Efficient synthesis of functionalized furans via ruthenium-catalyzed cyclization of epoxyalkyne derivatives

Article abstract of DOI:10.1021/jo020004h

Ruthenium catalyst TpRuPPh₃(CH₃CN)₂Cl is found to effect the cyclization of epoxyalkynes to furans in the presence of Et₃N. The reactions worked well for various epoxyalkynes with suitable oxygen and nitrogen functionalities with low loading of catalyst. It failed with disubstituted epoxyalkynes. The mechanism was elucidated by a deuterium labeling experiment that suggested that the mechanism involved a ruthenium-vinylidenium intermediate.

Full text of DOI:10.1021/jo020004h

3930
J . Org. Chem. 2002, 67, 3930-3932
Sch em e 1. Syn th esis of F u r a n s fr om
Efficien t Syn th esis of F u n ction a lized
Ep oxya lk yn es
F u r a n s via Ru th en iu m -Ca ta lyzed
Cycliza tion of Ep oxya lk yn e Der iva tives
Ching-Yu Lo,† Hongyun Guo,†,‡ J ian-J ou Lian,†
Fwu-Ming Shen,§ and Rai-Shung Liu*,†
Department of Chemistry, National Tsing-Hua University,
Hsinchu, 30043, and Department of Medical Technology,
Yuanpei Institute of Science and Technology, Hsinchu,
Taiwan, ROC
rsliu@mx.nthu.edu.tw
Received J anuary 2, 2002
Abstr a ct: Ruthenium catalyst TpRuPPh3(CH3CN)2Cl is
found to effect the cyclization of epoxyalkynes to furans in
the presence of Et3N. The reactions worked well for various
epoxyalkynes with suitable oxygen and nitrogen function-
alities with low loading of catalyst. It failed with disubsti-
tuted epoxyalkynes. The mechanism was elucidated by a
deuterium labeling experiment that suggested that the
by a ruthenium or palladium catalyst.8 Epoxyalkyne is
easily prepared by epoxidation of the corresponding
enyne, and one-step synthesis of furans from this sub-
strate is a convenient and useful route. There are two
known pathways for such transformations: (1) KH- or
KOBut-catalyzed transformation via a cumulene anion9
(Scheme 1, eq 1) and (2) Mo(CO)5‚Et3N-catalyzed cycliza-
tion via molybdenum vinylidene species (Scheme 1).10 The
former is for use with an internal alkyne whereas the
latter is suitable for a terminal alkyne. Although the
molybdenum system can be performed under mild condi-
tions, a high loading of catalyst (15 mol %) is required to
complete the reaction.9 In this study, we report an
efficient ruthenium-catalyzed synthesis11 of furan deriva-
tives from various epoxyalkynes with suitable oxygen and
nitrogen functionalities.
mechanism involved
mediate.
a ruthenium-vinylidenium inter-
Furan is an important subunit in many naturally
occurring compounds.1 It is also an important reaction
intermediate in organic synthesis.2 The metal-catalyzed
synthesis of furan derivatives has attracted considerable
attention.1-3 Several methods have been developed that
focused exclusively on palladium catalytic systems in-
cluding (1) cyclization of alkynones,4 (2) coupling of
propargyl carbonates with acetoacetates,5 (3) coupling of
aryl or allyl halides with allenyl ketones,6a,b and (4)
addition of phenol to a tethered alkyne group.6c,d The
synthesis of furans from allenyl ketones can also be
achieved by Rh(I) or Ag(I) catalyst.7 The direct transfor-
mation of γ-ethynylallyl alcohol to furan was catalyzed
Among various ruthenium complexes, we found that
TpRuPPh3(CH3CN)Cl (Tp ) trispyrazolylborate)12 (1a )
13
and TpRuPPh3(CH3CN)2BF4 (1b) effected the cycliza-
tion of epoxyalkyne 2; the optimum conditions were given
in Table 1. The reactions were performed by heating
epoxide 2 (1.0 M) with catalyst 1a or 1b in CH2ClCH2Cl
at 80 °C for 12 h (Table 1, entries 1-5). In the absence
of base, compounds 1a and 1b did not show pronounced
catalytic activities even though 10 mol % of these
catalysts was employed. The catalytic activities of cata-
lysts 1a and 1b were significantly enhanced in the
presence of Et3N. The desired furan 3 was obtained in
† National Tsing-Hua University.
