Carbon dioxide-mediated synthesis of 3(2H)-furanones from diyne alcohols

Article abstract of DOI:10.1016/j.tetlet.2011.08.130

A novel type of carbon dioxide-mediated reaction of diyne alcohols without any metal catalysts was reported. Carbon dioxide held the key to the success of this reaction, in which 3(2H)-furanones were selectively obtained in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2011.08.130

Tetrahedron Letters 52 (2011) 5956–5959
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbon dioxide-mediated synthesis of 3(2H)-furanones from diyne alcohols
⇑
Gaoqing Yuan , Zaijun He, Junhua Zheng, Zhengwang Chen, Huawen Huang, Dabin Shi,
⇑
Chaorong Qi, Huanfeng Jiang
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel type of carbon dioxide-mediated reaction of diyne alcohols without any metal catalysts was
reported. Carbon dioxide held the key to the success of this reaction, in which 3(2H)-furanones were
selectively obtained in moderate to high yields.
Received 29 June 2011
Revised 15 August 2011
Accepted 23 August 2011
Available online 31 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbon dioxide
3(2H)-Furanones
Diyne alcohols
Recently, it has been reported that the coupling reaction of
propargyl alcohols with CO2 could afford cyclic carbonates using
various metal salts and organic compounds as the catalysts.1 In
addition, carbon dioxide could also promote the rearrangement
of 3(2H)-furanones from diyne alcohols under the promotion of
CO2 without any metal catalysts.
The reaction of the model substrate 2-methyl-6-phenylhexa-
3,5-diyn-2-ol (1a) with CO2 was first investigated. With CuI as
the catalyst and MeCN/Et3N (volume ratio 10:1) as the mix-
solvent, 5-benzyl-2,2-dimethylfuran-3(2H)-one (2a) was obtained
in 25% yield (Table 1, entry 1). However, 2a was not obtained at
all in the absence of carbon dioxide (entry 2). This means that
CO2 plays a key role in the formation of 2a. The yield of 2a in-
creased when water was added into the reaction system (entry
3). In the absence of water, 2a was almost not formed (entry 5),
which indicated that the water was indispensable for this reaction.
1a could be also converted into 2a in a good yield without CuI,
implying that it is a metal-free catalytic reaction (entry 4). In addi-
tion, the reaction did not proceed without Et3N even in the pres-
ence of CO2 and water or acetonitrile as the solvent (entries 6–7).
In the present case, base Et3N practically acts as the catalyst. With
individual Et3N as the solvent, 2a was obtained only in a very low
yield (entry 8), so extra solvent (such as MeCN) was also crucial for
the reaction. Among the various mix-solvents examined (entries
9–14), MeCN/Et3N (volume ratio 10:1) appears to be more favor-
able for the reaction. The effect of these solvents on the reaction
may be related to their polarity. Also, the yield of 2a varied obvi-
ously with the reaction temperature, and 90 °C seemed to be
appropriate for the present reaction (entries 15–17).
of propargyl alcohols to afford
a
,b-unsaturated ketones.2 Our
investigations indicated that cuprous(I) well promoted the reac-
tion of propargyl alcohols with CO2 to form cyclic carbonates.3
We further studied on the reaction of diyne alcohols with CO2.
To our surprise, the obtained product is 3(2H)-furanones instead
of the desired cyclic carbonates. The interesting result inspires us
to investigate the synthesis of 3(2H)-furanones from diyne
alcohols.
The 3(2H)-furanones widely occur as key structural units in a
variety of natural products (e.g., geiparvarin,4 eremantholide A,5
jatrophone,4a,6 bullatenon,7 and pseurotin A8), and many of the
3(2H)-furanones have shown pharmaceutical activities such as
antitumor activity,4a,7c,9 antiproliferative activity,9a inhibitory
activity on COX-2,10 inhibitory activity on MAO,11 and several other
pharmaceutical activities.7b,12 Conventional approaches for the
synthesis of these serviceable compounds mainly rest on base-
catalyzed cyclization of c
-hydroxyalkynones7a and acid-catalyzed
cyclocondensation of 1-hydroxy 1,3-diketones.4a,13 There were also
many alternative methods such as the hydrogenations and
subsequent acidic hydrolysis of isoxazoles,7b,9a,14 base-catalyzed
cyclizations of 1-halo-2,4-diketones15 or b-keto esters,16 Lewis
acid-catalyzed aldol reaction of 3-silyloxyfurans,17 and the transi-
tion metal-catalyzed preparations of 3(2H)-furanones.18 In this
communication, we reported the first example of the preparation
Under the optimum reaction conditions (Table 1, entry 16), the
scope and the utility of this method were examined in detail, as
shown in Scheme 1. The reaction could tolerate various substrates
with aryl and alkyl R1 groups (2a–2j). It is worthy to note that the
electron-deficient groups on the R1 aromatic ring could give higher
yields (2f–2i), while the electron-rich group was unfavorable for
⇑
Corresponding authors. Tel./fax: +8620 87112906.
