Synthesis of 4-aryl-2(5h)-furanones by gold(I)-catalyzed intramolecular annulation

Article abstract of DOI:10.1002/adsc.201100069

A novel method that involves intramolecular annulation and a new type of rearrangement has been developed for the synthesis of 4-aryl-2(5H)-furanones. A variety of prop-2-ynyl 3-oxo-3-phenylpropanoates undergo annulation cyclization in the presence of chloro(triphenylphosphine)gold and trifluoromethanesulfonic to afford the desired products in moderate to high yields. Copyright

Full text of DOI:10.1002/adsc.201100069

COMMUNICATIONS
DOI: 10.1002/adsc.201100069
Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed
Intramolecular Annulation
Haifeng Sun,a He Huang,a Dengyou Zhang,a Enguang Feng,a Wangke Qian,a
Lei Zhang,a Kaixian Chen,a and Hong Liua,*
a
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological
Sciences, Chinese Academy of Sciences, Shanghai 201203, Peopleꢀs Republic of China
Fax : (+86)-21-5080-7042; e-mail: hliu@mail.shcnc.ac.cn
Received: January 27, 2011; Revised: March 20, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100069.
Abstract: A novel method that involves intramolec-
ular annulation and a new type of rearrangement
has been developed for the synthesis of 4-aryl-
2(5H)-furanones. A variety of prop-2-ynyl 3-oxo-3-
phenylpropanoates undergo annulation cyclization
in the presence of chloro(triphenylphosphine)gold
and trifluoromethanesulfonic to afford the desired
products in moderate to high yields.
gaseous CO, which is toxic, low product yields and
poor regioselectivity.
Recently, the application of intramolecular cycliza-
tion of 1,3-dicarbonyl compounds has been signifi-
cantly expanded by the use of metal catalysts or
Brønsted acids, and it has been found that this reac-
tion can be carried out at lower temperatures with a
wide variety of substrates.[12] The aforementioned in-
tramolecular cyclization has been shown to be a
Keywords: 4-aryl-2(5H)-furanones; gold(I) cata-
lysts; intramolecular annulations; prop-2-ynyl 3-
oxo-3-phenylpropanoates
4-Aryl-2(5H)-furanones constitute an important class
of heterocyclic compounds that have substantial bio-
logical activity. This furanone unit is found in many
naturally occurring products[1] such as cadiolide A
and pinusolide, as well as in synthetic pharmaceuticals
such as rofecoxib,[2] eucilat,[3] and L-784512
(Figure 1).[4]
In addition, 4-aryl-2(5H)-furanones are valuable in-
termediates in the total synthesis of natural prod-
ucts.[5] There are a number of synthetic approaches to
these interesting intermediates, including tandem cy-
clohydrocarbonylation/CO insertion of a-ketoalk-
ACHTUNGTRENNUNG
ynes,[6] Rh(I)-catalyzed CO gas-free cyclohydrocarbo-
nylation of alkynes with formaldehyde,[7] coupling-
cyclization of polymer-supported aryl iodides with
1,2-allenylcarboxylic acids,[8] Au-catalyzed isomeriza-
tion of cyclopropenes,[9] rhodium-catalyzed reaction
of internal alkynes with organoborons in a CO atmos-
phere,[10] and metal-halogen exchange of 3-bromo-2-
silyloxyfurans.[11] Unfortunately, these methods have
several disadvantages, including difficulty in handling
Figure 1. Examples of natural products and synthetic phar-
maceutical drugs.
Adv. Synth. Catal. 2011, 353, 1413 – 1419
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1413

