Cu(I) catalyst in DMF: An efficient catalytic system for the synthesis of furans from 2-(1-alkynyl)-2-alken-1-ones

Article abstract of DOI:10.1021/jo050191u

The cyclization of 2-(1-alkynyl)-2-alken-1-ones 1 proceeded very smoothly in the presence of alcohols 2 with a catalytic amount of Cu(I)Br in DMF at 80 °C, leading to the formation of highly substituted furans 3. The catalytic system reported herein is ea

Full text of DOI:10.1021/jo050191u

TABLE 1. Effect of Various Cu(I) Salts on the
Formation of Furansa
Cu(I) Catalyst in DMF: An Efficient
Catalytic System for the Synthesis of
Furans from 2-(1-Alkynyl)-2-alken-1-ones
Nitin T. Patil, Huanyou Wu, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8578, Japan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received January 31, 2005
entry
catalyst (10%)
time (h)
NMR yield (%)b
1
2
3
4
5
6
none
12
2
0c
32
CuI
CuBr
2
85 (91)c
42
CuCl
2
CuCl(PPh3)
CuCN
2
trace
11
2
a
Methanol (0.3 mmol) was added to a solution of 1 (0.2 mmol)
and catalyst (0.02 mmol) in DMF (0.2 mL) and the mixture was
b
heated at 80 °C for the specified time. Yields were determined
1
by H NMR spectroscopy with dibromomethane as an internal
c
standard. Isolated yields are shown in parentheses.
The cyclization of 2-(1-alkynyl)-2-alken-1-ones 1 proceeded
very smoothly in the presence of alcohols 2 with a catalytic
amount of Cu(I)Br in DMF at 80 °C, leading to the formation
of highly substituted furans 3. The catalytic system reported
herein is easy to handle, compared to the previously known
system wherein the reaction between 1 and 2 needed to use
moisture sensitive gold(III) chloride.
ing products. Although this method is general, it employs
a highly air-sensitive catalyst that requires special
handling.
Furans are an important class of heterocyclic com-
pounds which are extensively used as synthetic building
1
blocks and appear as a subunit in many natural products
2
and substances of relevance for industry. Considerable
effort has been directed toward the development of new
and efficient methodologies for the synthesis of furans.3
One of the reliable approaches for the synthesis of this
class of compounds is the cyclization of allenyl ketones
and 3-alkyn-1-ones by use of transition metal catalysts.4
Previous work in our laboratories has shown that CuI
in DMF is a highly effective catalytic system for the
synthesis of cyclic alkenyl ethers 5 from acetylenic
aldehydes 4.6 The proposed mechanism is that the
resonance-stabilized oxonium ion 6, formed by the nu-
cleophilic attack of the aldehydic oxygen to the copper
coordinated alkynes, is being trapped by alcohols to give
the desired products (eq 2).
3
Recently, an interesting AuCl -catalyzed cyclization of
2
-(1-alkynyl)-2-alken-1-ones leading to substituted furans
5
has been described (eq 1). We believe that the reaction
proceeds via the formation of an oxonium ion that is
trapped by various nucleophiles to afford the correspond-
(
1) Maier, M. In Organic Synthesis Highlights II; Waldmann, H.,
Ed.; VCH: Weinheim, Germany, 1995; pp 231-242.
2) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
984; Vol. 4, pp 657-712.
3) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819. (b) Gilchrist,
(
1
(
T. L. Contemp. Org. Synth. 1994, 1, 205-217. (c) Gilchrist, T. L.
Contemp. Org. Synth. 1995, 2, 337-356. (d) Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 1998, 615-628. (e) Hou, X. L.; Cheung, H. Y.;
Hong, T. Y.; Kwan, P. L.; Lo, T.-H.; Tong, S.-Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955-2020. (f) Tae, J.; Kim, K.-O Tetrahedron
Lett. 2003, 44, 2125-2128. (g) Gabriele, B.; Salerno, G.; Lauria, E. J.
Org. Chem. 1999, 64, 7687-7692. (h) Gabriele, B.; Salerno, G.; Pascali,
F. D.; Costa, M.; Chiusoli, G. P. J. Org. Chem. 1999, 64, 7693-7699.
(4) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285-2288. (b) Marshall, J. A.; Bartley, G.
S. J. Org. Chem. 1994, 59, 7169-7171. (c) Marshall, J. A.; Wang, X.-
J. J. Org. Chem. 1991, 56, 960-969. (d) Fukuda, Y.; Shiragami, H.;
Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816-5819. (e) Kel’in,
A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95-98. (f) Hou, X. L.;
Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry; Gribble,
G. W., Gilchrist, T. L., Eds.; Pergamon Press: Oxford, UK, 2002; Vol.
(6) Patil, N. T.;Yamamoto, Y. J. Org. Chem. 2004, 69, 5139-5142.
For other reports on synthesis of the cyclic alkenyl ethers, see: (a)
Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J.
Am. Chem. Soc. 2003, 125, 9028-9029. (b) Asao, N.; Nogami, T.;
Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764-765.
(c) Mondal, S.; Asao, N.; Nogami, T.; Yamamoto, Y. J. Org. Chem. 2003,
68, 9496-9498. (d) Yue, D.; Ca, N. D.; Larock, R. C. Org. Lett., 2004,
6, 1581-1584. (e) Wei, L.-L.; Wei, L.-M.; Pan, W.-B.; Wu, M.-J. Synlett
2004, 1497-1502.
1
6
4, pp 139-179. (g) Cacchi, S. J. Organomet. Chem. 1999, 576, 42-
4.
(
5) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
1
1164-11165.
1
0.1021/jo050191u CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/14/2005
J. Org. Chem. 2005, 70, 4531-4534
4531