‡ Visiting Scholar from Zhejiang Normal University, Zhejiang,
China.
§ Yuanpei Institute of Science and Technology.
(1) Donnelly, D. M. X.; Meegan, M. J . In Comprehensive Heterocycclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
1984; Vol. 4, pp 657-712.
(2) For the synthesis of furan derivatives, see the following review
papers. (a) Hou X.-L.; Cheung, H. Y.; Hong, T. Y.; Kwan, P. L.; Lo,
T.-H.; Tong, S.-P.; Wong, H. N. C. Tetrahedron 1998, 54, 1955. (b)
Lipshutz, B. H. Chem. Rev. 1986, 86, 759.
(3) Li, J . J .; Gribble, G. W. In Palladium in Heterocyclic Chemistry;
Pergamon: New York, 2000.
(4) (a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J . Org.
Chem. 1991, 56, 5816. (b) Okuro, K.; Furuune, M.; Miura, M.; Nomura,
M. J . Org. Chem. 1992, 57, 475. (c) Kel’in A. V.; Gevorgyan, V. J . Org.
Chem. 2002, 67, 95.
(8) (a) Seiller, B.; Bruneau, C.; Dixneuf, P. H. J . Chem. Soc., Chem.
Commun. 1994, 493. (b) Seiller, B.; Bruneau, C.; Dixneuf, P. H.
Tetrahedron 1995, 51, 13089. (c) Gabriele, B.; Salerno, G.; De Pascali
F.; Costa, M.; Chiusoli, G. P. J . Org. Chem. 1999, 64, 7693. (d) Gabriele,
B.; Salerno, G.; Lauria, E. J . Org. Chem. 1999, 64, 7687.
(9) (a) Marshall, J . A.; DuBay, W. J . J . Am. Chem. Soc. 1992, 114,
1450. (b) Marshall, J . A.; DuBay, W. J . J . Org. Chem. 1991, 56, 1685.
(10) McDonald, F. E.; Schultz, C. C. J . Am. Chem. Soc. 1994, 116,
9363.
(11) For review papers on ruthenium-catalyzed reactions, see: (a)
Naota, T.; Takaya, H.; Murahashi, S. Chem. Rev. 1998, 98, 2599. (b)
Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225. (c) Trost,
B. M.; Toste. F. D.; Pinkerton, A. B. Chem. Rev. 2001, 2067. (d)
Bruneau C.; Dixneuf, P. H. Acc. Chem. Res. 1999, 32, 311.
(12) Chan, W. C.; Lau, C. P.; Chen, Y.-Z.; Fang, Y.-Q.; Ng, S.-M.;
J ia, G. Organometallics 1997, 16, 34.
(5) For this reaction, see the following review paper. Tsuji, J .;
Mandai, T. In Metal-catalyzed cross coupling reaction; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: Weinhein, 1998.
(6) (a) Ma, S.; Zhang, J . J . Chem. Soc., Chem. Commun. 2000, 117.
(b) Ma, S.; Li, L. Org. Lett. 2000, 2. 941. (c) Roshchin, A. I.; Kel’chevski,
S. M.; Bumagin, N. A. J . Organomet. Chem. 1998, 560, 163. (d)
Pearlman, B. A.; MacNamara, J . M.; Hasan, I.; Hatakeyama, S.;
Sekizaki, H.; Kishi, Y. J . Am. Chem. Soc. 1981, 103, 4248.
(7) (a) Marshall, J . A.; Robinson, E. D. J . Org. Chem. 1990, 55, 3540.
(b) Marshall, J . A.; Wang, X.-J . J . Org. Chem. 1991, 56, 960. (c)
Marshall, J . A.; Bartley, G. S. J . Org. Chem. 1994, 59, 7169.
(13) (a) Slugovc, C.; Mereiter, K.; Zobets, E.; Schmidt, R.; Kirchner,
K. Organometallics 1996, 15, 5275. (b) Takahashi, Y.; Akita, M.;
Hikichi, S.; Moro.-oka, Y. Inorg. Chem. 1998, 37, 3194.
