Copper-Catalyzed domino rearrangement/dehydrogenation oxidation/carbene Oxidation for One-Pot regiospecific synthesis of highly functionalized polysubstituted furans

Article abstract of DOI:10.1021/ol900364y

A novel and efficient method for the regiospecific synthesis of polysubstituted furan aldehydes/ketones has been developed via a coppers-catalyzed rearrangement/dehydrogenation oxidation/carbene oxidation sequence of 1,5-enynes in situ formed from alkynol

Full text of DOI:10.1021/ol900364y

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1931-1933
Copper-Catalyzed Domino
Rearrangement/Dehydrogenation
Oxidation/Carbene Oxidation for One-Pot
Regiospecific Synthesis of Highly
Functionalized Polysubstituted Furans
Hua Cao, Huanfeng Jiang,* Wenjuan Yao, and Xiaohang Liu
School of Chemistry and Chemical Engineering, South China UniVersity of
Technology, Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received February 19, 2009
ABSTRACT
A novel and efficient method for the regiospecific synthesis of polysubstituted furan aldehydes/ketones has been developed via a copper(I)-
catalyzed rearrangement/dehydrogenation oxidation/carbene oxidation sequence of 1,5-enynes in situ formed from alkynols and diethyl but-
2-ynedioate under atmospheric pressure. The domino reaction proceeds smoothly under mild conditions with commercially available catalysts
and affords highly functionalized furans in moderate to good yields.
The development of new domino processes that construct
highly functionalized polysubstituted organic compounds
from easily available starting materials is an important goal
of synthetic chemistry and also represents a continuing
challenge.1 Recently, transition-metal-catalyzed domino pro-
cesses have been widely examined for the synthesis of
polysubstituted furans,2 which have appeared as key struc-
tural units in many important pharmaceuticals3 and bioactive
natural products.4 To achieve this goal, we are particularly
attracted to the possibilities of combining fundamental
reaction strategies to access highly functionalized polysub-
stituted furans5 that are difficult to be accessed by other
protocols. In this context, we wish to report a new type of
domino processscopper(I)-catalyzed rearrangement/dehy-
drogenation oxidation/carbene oxidation6 sequence of 1,5-
enynes which are formed in situ from alkynols and diethyl
but-2-ynedioate.
We began by treating 1,5-enyne (3a), the adduct of 1a
with 2a in the presence of a catalytic amount of DABCO
(1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Taylor, R. J. K.;
Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851. (c) Ikeda, S.
Acc. Chem. Res. 2000, 33, 511. (d) Tietze, L. F.; Kinzel, T.; Brazel, C. C.
Acc. Chem. Res. 2009, 42, 367. (e) Kim, B. G.; Snapper, M. L. J. Am.
Chem. Soc. 2006, 128, 52. (f) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (g) Mallagaray, I.; Dom´ınguez,
G.; Gradillas, A.; Castells, J. P. Org. Lett. 2008, 10, 597. (h) Bertrand,
M. B.; Wolfe, J. P. Org. Lett. 2006, 8, 4661.
(3) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (b) Hou, X. L.;
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955.
(4) (a) Donnelly, D. M. X.; Meegan, M. J. Comp. Heterocycl. Chem.
1984, 4, 657. (b) Dean, F. M. AdV. Heterocycl. Chem. 1982, 30, 167. (c)
Bosshard, P.; Eugster, C. H. AdV. Heterocycl. Chem. 1966, 7, 378.
(5) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b) Zinsmeister, H. D.;
Becker, H.; Eicher, T. Angew. Chem., Int. Ed. 1991, 30, 130. (c) Miki, K.;
Yokoi, T.; Nishino, F.; Ohe, K.; Uemura, S. J. Organomet. Chem. 2002,
645, 228. (d) Miki, K.; Yokoi, T.; Nishino, F.; Kato, Y.; Washitake, Y.;
Ohe, K.; Uemura, S. J. Org. Chem. 2004, 69, 1557.
(2) (a) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46,
5195. (b) Ma, S.; Li, L. Org. Lett. 2000, 2, 941. (c) Pearlman, B. A.;
McNamara, J. M.; Hasan, I.; Sekizaki, H.; Kishi, Y. J. Am. Chem. Soc.
1981, 103, 4248. (d) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005,
7, 3925. (e) Yao, T. L.; Zhang, X. X.; Larock, R. C. J. Am. Chem. Soc.
2004, 126, 11164. (f) Hu, Y. H.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org.
Chem. 2002, 67, 2365.
10.1021/ol900364y CCC: $40.75
Published on Web 03/26/2009
 2009 American Chemical Society