TABLE 2. CuBr-Catalyzed Cyclization Reaction of 2-(1-Alkynyl)-2-alken-1-onesa
a
The reactions of 2-(1-alkynl)-2-alken-1-ones 1 (0.2 mmol) with alcohols 2 (0.3 mmol) in the presence of CuBr (10 mol %) were carried
b
out at 80 °C in DMF (0.2 mL). Isolated yields.
We hypothesized that cyclization of 2-(1-alkynyl)-2-
alken-1-ones 1 might also proceed under our previously
developed catalytic system, i.e., Cu(I) in DMF. Indeed,
our hypothesis proved correct and we report herein a
detailed study on the Cu(I)-catalyzed cyclization of 2-(1-
alkynyl)-2-alken-1-ones to substituted furans.
The results of varying the Cu(I) salts are summarized
in Table 1. The reaction of 1a with methanol 2a at 80 °C
in the absence of any catalyst did not yield any desired
product, the starting material being decomposed (Table
1, entry 1). As anticipated, the use of a copper(I) catalyst
such as CuI gave the desired product 3a, albeit in 32%
yield (entry 2). Surprisingly, when CuBr was employed
as a catalyst, the desired product 3a was isolated in 81%
yield (entry 3). The use of other copper(I) catalysts such
3
as CuCl, CuCl(PPh ), and CuCN, however, was not
1
satisfactory as judged by the H NMR spectra of the crude
reaction mixture (entries 4-6). The reason for the vary-
4532 J. Org. Chem., Vol. 70, No. 11, 2005