10.1021/jo020004h CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/26/2002

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3931
Ta ble 1. Con d ition s for Ru th en iu m -Ca ta lyzed Syn th esis
of F u r a n sa
Ta ble 2. Con d ition s for Ru th en iu m -Ca ta lyzed Syn th esis
of F u r a n sa
a
Concentration of compound 2 is prepared to be 1.0 M (a) 80
°C, 12 h for entries 1-5, 9-12. 80 °C, 24 h. c 70 °C, 72 h. Yields
were reported after purification from TLC-plate. e 2.0 mol% cata-
lyst was used in entries 9-12.
b
d
91% yield when 2.0 mol % of catalyst 1a and Et3N (50
mol %) were used. This catalytic reaction is highly
dependent on the solvent. Catalyst 1a became less active
or actually inactive if CH3CN (0% yield), THF (14% yield),
or ethyl alcohol (0% yield) was used as the solvent (Table
1, entries 6-8). We also examined catalytic reactions for
various ruthenium complexes to study the key factors in
this catalytic activity. RuCl2(PPh3)3 (2.0 mol %) gave
furan 3 in 49% yield (Table 1, entry 9). On the other
hand, it was much less active for CpRuCl(PPh3)2 (5%
yield) and became inactive for TpRuCl(PPh3)2 and TpRu-
(COD)2Cl. The poor activities of TpRu(PPh3)2Cl and
CpRuCl(PPh3)2 suggest that basicity and a labile CH3-
CN in catalyst 1a is crucial for cyclization.
We prepared a series of epoxyalkynes 4-15 bearing
various functionalities. In a standard procedure, the
substrate (1 M) was heated with catalyst 1a in 1,2-
dichloroethane (80 °C), with the optimum conditions
given in Table 2. Most of the catalytic reactions were
achieved with 1-2 mol % of catalyst 1a . The reported
yields of furans are after purification on a silica column.
Entries 1 and 2 of Table 2 show the syntheses of
2-substituted furans 16 (84%) and 17 (91%), respectively,
which were achieved by a small amount of catalyst 1a
(1 mol %). This catalyst works well with cis-epoxide 6 to
give furan 3 in 71% yield and can also be used for the
synthesis of 3-substituted furan 18 (67% yield). For
substrates 8 and 9 which each have an alcohol function-
ality, furan 19 was obtained in respective yields of 86%
and 83%. Similarly, the benzoate derivative 20 was
produced efficiently from epoxides 10 and 11 (Table 2,
entries 7 and 8). This catalytic reaction also works well
a
Concetration of epoxyalkynes was prepared at 1.0-1.1 M.
b
The yields of furans were reported after purification from the
TLC plate.
for the synthesis of fused furan 21 from cyclohexene
oxides 12. We also prepared a complex molecule 13 to
examine its feasibility in catalytic reaction, and the
corresponding furan 22 was obtained in 78% yield. This
reaction was extended to the synthesis of furan 23 (89%
yield) bearing a tosylamino group (entries 11). The
catalytic activity of 1a was completely inhibited by the
nitrile group in compound 15, even though 10 mol % of
1a was used. The corresponding furan 24 was obtained
in 45% yield by using ruthenium cationic species 1b (10
mol %) in the presence of Et3N (0.5 equiv).
While catalyst 1a is not suitable for furan synthesis
using disubstituted epoxyalkyne 25 under the same
conditions; its terminal alkyne analogue 7 gave furan 20
in 67% yield (Table 2, entry 4). This suggests that the
mechanism of cyclization (Scheme 2, eq 2) is analogous
to that with Mo(CO)5‚Et3N proposed by McDonald and
Schlutz.10 Several TpRuL2Cl complexes formed ruthenium-
vinylidene complexes upon treatment with a terminal
alkyne.13 Intramolecular attack of species A at its central
carbon gave ruthenium-furylidene B, and subsequently
ruthenium-furyl anion C. The high basicity of species C
is expected promote protonation with Et3NH+ to form
furan and an active TpRuCl(PPh3) species. To confirm
the reaction mechanism, we prepared a deuterated
sample d 1-2, which was converted to 3 with deuterium
(78%) at the C3-carbon, consistent with the proposed
mechanism. The bulky Tp ligand of 1a has two important

3932 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Cl11 were prepared according to the methods in the literature.
trans-3-Methyl-2-penten-4-yn-1-ol, cis-3-methyl-2-penten-4-yn-
1-ol, RuCl2(PPh3)3, and CpRu(PPh3)2Cl were obtained com-
mercially without purification. Compounds 8, 9, and 19 were
reported previously.9 Spectral data of compounds 4-7, 10-18,
and 20-25 in repetitive experiments are provided in the
Supporting Information.