E-mail addresses: gqyuan@scut.edu.cn (G. Yuan), jianghf@scut.edu.cn (H. Jiang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.130

G. Yuan et al. / Tetrahedron Letters 52 (2011) 5956–5959
5957
Table 1
O
R2
R3
Optimization of reaction conditionsa
R2
CO2, H2O
R1
OH
R1
O
o
CO2
R3
Solvent, 90 C
O
2
OH
1
O
1a
2a
O
O
O
Entry Solvent
Cat H2O
(equiv)
Temp
(°C)
CO2
(MPa)
Yield
(%)b
t-Bu
O
O
O
O
1
MeCN/Et3N
CuI
CuI
—
—
80
80
80
80
80
2
25
(10:1)
2a, 79%
2b, 75%
2c, 75%
2f, 86%
2
MeCN/Et3N
(10:1)
0
2
2
2
n.p
66
O
O
O
O
Ph
F
3
MeCN/Et3N
(10:1)
MeCN/Et3N
(10:1)
MeCN/Et3N
(10:1)
CuI 10
O
O
4c
5
CuI
—
—
Trace
71
2d, 76%
2e, 47%
10
O
O
O
O
O2N
F
6
7
8
9
H2O
MeCN
Et3N
DMF/Et3N (10:1)
DMSO/Et3N
(10:1)
—
—
—
—
—
—
80
80
80
80
80
2
2
2
2
2
n.p
n.p
11
55
45
10
10
10
10
O
F
O
O
2h, 85%
2g, 81%
2i, 87%
2l, 78%
10
O
O
11
12
THF/Et3N (10:1)
MeNO2/Et3N
(10:1)
—
—
10
10
80
80
2
2
Trace
23
O
O
O
O
n-Hep
13
14
15
16d
17
toluene/Et3N
(10:1)
dioxane/Et3N
(10:1)
MeCN/Et3N
(10:1)
MeCN/Et3N
(10:1)
—
—
—
—
—
10
10
10
10
10
80
80
100
90
rt
2
2
2
2
2
Trace
Trace
82
2j, 68%
2k, 81%
O
O
O
O
O
O
O
Ph
83(79)
33
2n, 68%
2m, 71%
2o, 75%
MeCN/Et3N
(10:1)
O
O
Br
Br
Ph
a
Reaction conditions: substrates (0.25 mmol), MeCN/Et3N (10:1) as the solvent
(2 mL), 36 h.
O
O
O
b
Determined by GC–MS. Number in parentheses is isolated yield.
Distilled solvent.
83% of 1a was converted.
2q, 80%
2p, 77%
2r, 73%
c
d
O
n-Pentyl
O
O
2s, 23%
2t, 25%
the reaction (2e). In addition, the tertiary diyne alcohols with alkyl
and aryl R2 or R3 groups, even with five- or six-membered ring
substituents, could be smoothly converted into the corresponding
product in good yields (2k–2r), whereas the reactions with second-
ary diyne alcohols gave fairly low yields (2s,2t). Obviously, the
yield of the target product is influenced by the structure and prop-
erty of diyne alcohols. The molecular structure of representative
product 2r is further confirmed by an X-ray diffraction study
(Fig. 1).
Scheme 1. Carbon dioxide-mediated synthesis of 3(2H)-furanones. Reaction
conditions: substrates (0.25 mmol), MeCN/Et3N (10:1) as the solvent (2 mL), CO2
(2 MPa), H2O (10 equiv), 90 °C, 36 h. Isolated yield, unconverted substrates were
recovered.
