mmol), K2CO3 (0.6 mmol), THF (3 mL), reflux. b Isolated yield based on
1. c The reaction was conducted in refluxing acetonitrile. d Ar ) p-MeOC6H4.
f
e R ) n-C10H21. Z:E ) 83:17 determined by H NMR (300 MHz).
1
Table 1. Optimization of the Synthesis of 2a from 1a
(entry 5, Table 1). Lowering the amounts of CuI and
DMCHDA resulted in a slight decrease of the yield of 2a
(entry 9, Table 1). We next examined the effects of different
bases. It turned out that K2CO3 was superior to Cs2CO3,
K3PO4, and Na2CO3 (entries 5-8, Table 1). As a comparison,
the coupling did not proceed at all without either CuI or the
ligand or the base (entries 10-12, Table 1).
With the optimized combination (entry 5, Table 1) in hand,
we then examined the generality of this method (Table 2).
Substrates 1a-1f bearing different substituents at the C-2
position all afforded the expected cyclization products in high
yields (entries 1-6, Table 2). Dialkyl substitution at the C-2
entrya
ligand (mol %)b
base
yield (%)c
1
2
3
4
5
6
7
8
Phen (20)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
Na2CO3
K2CO3
K3PO4
none
0
0
L-proline (20)
TMEDA (20)
DMEDA (20)
DMCHDA (20)
DMCHDA (20)
DMCHDA (20)
DMCHDA (20)
DMCHDA (10)
none
25
76
87
60
27
0
76
0
0
(7) For reviews, see:(a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337. (d) Deng, W.; Liu, L.; Guo, Q.-X. Chin. J. Org. Chem. 2004,
24, 150. (e) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(f) Chemler, S. R.; Fuller, P. H. Chem. Soc. ReV. 2007, 36, 1153. (g) Evano,
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Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (i) Evano, G.; Toumi, M.; Coste,
A. Chem. Commun. 2009, 4166.
9d
10
11
12e
DMCHDA (20)
DMCHDA (20)
K2CO3
0
a Reaction conditions: 1a (0.3 mmol), CuI (0.03 mmol), ligand (0.06
mmol), base (0.6 mmol), THF (3 mL), reflux, 6 h. b Phen: 1,10-
phenanthroline. TMEDA: N,N,N′,N′-tetramethylethylenediamine. DMEDA:
N,N′-dimethylethylenediamine. DMCHDA: trans-N,N′-dimethylcyclo-
hexane-1,2-diamine. c Isolated yield based on 1a. d 5 mol % of CuI was
used. e No CuI was used.
(8) (a) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young,
L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379. (b) Yamamoto, T.; Kurata,
Y. Can. J. Chem. 1983, 61, 86. (c) Yamamoto, T. Synth. Commun. 1979,
9, 219.
Org. Lett., Vol. 11, No. 18, 2009
4085

model compound 5-bromo-3-phenylhex-5-enoic acid (3a)
failed to give the cyclization product δ-lactone 4a under the
optimized conditions, while 3a gradually decomposed. With
the assumption that bromide 3a might not be reactive enough,
5-iodo-3-phenylhex-5-enoic acid (5) as the iodo-analogue of
3a was prepared and subjected to the above conditions.
However, no expected product could be observed either. This
led us to think that the true reason might be the instability
of product 4a under the reaction conditions. Thus, the amount
of the base K2CO3 was reduced to 50 mol % to make the
reaction solution less basic. Indeed, such a modification
allowed the isolation of δ-lactone 4a in 84% yield from the
reaction of bromide 3a in refluxing acetonitrile. The reop-
timized conditions (10 mol % CuI, 20 mol % DMCHDA,
50 mol % K2CO3, CH3CN, reflux) were then applied to the
reactions of a variety of carboxylic acids, and the results
are summarized in Table 3. 5-Bromohex-5-enoic acids
3a-3c afforded the corresponding exo-lactones 4a-4c in
high yields. Aromatic carboxylic acid 3d also underwent
smooth cyclization to furnish the isochromanone 4d. The
cross-coupling in a 5-endo-like mode was also successful
as exemplified by the reaction of 3e from which furanone
4e was obtained as the isomerized product. The 6-endo-like
cyclization (3f) was also implemented in a good efficiency.
More importantly, the reoptimized conditions now allowed
the retention of configuration of the CdC bond as evidenced
by the reactions of 1i and 1j (entries 7 and 8, Table 3).
The results in Tables 2 and 3 prompted us to investigate
the O-vinylation via a four-membered ring closure. Such a
mode of cyclization was found by us to be fundamentally
preferred over other modes of cyclization in Cu(I)-catalyzed
intramolecular O-,9d N-,9f S-,9i and C-vinylation9g reactions.