Sch em e 2. Mech a n ism for Ca ta lytic Cycliza tion
Syn th esis of tr a n s-3-Ben yloxym eth yl-2-eth yn yl-2-m eth -
yl-2-oxir a n e (2). To a THF solution (30 mL) of trans-3-methyl-
2-penten-4-yn-1-ol (3.00 g, 31.2 mmol) was added NaH (1.24 g,
31.2 mmol), and the mixture was stirred for 4 h at 23 °C. To
this solution was added benzyl bromide (5.31 g, 31.2 mmol), and
the solution was stirred for 12 h at 25 °C before addition of a
saturated NH4Cl solution. The organic layer was extracted with
diethyl ether, concentrated, and eluted through a short silica
column (hexane/ether ) 5/1) to give its benzyl derivative as a
colorless oil (4.15 g, 22.5 mmol). To a CH2Cl2 solution (50 mL)
of this benzyl ether (2.00 g, 10.7 mmol) was added m-chlorop-
eroxybenzoic acid (3.70 g, 21.5 mmol), and this white suspension
was stirred for 24 h at 26 °C before treatment with an aqueous
NaHCO3 solution. The organic layer was extracted with diethyl
ether, concentrated, and eluted through a basic alumina column
with diethyl ether as the eluent affording the epoxide 2 (1.52 g,
1
7.50 mmol) as a colorless oil: IR (neat) 2208 (m), 1610 (w); H
NMR (400 MHz, CDCl3) δ 7.34-7.26 (5 H, m, Ph), 4.56 (2 H,
ABq, J ) 12.0 Hz), 3.64 (1H, dd, J ) 11.2, 5.6 Hz), 3.53 (1H, d,
J ) 11.2, 5.6 Hz), 3.40 (1H, t, J ) 5.6 Hz), 2.29 (1H, s), 1.47
(3H, s); 13C NMR (100 MHz, CDCl3) δ 137.5, 128.4, 127.8, 83.6,
73.3, 70.2, 67.5, 62.2, 49.9, 18.3; HRMS calcd for C13H14O2
202.0944, found 202.0935.
Exp er im en ta l P r oced u r es for Ca ta lytic Rea ction s. Syn -
th esis of 3-Ben zyloxym eth yl-3-m eth ylfu r a n (3). To a dichlo-
roethane (0.30 mL) solution of epoxide 2 (100 mg, 0.49 mmol)
were added TpRuCl(PPh3)(CH3CN)Cl (6.47 mg, 0.010 mmol) and
Et3N (25 mg, 0.25 mmol). The mixture was heated at 80 °C for
12 h. The solution was concentrated and eluted through a silica
column to afford compound 3 as a colorless oil (91 mg, 0.45
mmol): IR (neat) 2210 (m), 1608 (w), 1600 (w); 1H NMR (400
MHz, CDCl3) δ 7.33 (1H, s), 7.31-7.28 (5 H, m, Ph), 6.22 (1 H,
s), 4.53 (2 H, s), 4.46 (2 H, s), 2.03 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 147.4, 142.0, 138.4, 128.6, 128.0, 127.8, 119.2, 113.1,
71.9, 62.0, 49.9, 10.0; HRMS calcd for C13H14O2 202.0944, found
202.0941.
features in this catalytic reactions:12 (1) it facilitates
dissociation of CH3CN and (2) it increases the basicity
of ruthenium center to offer stabilization of ruthenium-
furylidene B.
In summary, we have reported a new ruthenium
system to effect the cyclization of terminal epoxyalkynes
to furan derivatives. This catalytic reaction requires less
catalyst than the previous molybdenum system.10 This
reaction is compatible with oxygen and nitrogen func-
tionalities tethered in complex molecules. Further modi-
fication of the catalyst and the application of this reaction
are under investigation.
Ack n ow led gm en t. Financial support of this work
by the National Science Council, Taiwan, is gratefully
acknowledged.
Exp er im en ta l Section
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere in oven-dried glassware using standard
syringe, cannula, and septa apparatus. Benzene, diethyl ether,
tetrahydrofuran, and hexane were dried with sodium benzophe-
none and distilled before use. 1,2-Dichloroethane was dried
over CaH2 and distilled before use. TpRuPPh3(CH3CN)Cl,11
TpRuPPh3(CH3CN)2PF6,11 TpRu(COD)Cl,12a and TpRu(PPh3)2-
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 4-7, 10-18, and 20-25 in repetitive experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O020004H