Benzylic oxidation is a fundamental transformation in organic
chemistry because the product ketones can serve as valuable build-
ing blocks for the manufacture of speciality chemicals in pharma-
ceuticals and agrochemicals. Our studies showed that 2a could be
oxidized into 5-benzoyl-2,2-dimethylfuran-3(2H)-one (3a) in 98%
yield with Et3N as catalyst and O2 as the sole oxidant (Scheme
2). Inspired by this result, we further investigated the one–pot syn-
thesis of 3a from 1a in the presence of CO2 and O2.
As expected, 3a could be obtained in a good yield at 90 °C in the
mix-solvent MeCN/Et3N for 48 h, under CO2 (2 MPa) and O2
(0.6 MPa).19 The scope of the reaction with various diyne alcohols
was further examined, as summarized in Scheme 3. The alkyl
group on the benzene ring has a slight impact on the reaction.
The electron-withdrawing group increased the reaction yield
(3d), while the electron-donating group decreased the reaction
yield (3b,3c).The symmetric and asymmetric propargyl alcohols
or the propargyl alcohols with a five-or six-membered ring could
be smoothly converted into the corresponding products in high
Figure 1. X-ray structure of 2r.
yields (3e–3h). The reaction was also feasible for the substrate
with bromine substituted benzene ring (3i).
To understand the reaction mechanism, some control experi-
ments were done (Scheme 4). With 1m as a substrate, 4m was ob-
tained in 13% yield at 30 °C for 12 h under 2 MPa of CO2. It was
found that 4m could be also converted into 2m under the optimum

5958
G. Yuan et al. / Tetrahedron Letters 52 (2011) 5956–5959
O
O
O
O
O
O2 (1 atm)
O
OH
1M NaOH aq.
t-BuOH, r.t.
Ph
MeCN, Et3N
80 oC, 24 h
Ph
O
O
O
2a
3a
Ph
79% yield
Ph
Scheme 2. Oxidation of 5-benzyl-2,2-dimethyl-3(2H) furanone (2a) into 5-ben-
zoyl-2,2-dimethyl-3(2H)-furanone (3a). Reaction conditions: 2a (0.25 mmol),
MeCN (2 mL), Et3N (1 equiv), O2 (1 atm), 80 °C.
Scheme 5. Yamada’s work.
O
O
O
O
O
R2
R3
R2
OH
OH
H2O, base
CO2
CO2, O2, H2O
Ph
R1
OH
R1
Ph
Ph
base
CO2
o
O
R3
Solvent, 90 C
1a
Ph
A
B
O
1
3
O
•
Ph
base
O2
Ph
base
O
base
O
O
O
O
O
O
O
O
O
HO
C
2a
Scheme 6. A possible reaction mechanism.
3a
O
O
O
O
O
O
3c, 50%
3a, 77%
3b, 75%
O
O
O
O2N
from carbon dioxide, and the other oxygen atom originates from
diyne alcohol rather than water. Based on the above-mentioned
experimental results and the literatures,1a,20,21 a possible mecha-
nism is proposed in Scheme 6. Carbon dioxide first reacts with
1a to form A under the catalysis of base (Et3N). The cyclic carbon-
ate could get hydrolyzed in the presence of base and water giving
rise to an alpha-hydroxy ketone (B),1a followed by the isomeriza-
tion process of alpha-substituted alkyne to the allenylketone
(C).20 Finally, C is converted into 2a through base-catalyzed
endo-mode cyclization,21 and 2a could be oxidized to 3a in the
presence of a base and an oxidant. In fact, the exact mechanism
of the reaction is still unclear and details are needed to study
further.
O
O
O
O
O
O
3d, 83%
3e, 77%
3f, 80%
O
O
Br
O
O
O
O
3h, 73%
O
O
3g, 73%
3i, 81%
Scheme 3. One-pot synthesis of 5-benzoyl-3(2H)-furanones. Reaction conditions:
(0.25 mmol), MeCN/Et3N (10:1) as the solvent (2 mL), CO2 (2 MPa), O2 (0.6 MPa),
H2O (10 equiv), 90 °C, 48 h. Isolated yield, unconverted substrates were recovered.
In conclusion, in the mix-solvent MeCN/Et3N various diyne
alcohols are efficiently promoted by CO2 to afford substituted
3(2H)-furanones without any metal catalysts in moderate to high
yields. The present work provides an efficient and valuable route
for the synthesis of 3(2H)-furanones derivatives.