Therefore, substrates such as bromide 6 were subjected to
the same treatment as above. To our disappointment, no
expected products such as 7 could be obtained. Only ketones
such as 9 were isolated in low yields (∼20%). A plausible
explanation was that the cyclization of 6 indeed took place
to give the ꢀ-lactone 7, which then underwent ring opening
to generate the ꢀ-keto acid 8. Further decarboxylation of 8
led to the formation of 9 (Scheme 1). The easy decarboxy-
Table 3. Copper-Catalyzed Cyclization of Bromoenoic Acids
a Reaction conditions: 3 or 1 (0.3 mmol), CuI (0.03 mmol), DMCHDA
(0.06 mmol), K2CO3 (0.15 mmol), CH3CN (3 mL), reflux. b Isolated yield
based on 3 or 1. c R ) n-C10H21.
position speeded up the coupling presumably because of the
Thorpe-Ingold effect (entries 5 and 6, Table 2). Substrates
1g-1j having an internal CdC bond also underwent smooth
coupling reactions (entries 7-10, Table 2). The configuration
of the CdC double bond was nicely retained in the cases of
1g and 1i, while partial isomerization occurred for the
reaction of 1j in a (Z)-configuration (entry 10, Table 2).
The above cross-coupling dealt with the cyclization in a
5-exo-like mode. We then extended this method to the
coupling via a six-membered ring closure. Surprisingly, the
Scheme 1
(9) (a) Fang, Y.; Li, C. Chem. Commun. 2005, 3574. (b) Hu, T.; Li, C.
Org. Lett. 2005, 7, 2035. (c) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (d)
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C. J. Org. Chem. 2008, 73, 8665. (i) Zhao, Q.; Li, L.; Fang, Y.; Sun, D.;
Li, C. J. Org. Chem. 2009, 74, 459.
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124, 11684.
4086
Org. Lett., Vol. 11, No. 18, 2009

conditions. Within 3 h, all the diketene decomposed, and
the ketone 11 was obtained in 21% yield. The similar
outcome of the reactions of 10 and 6 strongly suggests that
the O-vinylation of carboxylic acids via a four-membered
ring closure is in fact an efficient process.
Table 4. Cycloisomerization of Alkynoic Acids 15
During our investigation on the functional group tolerance
of the above O-vinylation processes, we found that the
copper-catalyzed reaction of carboxylic acid 12 gave not only
the expected coupling product 13 but also the cycloisomer-
ization product 14, the latter being the major product
(Scheme 1). When a catalytic amount (10 mol %) of K2CO3
was used, product 14 was obtained in 70% yield, while only
a trace amount of 13 could be detected. The formation of
14 indicated that the same catalyst system could be utilized
for the cycloisomerization of alkynoic acids. Therefore, a
number of alkynoic acids were subjected to the aforemen-
tioned experimental conditions without further optimization,
and the results are summarized in Table 4. Exo-lactones were
achieved in all cases. For internal alkynes, the (Z)-stereo-
selectivity was observed (entries 4 and 5, Table 4). The
reaction of malonic acid 15f afforded the monocycloisomer-
ization product 13 in 90% yield (entry 6, Table 4). Appar-
ently, the copper-catalyzed decarboxylation occurred prior
to cyclization. The cyclization of hex-5-ynoic acids was also
successfully implemented (entries 7-10, Table 4). It should
be noted that Mindt and Schibli recently reported the first
examples of Cu(I)-catalyzed cycloisomerization of alkynoic
acids in aqueous media.6a Our method serves as a useful
complement especially for those substrates that are insoluble
or poorly soluble in water.
In conclusion, we have successfully developed the first
examples of Cu(I)-catalyzed intramolecular O-vinylation of
carboxylic acids leading to the convenient and efficient
synthesis of five- and six-membered enol lactones under mild
conditions. The same catalyst system also allows the efficient
cycloisomerization of alkynoic acids. This chemistry should
be of useful application in organic synthesis.
a Reaction conditions: 15 (0.3 mmol), CuI (0.03 mmol), DMCHDA
(0.06 mmol), K2CO3 (0.03 mmol), THF (3 mL), reflux. b Isolated yield based
on 15. c The reaction was conducted in refluxing acetonitrile. d Z:E ) 7:1
1
determined by H NMR (300 MHz).
Acknowledgment. This project was supported by the
NSFC (Grant Nos. 20672136, 20702060, and 20832006) and
by the STCSM (Grant No. 07XD14038).
lation of ꢀ-keto acids under Ullmann coupling conditions
was previously observed by us.14 To provide more evidence
on this analysis, the diketene 10 was prepared according to
the literature procedure15 and treated under the above
Supporting Information Available: Experimental pro-
cedures for O-vinylation and cycloisomerization and char-
acterizations of 1-16. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427.
(15) (a) Clemens, R. J. Chem. ReV. 1986, 86, 241. (b) Kato, T. Acc.
Chem. Res. 1974, 7, 265.
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