Haifeng Sun et al.
COMMUNICATIONS
Table 1. Optimization of the reaction conditions for the syn-
thesis of 2a.[a]
AHCTUNGTRENNUNG
Entry Catalyst/Additive
Acid
Solvent Yield[b]
1
2
3
4
5
6
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
N
–
DCE
DCE
DCE
DCE
DCE
0%
HOTf
HOTf
HOTf
HOTf
45%
85%
82%
65%
61%
75%
78%
77%
40%
76%
40%
64%
23%
17%
HOTf[e] DCE
7[f]
8[g]
9
C1/H2O
C2/H2O
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
TFA
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
tert-butylphosphine]gold(I),
(acetonitrile)[(2-biphe-
AuBr3/H2O
–/H2O
AgOTf/H2O
AgBF4/H2O
AgSbF6/H2O
nyl)di-tert-butylphosphine]gold(I), and AuBr3, were
less effective (entries 7-9, Table 1). The yield of the
product decreased when the reaction was carried out
in the absence of AuClACTHNUTRGNE(UNG PPh3) (entry 10, Table 1).
Ag and Cu catalysts could also be used in the reac-
tion, but the product yields were lower than that
10
11
12
13
14
15
16
17
18
19
20
21
22[h]
Cu
ACHTUNGTRENNUNG(OTf)2/H2O
CuOTf/H2O
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
CH3CN 24%
toluene 61%
achieved with AuClACHTUNTRGNEUNG(PPh3) (entries 11–15, Table 1).
There was no improvement in the yield of 2a when
the solvent was changed from 1,1-dichloroethane to
toluene, acetonitrile, or dichloromethane (entries 16–
18, Table 1). In fact, no conversion was observed
when the reaction was carried out in THF (entry 19,
Table 1). Several Brønsted and Lewis acids were also
investigated (entries 20 and 21, Table 1) and the
yields were reduced drastically to 33% and 0% when
HOTf was replaced with CF3COOH or AlCl3, respec-
tively. When the temperature was increased, the reac-
tion was accelerated: the reaction proceeded to com-
pletion in 1 h at 408C. However, in this case, the cycli-
zation product was obtained in a low (40%) yield
(entry 22, Table 1).
After identifying the optimum reaction conditions,
we proceeded to explore the scope and generality of
our method. As shown in Table 2, several functional
groups were tolerated in the reaction, including halo-
gens, electron-donating groups, and electron-with-
drawing substituents on the aryl ring, and the desired
products were isolated in moderate to high yields.
DCM
THF
DCE
DCE
DCE
62%
0%
33%
0%
AlCl3
HOTf
40%
[a]
Unless otherwise noted, reaction conditions are as fol-
lows: 60 mg 1a, 5% AuCl(PPh3), 10.0 equiv. H2O,
10.0 equiv. HOTf and 2.5 mL 1,2-dichloroethane were
added at room temperature and the reaction mixture was
stirred for 12 h.
Isolated yield.
5.0 equiv. H2O were added.
15.0 equiv. H2O were added.
5.0 equiv. HOTf were added.
C1 is chloro[(1,1’-biphenyl-2-yl)di-tert-butylphosphine]-
gold(I).
C2 is (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]-
gold(I) hexafluoroantimonate. DCE is dichloroethane
and HOTf is trifluoromethanesulfonic acid.
Reaction was conducted at 408C.
AHCTUNGTRENNUNG
[b]
[c]
[d]
[e]
[f]
[g]
[h]
useful tool for the synthesis of five-membered Generally, the yield was 80–88% when the benzyl
rings.[12b,13] However, very few methods have been de- group had neutral (entry 1, Table 2) or electron-rich
veloped for the synthesis of 4-aryl-2(5H)-furanones substituents, such as tert-butyl (entry 2, Table 2),
through cyclization of 1,3-dicarbonyl compounds.[14] methyl (entries 3–5, Table 2), and phenyl (entry 6,
In this research we have developed a novel approach Table 2). Interestingly, reactions involving substrates
that involves the use of a phosphine-Au(I) complex with weakly electron-withdrawing substituents such as
and a Brønsted acid for the synthesis of 4-aryl-2(5H)- chloride proceeded smoothly to afford the desired
furanones and carried out preliminary mechanistic products (entries 7–9, Table 2); on the other hand,
studies.
substrates with ester groups gave the products in satis-
In our initial study, treatment of prop-2-ynyl 2- factory yields [entries 10 and 11 (77% and 78%
benzyl-3-oxo-3-phenylpropanoate (1a) with 5% AuCl- yields, respectively), Table 2]. Substrates with the
1414
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1413 – 1419

Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed Intramolecular Annulation
Table 2. Gold(I)-catalyzed cyclization of prop-2-ynyl 2-benzyl-3-oxo-3-phenylpropanoates mediated by HOTf.[a]
Entry
1
Substrate
Product
Yield
85%
2a
2b
2
81%
3
4
5
6
7
8
2c
2d
2e
2f
2g
2h
81%
85%
88%
80%
80%
84%
9
2i
85%
Adv. Synth. Catal. 2011, 353, 1413 – 1419
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1415