O
O
O
CO2, 30 oC, H2O
MeCN/Et3N, 12 h
Acknowledgments
Ph
Ph
OH
1m
4m 13% yield
We thank National Natural Science Foundation of China (No.
21172079), the National Basic Research Program of China
(2010CB732206), the Guangdong Natural Science Foundation
(10351064101000000), and the Fundamental Research Funds for
the Central Universities (2011zz007) for financial support.
O
O
O
O
O
optimum conditions
Ph
Ph
2m,
95% yield
O
4m
Supplementary data
H218O (10 equiv)
CO2 (2 MPa), 90 oC
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.130.
Ph
OH
Ph
O
MeCN/Et3N (10:1) a
2a
1a
77% yield
References and notes
Scheme 4. Control experiments. Reaction conditions: 1m (0.25 mmol), 4m
(0.05 mmol), 1a (0.25 mmol), MeCN/Et3N (10:1) as the solvent (2 mL), CO2
(2 MPa), H2O (10 equiv), distilled solvent.
1. (a) Yoshida, S.; Fukui, K.; Kikuchi, S.; Yamada, T. J. Am. Chem. Soc. 2010, 132,
4072; (b) Kayaki, Y.; Yamamoto, M.; Ikariya, T. J. Org. Chem. 2007, 72, 647; (c)
Yamada, W.; Sugawara, Y.; Cheng, H.; Ikeno, T.; Yamada, T. Eur. J. Org. Chem.
2007, 2604; (d) Kayaki, Y.; Yamamoto, M.; Ikariya, T. Angew. Chem., Int. Ed.
2009, 48, 4194; (e) Minakata, S.; Sasaki, I.; Ide, T. Angew. Chem., Int. Ed. 2010, 49,
1309.
a
conditions. These results indirectly indicated that the formation of
2a might undergo the intermediates of cyclic carbonates. To
further understand the role of water in this reaction, H218O as
the isotope label was used to trace the reaction. It was observed
that the product 2a did not contain 18O (Scheme 4). According to
the experimental results and Yamada’s work1a (Scheme 5), we
deduce that the oxygen atom of the carbonyl group in 2a results
2. Sugawara, Y.; Yamada, W.; Yoshida, S.; Ikeno, T.; Yamada, T. J. Am. Chem. Soc.
2007, 129, 12902.
3. (a) Jiang, H.; Wang, A.; Liu, H.; Qi, C. Eur. J. Org. Chem. 2008, 2309; (b) Yuan, G.;
Zhu, G.; Chang, X.; Qi, C.; Jiang, H. Tetrahedron 2010, 66, 9981.
4. (a) Jerris, P. J.; Smith, A. B., III J. Org. Chem. 1981, 46, 577; (b) Chimichi, S.;
Boccalini, M.; Cravottob, G.; Rosatic, O. Tetrahedron Lett. 2006, 47, 2405; (c)
Chimichi, S.; Boccalini, M.; Salvador, A.; Dall’Acqua, F.; Basso, G.; Viola, G.
ChemMedChem 2009, 4, 769.

G. Yuan et al. / Tetrahedron Letters 52 (2011) 5956–5959
5959
5. Le Quesne, P. W.; Levery, S. B.; Menachery, M. D.; Brennan, T. F.; Raffauf, R. F. J.
Chem. Soc., Perkin Trans.1 1978, 1572.
6. (a) Kupchan, S. M.; Sigel, C. W.; Matz, M. J.; Gilmore, C. J.; Bryan, R. F. J. Am.
Chem. Soc. 1976, 98, 2295; (b) Smith, A. B., III; Malamas, M. S. J. Org. Chem. 1982,
47, 3442.
7. (a) Parker, W.; Raphael, R. A.; Wilkinson, D. I. J. Chem. Soc. 1958, 3871; (b)
Felman, S. W.; Jirkovsky, I.; Memoli, K. A.; Borella, L.; Wells, C.; Russell, J.; Ward,
J. J. Med. Chem. 1992, 35, 1183; (c) Reiter, M.; Turner, H.; Mills-Webb, R.;
Gouverneur, V. J. Org. Chem. 2005, 70, 8478.
13. (a) Gogoi, S.; Argade, N. P. Tetrahedron 2006, 62, 2999; (b) Smith, A. B., III;
Levenberg, P. A.; Jerris, P. J.; Scarborough, R. M.; Wovkulich, P. M. J. Am. Chem.
Soc. 1981, 103, 1501.