(10 mol %),7 with 2.5 mol % of AgBF4 or CuI in DMF at
8
80 °C. It is unexpected that different polysubstituted furan
rings, 3aa and 4aa, were obtained highly regiospecifically
(Scheme 1). Since rare general procedures are available for
Table 2. Cu(I)-Catalyzed One-Pot Synthesis of Furan
Scheme 1
.
Ag- or Cu-Catalyzed One-Pot Synthesis of Furan
Derivatives
the synthesis of R-carbonyl polysubstituted furans, our
attention was piqued by the potential of this novel transfor-
mation, which would make possible an expedient synthetic
route for furan aldehydes/ketones. Hence, we decided to
optimize the reaction conditions for the formation of formyl-
furan with 1a and 2a as substrates (Table 1).
Table 1. Optimization of Reaction Conditions
entry
Cu cat.
solvent
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
toluene
THF
1,4-dioxane
DMF
DMF
DMF
DMF
T (°C)
yielda (%)
1
2
3
4
5
6
7
8
CuCl
CuI
50
50
50
50
50
50
50
50
50
50
rt
53
71
62
19
59
23
45
44
19
27
8
CuBr
CuO
Cu2O
CuBr2
CuI
CuI
CuI
CuI
CuI
9
10
11
12
13
14
CuI
CuI
CuI
80
30
100
78
31
74
a Isolated yields.
Various copper catalysts were initially examined for the
desired process to screen the optimal reaction conditions. In
a typical procedure, 1a (0.5 mmol), 2a (0.5 mmol), and
(6) For reveiws, see: (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998,
98, 911. (b) Raper, E. S. Coord. Chem. ReV. 1994, 129, 91. (c) Raper,
E. S. Coord. Chem. ReV. 1985, 61, 115. For copper carbene complexes,
see:(d) Kirmse, W. Angew. Chem., Int. Ed. 2003, 42, 1088. For copper
carbene oxidation, see: (e) Barluenga, J.; Riesgo, L.; Vicente, R.; Lo´pez,
L. A.; Toma´s, M. J. Am. Chem. Soc. 2008, 130, 13528.
a Isolated yields.
(7) Fan, M. J.; Lian, G. Q.; Liang, Y. M. Tetrahedron 2006, 62, 6782.
1932
Org. Lett., Vol. 11, No. 9, 2009

DABCO in CH2Cl2 were stirred for 10 min at room
temperature, and then the solution was evaporated to dryness
under reduced pressure. Subsequently, 2.5 mol % of CuCl
and DMF were added at 50 °C. After completion of the
reaction (monitored by TLC), 3aa was isolated in 53% yield
(entry 1). When CuI and CuBr were used as the catalyst,
the reaction gave 3aa in 71% and 62% yields, respectively
(entries 2 and 3). Other catalysts were employed in the
reaction but only led to moderate yields (entries 4-6).
Different solvents and temperatures were also examined
(entries 7-14), and the best result was obtained by using
DMF at 80 °C (entry 12).
Scheme 2. Plausible Reaction Mechanism
With the optimal reaction conditions in hand, that is, CuI
as the suitable catalyst and DMF as the solvent, we next
explored the scope of a one-pot regiospecific synthesis of
polysubstituted furan aldehydes/ketones (Table 2). All of the
substrates provided similar isolated yields for the formation
of furan aldehydes/ketones. The reaction was found to
tolerate a broad substitution range for R1 and R2 (including
alkyl, aryl). We found that substituents presented on the para
and meta positions of the aromatic group of an alkynol such
as 2d, 2g, or 2l have no negative effects on the reaction.
However, if more sterically hindered ortho substitutents on
an aromatic group such as 2e or 2f were employed, the
corresponding products were obtained in lower yields. When
other alkynoates, such as ethyl propiolate or ethyl but-2-
ynoate, were used, no desired products were detected.
As Table 2 illustrated, susceptible aldehyde products were
formed without further oxidation to acid, which indicated a
direct carbene-oxidation process. Interestingly, the desired
products were only detected with copper salt as a catalyst in
anhydrous DMF under atmospheric pressure, which revealed
that the oxygen atom of R-carbonyl furans originated from
molecular oxygen.
On the basis of these experimental results, a tentative
mechanistic interpretation of the preceding observations is
proposed in Scheme 2. DABCO-promoted nucleoaddition
of propargyl alcohol to electron-deficient alkynoates formed
enyne adduct A.7 A 6-endo-dig addition of the enol ether
onto copper(I)-alkyne complex B resulted in the formation
of intermediate C, which collapsed into the ꢀ-allenic ketone
D.9 Then, a rearrangement took place in which ꢀ-allenic
ketone D was converted to carbene complex E10 in the
presence of a copper catalyst and air. Subsequently, carbene
complex E underwent sequential dehydrogenation oxidation
and carbene oxidation11 with an oxygen metathesis to give
3 as the desired product.
In summary, we have developed a new type of copper(I)-
catalyzed domino process which proceeds through a rear-
rangement/dehydrogenation oxidation/carbene oxidation se-
quence of 1,5-enynes, which is formed in situ from alkynols
and 1a under atmospheric pressure. This domino process
provides an efficient method for the regiospecific synthesis
of furan aldehydes/ketones which are useful synthetic
intermediates for bioactive compounds. Further studies into
the scope and synthetic applications of this reaction are being
carried out in our laboratory.
Acknowledgment. We thank the National Natural Foun-
dation of China (Nos. 20332030, 20572027, 20625205, and
20772034) and Guangdong Natural Science Foundation (No.
07118070) for financial support.
Supporting Information Available: Experimental pro-
cedure and characterization of compounds 3aa-3al. This
material is available free of charge via the Internet at
http://pubs.acs.org
(8) It was also found that when AgBF4 was used as a catalyst, normal
furan product was produced; a similar result has been reported before:Suhre,
M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
OL900364Y
(9) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(b) Grissom, J. W.; Kilingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem.
1997, 62, 603. (c) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M.
Chem.sEur. J. 2003, 9, 2627.
(11) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680.
(b) Perdicchia, D.; Licandro, E.; Maiorana, S.; Vandoni, B.; Baldoli, C.
Org. Lett. 2002, 4, 827. (c) Barluenga, J.; Andina, F.; Ferna´ndez-Rodr´ıguez,
M. A.; Garc´ıa-Garc´ıa, P.; Merino, I.; Aguilar, E. J. Org. Chem. 2004, 69,
7352. (d) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.; Toste,
F. D. J. Am. Chem. Soc. 2007, 129, 5838.
(10) (a) Go´mez-Gallego, M.; Manchen˜o, M. J.; Sierra, M. A. Acc. Chem.
Res. 2005, 38, 44. (b) Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96,
271. (c) Sierra, M. A. Chem. ReV. 2000, 100, 3591.
Org. Lett., Vol. 11, No. 9, 2009
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