Haifeng Sun et al.
COMMUNICATIONS
Table 2. (Continued)
Entry
Substrate
Product
Yield
78%
10
2j
11
12
2k
77%
2l
0%
13
14
2m
68%
2n
2o
65%
0%
15
[a]
Unless otherwise noted, 0.2 mmol substrates, 10.0 equiv. H2O, 5% AuCl
added at room temperature.
ACHTUNGRTENN(UNG PPh3), 10.0 equiv. HOTf and 2.5 mL DCE were
strongly electron-withdrawing nitro group did not ed in the reaction. Substrates with an internal alkyne
afford the cyclization product (entry 12, Table 2). did not give any cyclization product (entry 10,
Moreover, compounds with a fluoro substituent at the Table 3).
4- or 2-position of the 3-phenyl ring afforded the cyc-
The structure of 2a was confirmed by 1H NMR,
lization product in 65% and 68% yields, respectively 13C NMR, mass spectrometry and X-ray crystallogra-
(entries 13 and 14, Table 2). When an internal alkyne phy (Figure 2).
substrate was treated with the standard condition, no
product was observed (entry 15, Table 2).
On the basis of our previous knowledge and the re-
sults of our present studies, a plausible mechanism as
We also observed that the present protocol could shown in Scheme 1 is proposed for this process. Reac-
be used for the direct cyclization of prop-2-ynyl 3- tion of substrate 1a under the catalysis of AuCl(PPh3)
ACHTUNGTRENNUNG
oxo-3-phenylpropanoates (Table 3). More important- catalysis affords intermediate 4 in the presence of
ly, the product yields were high in this case, and the water. The protonation of the ketone (4, Scheme 1)
reaction time was reduced to 10 h. As reported in the would therefore facilitate the regioselective intramo-
previous studies, electron-neutral (entry 1, Table 3), lecular cyclization, leading to the formation of species
electron-donating, and electron-withdrawing groups 5. Subsequently, an AcOH was removed by an intra-
such as nitro (entries 2 and 3, Table 3), methoxy (en- molecular synergic effect. Finally the target product
tries 4–6, Table 3), fluoro (entries 7 and 8, Table 3), 2a would be formed through a double bond transfer.
and chloro groups (entry 9, Table 3) were well tolerat-
1416
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1413 – 1419

Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed Intramolecular Annulation
Table 3. Gold(I)-catalyzed cyclization of prop-2-ynyl 3-oxo-
3-phenylpropanoates mediated by HOTf.[a]
Entry R4
R5
H
Product
Yield[b]
1
2
3
4
H
3a 92%
p-NO2
m-NO2
p-CH3O
H
H
H
3b 87%
3c 80%
3d 85%
Figure 2. X-ray crystallographic structure of 2a.
that the alkyne group may undergo degradation in
the process. The reaction of 1a under the standard re-
action conditions with D2O as additive afforded the
deuterated cyclization product on 5-position [Eq. (2)].
The non-deuterated product was observed when the
deuterated substrate on 2-position reacted with H2O
as additive [Eq. (3)]. These results indicated that the
water may also participate in the reaction in the
double bond transfer process. These deuterium label-
ing experiments could support our mechanistic hy-
potheses.
In summary, we have developed a novel Au(I)-cata-
lyzed, HOTf-mediated reaction for the synthesis of 4-
aryl-2(5H)-furanones. The reaction can be carried out
under ambient temperature conditions, and it shows
excellent tolerance to various functional groups; fur-
thermore, the desired products are obtained in good
to excellent yields. The high regioselectivity and mild
reaction conditions are expected to make this method
a valuable tool for the synthesis of 2(5H)-furanone
frameworks.
5
o-CH3O
H
3e 87%
6
7
8
9
m-CH3O
p-F
H
H
H
H
3f 91%
3g 93%
3h 91%
3i 88%
o-F
m-Cl
10
H
CH3
3j 0%
[a]
[b]
Unless otherwise noted, 0.2 mmol substrate, 10.0 equiv.
H2O, 5% AuCl(PPh3), 10.0 equiv. HOTf and 2.5 mL
DCE were added at room temperature.
Isolated yield.
AHCTUNGTRENNUNG
Experimental Section
General Procedure for the Synthesis of 3-Benzyl-4-
phenyl-2(5H)-furanone (2a) as an Example
To probe the reaction mechanism, we performed la-
beling studies using the deuterated additive and start-
ing materials (Scheme 2). A non-deuterated product
was obtained under standard conditions using deuter-
A mixture of 1a (0.2 mmol, 58.4 mg), 10.0 equiv. H2O
(2 mmol, 36 mg), AuCl
ACHTUNGRTEN(NUNG PPh3) (0.01 mmol, 5 mg) and HOTf
(2 mmol, 300 mg) in 1,2-dichloroethane (2.5 mL) was stirred
ated terminal alkyne [Eq. (1)], which demonstrated at room temperature in a sealed tube under argon protec-
Adv. Synth. Catal. 2011, 353, 1413 – 1419
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1417