14. (a) Manfredini, S.; Baraldi, P. G.; Bazzanini, R.; Guarneri, M.; Simoni, D.;
Balzarini, J.; De Clercq, E. J. Med. Chem. 1994, 37, 2401; (b) Saxena, R.; Singh, V.;
Batra, S. Tetrahedron 2004, 60, 10311.
15. (a) Langer, P.; Krummel, T. Chem. Commun. 2000, 967; (b) Langer, P.; Krummel,
T. Chem,-Eur. J. 2001, 7, 1720; (c) Shamshina, J. L.; Snowden, T. S. Tetrahedron
Lett. 2007, 48, 3767.
8. (a) Ishikawa, M.; Ninomiya, T. J. Antibiot. 2008, 61, 692; (b) Ishikawa, M.;
Ninomiya, T.; Akabane, H.; Kushida, N.; Tsujiuchi, G.; Ohyama, M.; Gomi, S.;
Shito, K.; Murata, T. Bioorg. Med. Chem. Lett. 2009, 19, 1457.
9. (a) Chimichi, S.; Boccalini, M.; Cosimelli, B.; Dall’Acqua, F.; Viola, G. Tetrahedron
2003, 59, 5215; (b) Rappai, J. P.; Raman, V.; Unnikrishnan, P. A.; Prathapan, S.;
Thomas, S. K.; Paulose, C. S. Bioorg. Med. Chem. Lett. 2009, 19, 764.
10. Shin, S. S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K.-W.; Moh, J. H.; Kim, J. K.;
Jeong, Y. S.; Kim, J. Y.; Choi, Y. H.; Koh, H.-J.; Park, Y.-H.; Oh, Y. I.; Noh, M.-S.;
Chung, S. J. Med. Chem. 2004, 47, 792.
11. Carotti, A.; Carrieri, A.; Chimichi, S.; Boccalini, M.; Cosimelli, B.; Gnerre, C.;
Carotti, A.; Carrupt, P.-A.; Testa, B. Bioorg. Med. Chem. Lett. 2002, 12, 3551.
12. (a) Mack, R. A.; Zazulak, W. I.; Radov, L. A.; Baer, J. E.; Stewart, J. D.; Elzer, P. H.;
Kinsolving, C. R.; Georgiev, V. S. J. Med. Chem. 1988, 31, 1910; (b) Kimura, T.;
Takeuchi, T.; Kumamoto-Yonezawa, Y.; Ohashi, E.; Ohmori, H.; Masutani, C.;
Hanaoka, F.; Sugawara, F.; Yoshida, H.; Mizushina, Y. Bioorg. Med. Chem. 2009,
17, 1811.
16. (a) Kato, K.; Nouchi, H.; Ishikura, K. P.; Takaishi, S.; Motodate, S.; Tanaka, H.;
Okudaira, K.; Mochida, T.; Nishigaki, R.; Shigenobu, K.; Akita, H. Tetrahedron
2006, 62, 2545; (b) Trofimov, B. A.; Shemyakina, O. A.; Mal’kina, A. G.; Igor, A.
U.; Kazheva, O. N.; Alexandrov, G. G.; Dyachenko, O. A. Org. Lett. 2010, 12, 3200.
17. Winkler, J. D.; Oh, K.; Asselin, S. M. Org. Lett. 2005, 7, 387.
18. (a) Kirsch, S. F.; Binder, J. T.; Liebert, C.; Menz, H. Angew. Chem., Int. Ed. 2006, 45,
5878; (b) Egi, M.; Azechi, K.; Saneto, M.; Shimizu, K.; Akai, S. J. Org. Chem. 2010,
75, 2123; (c) Marson, M. C.; Edaan, E.; Morrell, J. M.; Coles, S. J.; Hursthouse, M.
B.; Davies, D. T. Chem. Commun. 2007, 2494; (d) Silva, F.; Reiter, M.; Mills-
Webb, R.; Sawicki, M.; Klar, D.; Bensel, N.; Wagner, A.; Gouverneur, V. J. Org.
Chem. 2006, 71, 8390.
19. For details seeing Supplementary data.
20. Liu, H.; Feng, W.; Kee, C. W.; Leow, D.; Loh, W.-T.; Tana, C.-H. Adv. Synth. Catal.
2010, 352, 3373.
21. Poonoth, M.; Krause, N. J. Org. Chem. 2011, 76, 1934.