8
SCHEME 1. A Proposed Mechanism for the
Cyclization of 2-(1-Alkynyl)-2-alken-1-ones
oxonium ion I (path A), which upon subsequent trapping
with alcohols followed by protonation with regeneration
of the Cu(I) catalyst produces the furans. (ii) The activa-
tion of carbonyl group occurs through the coordination
9
of Cu(I) to carbonyl oxygen and the π-bond of the alkyne,
which increases the electrophilicity at the â-position
thereby facilitating the addition of methanol in Michael
addition fashion (path B) to form intermediate II. The
alkynyl ketone intermediate II formed in this way might
undergo in situ cyclization in the presence of Cu(I) salts
to produce furans.10 It should be noted that the reaction
did not proceed in other organic solvents such as benzene,
2 2
toluene, CH Cl , THF, 1,4-dioxane, etc. The use of DMF
is essential for this reaction. This observation indicates
that DMF may act as a Lewis base that deprotonates a
proton from methanol thereby facilitating the nucleo-
philic addition of methanol. Although it is very difficult
to determine the precise reaction pathway, we believe the
former mechanism since the metal-catalyzed formation
ing efficiencies by different Cu(I) salts is not clear at
present.
The optimum reaction stoichiometry was found to be
1
a:2a:CuBr ) 1:1.5:0.1 for the formation of 3a. Next we
8
of oxonium ion is well-known in the literature for these
investigated the annulation reaction of various 2-(1-
alkynyl)-2-alken-1-ones 1. The results are summarized
in Table 2. Treatment of 1a with n-butanol 2b under the
standard conditions gave the desired product 3b in 66%
yield (entry 1). The reaction of the secondary alcohol
i-PrOH with 1a proceeded smoothly to afford product 3c
in 62% yield (entry 2). However, in the case of tert-butyl
alcohol 2d a complex mixture of unidentified products
was obtained indicating that tertiary alcohols are not
suitable nucleophiles in this reaction (entry 3). Upon
treatment with homoallyl alcohol 2e and 3-phenyl-2-
propyn-1-ol 2f, the substrate 1a underwent smooth
annulation reactions giving rise to the corresponding
furans 3e and 3f in 66% and 43% yields, respectively
types of substrates.
In conclusion, we have applied our newly developed
catalytic system, Cu(I) salts in DMF, for the efficient
cyclization of 2-(1-alkynyl)-2-alken-1-ones, which leads
to the formation of highly functionalized furans. Although
relatively high temperature (80 °C) was needed for the
complete reaction, the availability of inexpensive Cu(I)
salts and avoidance of drybox use compares favorably
with the previously reported gold-catalyzed reaction.
Further applications of this catalytic system are being
investigated in our laboratory.
Experimental Section
(entries 4 and 5). The substituent on the aromatic ring
1H and 13C spectra were operated at 400 and 100 MHz,
1
of R does not affect the efficiency of the reaction. Thus
when substrates 1b, 1c, and 1d were treated with
methanol under the standard conditions, the correspond-
ing furans 3g, 3h, and 3i were obtained in good yields
respectively, all referenced to internal tetramethylsilane (TMS)
at 0.0 ppm. Reactions were monitored by thin-layer chromatog-
raphy (Merck 60 F254). Column chromatography was performed
on neutral silica gel (60N, 100-210 µm) and elution with a
hexane/AcOEt, 99:1, solvent system. All substrates 1a-g were
prepared by the known literature procedures from readily
(entires 6-8). Upon treatment with MeOH and i-PrOH,
the substrate 1e gave the products 3j and 3k, respec-
tively, in high yields (entries 9-10). Employing 2-(1-
alkynyl)-2-alken-1-ones 1f as a substrate, the annulation
proceeded well with methanol and i-PrOH to give the
products 3l and 3m in 89% and 79% yield, respectively
5
available alkenones and alkynes. MeOH, i-PrOH, and DMF
were purchased from “Wako Pure Chemical Industries Ltd” and
used as such without further drying. Cu(I)Br was purchased
from Aldrich. The catalyst was weighed and added to the
reaction in the air.
The preparation of 3a is representative. To a mixture of 2-(1-
alkynyl)-2-alken-1-one 1a (0.040 g, 0.2 mmol), MeOH (0.010 g,
(
entries 11 and 12). As mentioned in entries 13 and 14,
the acyclic substrate 1g underwent smooth annulation
reactions with MeOH and i-PrOH to produce furans 3n
and 3o in 74% and 66% yield, respectively.
0
.3 mmol), and Cu(I)Br (0.003 g, 0.02 mmol) was added DMF
(
0.2 mL) and the resulting solution was stirred until the
disappearance of starting material on TLC at 80 °C. Water (10
mL) was added and the product was extracted with ethyl acetate.
The extracts were washed with water and dried over anhydrous
A proposed mechanism is shown in Scheme 1. There
are two conceivable pathways: (i) The nucleophilic attack
of carbonyl oxygen to the copper coordinated alkynes7
might result in the formation of the resonance stabilized
(8) Such type of transition metal catalyzed oxonium ion formation
is known in the case of the compound containing alkynes tethered with
carbonyl groups, see: (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara,
T.; Yamamoto. Y. J. Am. Chem. Soc. 2002, 124, 12650-12651. (b) Asao,
N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458-
7459. (c) Sato, K.; Yudha, S. S., Asao, N.; Yamamoto, Y. Synthesis 2004,
9, 1409-1412. (d) Asao, N.; Nogami, T.; Lee, S.; Yamamoto Y. J. Am.
Chem. Soc. 2003, 125, 10921-10925. (e) Kusama, H.; Funami, H.;
Shido, M.; Hara, Y.; Takaya, J.; Iwasawa N. J. Am. Chem. Soc. 2005,
127, 2709-2716. (f) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew.
Chem., Int. Ed. 2004, 43, 1239-1239.
(9) The simultaneous coordination of copper(I) salts to the π-bond
of alkynes and heteroatoms is known, see: Kamijo, S.; Yamamoto, Y.
J. Org. Chem. 2003, 68, 4764-4771.
(10) (a) Kelin, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95-98.
(b) Reference 5.
(
7) The complexation between alkyne and Cu(I) salts is known,
see: (a) Macomber, D. W.; Rausch, M. D. J. Am. Chem. Soc. 1983,
05, 5325-5329. More recently such complexation has been applied
1
to the synthesis of alkynylcopper, see: (b) Ito, H.; Arimoto, K.; Sensui,
H.-O.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977-3980. (c) Ikeg-
ashita, K.; Nishihara, Y.; Hirabayashi, K.; Mori, A.; Hiyama, T. Chem.
Commun. 1997, 1039-1040. (d) Nishihara, Y.; Ikegashita, K.; Mori,
A.; Hiyama, T. Chem. Lett. 1997, 1233-1234. (e) Nishihara, Y.;
Ikegashita, K.; Mori, A.; Hiyama, T. Tetrahedron Lett. 1998, 39, 4075-
4
078. (f) Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.-I.;
Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780-1787. (g) Nishihara,
Y.; Takemura, M.; Mori, A.; Osakada, K. J. Organomet. Chem. 2001,
6
20, 282-286.
J. Org. Chem, Vol. 70, No. 11, 2005 4533

sodium sulfate. The solvent was removed, and the residue was
then filtered through a short silica gel column with hexane/
AcOEt, 99:1, as eluent to give pure product 3a (0.037 g, 81%).
Supporting Information Available: Experimental de-
tails, characterization data of compounds 3b, 3c, 3e, 3g, 3h,
1
3
k, 3m, and 3o and H NMR of spectra of all compounds 3a-
o. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. N.T.P. thanks the Japan Society
for the Promotion of Science (JSPS) for a postdoctoral
research fellowship.
JO050191U
4534 J. Org. Chem., Vol. 70, No. 11, 2005