Haifeng Sun et al.
COMMUNICATIONS
Scheme 1. A plausible mechanism.
References
[1] a) D. M. Howard, C. Vallapa, S. L. Dong, M. P. Allen, J.
Nat. Prod. 1991, 54, 286–289; b) C. M. Shi, J. A. Ray-
mond, J. Org. Chem. 1991, 56, 6275–6280; c) J. S. Ca-
meron, L. H. Robert, J. Jamaluddin, T. Akbar, V. B. Mi-
chelle, M. I. Chris, J. Org. Chem. 1998, 63, 4147–4150;
d) E. E. Shults, J. Velder, H. G. Schmalz, S. V. Chernov,
T. V. Rubalava, Y. V. Gatilov, G. Henze, G. A. Tolsti-
kov, A. Prokop, Bioorg. Med. Chem. Lett. 2006, 16,
4228–4232; e) K. A. Koo, M. K. Lee, S. H. Kim, E. J.
Jeong, T. H. Oh, Y. C. Kim, Br. J. Pharmacol. 2007,
150, 65–71; f) J. K. Son, D. H. Kim, M. H. Woo, J. Nat.
Prod. 2003, 66, 1369–1372.
[2] C. Francisco, A. Merce, F. R. Raquel, C. Monica, W.
Graham, Bioorg. Med. Chem. Lett. 2006, 16, 3209–
3212.
[3] B. John, L. Nicolas, O. Michel, T. Martin, Tetrahedron
Lett. 1998, 39, 7665–7668.
[4] T. Lushi, Y. C. Cheng, D. L. Robert, R. V. Thomas, J. R.
Paul, Tetrahedron Lett. 1998, 39, 3961–3964.
[5] I. S. Marcos, L. Casraneda, P. Basabe, D. Diez, J. G.
Urones, Tetrahedron 2009, 65, 9256–9263.
Scheme 2. Experiments with deuterated substrates.
tion for 12 h. After the reaction was completed as moni-
tored by TLC, the solvent was removed under reduced pres-
sure, and the residue was purified by column chromatogra-
[6] H. P. Kang, Y. K. So, K. C. Young, Org. Biomol. Chem.
2005, 3, 395–398.
[7] F. Koji, M. Tsumoru, T. Ken, K. Kiyomi, Chem.
Commun. 2005, 3295–3297.
1
phy. H NMR (CDCl3, 300 MHz): d=7.45 (m, 5H), 7.26 (m,
5H), 5.12 (s, 2H), 3.90 (s, 2H); 13C NMR (CDCl3,
100 MHz): d=157.0, 137.6, 131.0, 130.5, 129.1, 128.7, 128.2,
127.2, 126.6, 125.8, 70.8, 30.0; HR-MS (EI): m/z=250.0991,
calcd. for C17H14O2 [M]+: 250.0994.
[8] S. M. Ming, D. D. Hui, Y. W. Zhong, J. Comb. Chem.
2002, 4, 239–247.
[9] C. L. Kun, Z. Yi, B. W. Jian, Tetrahedron Lett. 2009, 50,
2956–2959.
[10] A. Levent, K. Melih, A. A. Ozage, N. D. Fatma, Y. O.
Fatma, Tetrahedron 2009, 65, 9125–9133.
[11] B. John, P. L. Richard, J. Org. Chem. 2008, 73, 8109–
8112.
Acknowledgements
[12] a) J. J. Kennedy-Smith, S. T. Taben, F. D. Toste, J. Am.
Chem. Soc. 2004, 126, 4526–4527; b) B. K. Corkey, ;
F. D. Toste, J. Am. Chem. Soc. 2005, 127, 17168–17169;
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (Grants
20872153, 21021063 and 81025017).
1418
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1413 – 1419

Synthesis of 4-Aryl-2(5H)-furanones by Gold(I)-Catalyzed Intramolecular Annulation
c) C. L. Deng, T. Zou, Z. Q. Wang, R. J. Song, J. H. Li,
J. Org. Chem. 2009, 74, 412–414; d) Y. Itoh, H. Tsuji,
K. Yamagata, K. Endo, I. Tanaka, M. Nakamura, E.
Nakamura, J. Am. Chem. Soc. 2008, 130, 17161–17167;
e) Q. Gao, B. F. Zheng, J. H. Li, D. Yang, Org. Lett.
2005, 7, 2185–2187; f) S. T. Staben, J. J. Kennedy-
Smith, F. D. Toste, Angew. Chem. 2004, 116, 5464–
5466; Angew. Chem. Int. Ed. 2004, 43, 5350–5352;
g) M. A. Boaventura, J. Drouin, J. M. Conia, Synthesis
1983, 801–804.
[13] a) M. L Li, T. Yang, D. J. Dixon, Chem. Commun.
2010, 46, 2191–2193; b) T. Yang, A. Ferrali, F. Sladoje-
vich, L. Campbell, D. J. Dixon, J. Am. Chem. Soc. 2009,
131, 9140–9141.
[14] C. Y. Zhou, C. M. Che, J. Am. Chem. Soc. 2007, 129,
5828–5829.
[15] CCDC 803457 contains the supplementary crystallo-
graphic data for 2a. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Adv. Synth. Catal. 2011, 353, 1413 – 1419
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1419