Cu(I)-catalyzed regioselective synthesis of polysubstituted furans from propargylic esters via postulated (2-Furyl)carbene complexes

Article abstract of DOI:10.1021/ja8058342

Polysubstituted furan derivatives are regioselective obtained from (bis-alkynyl)methyl carboxylates in the presence of catalytic amounts of copper(I) salts. This multistep process is consistent with the intermediacy of a copper(I) (2-furyl)carbene complex which is intercepted by suitable trapping reagents. Copyright

Full text of DOI:10.1021/ja8058342

Published on Web 09/19/2008
Cu(I)-Catalyzed Regioselective Synthesis of Polysubstituted Furans from
Propargylic Esters via Postulated (2-Furyl)carbene Complexes
Jose´ Barluenga,* Lorena Riesgo, Rube´n Vicente, Luis A. Lo´pez, and Miguel Toma´s
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad Asociada al CSIC, UniVersidad de
OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo Spain
Received July 25, 2008; E-mail: barluenga@uniovi.es
Scheme 1. Cu(I)-Catalyzed Reaction of Diynes 1a and 1b and
Triethylsilane 3a
The transition metal-catalyzed transformations of propargyl esters
have become in recent years a powerful key process which has led
to the development of a variety of cycloisomerization as well as
atom-economy cascade reactions.1 Although the reaction course
has not been well-established yet, it is assumed that the process
initiates by either 1,2- or 1,3-acyloxy migration giving rise to metal
vinyl carbenes and metal-coordinate allenes, respectively, as reactive
intermediates.2 Recent studies from our laboratory3 revealed that
(i) the use of an alkoxy group as the alkyne substituent controls
perfectly the regiochemistry (1,3- in preference to 1,2-acyloxy
migration) leading to the Knoevenagel adducts and (ii) Pt(II) and
Cu(I) catalysts are stereochemically complementary leading to the
(Z)- and (E)-adducts, respectively. It was also noted that the
unsymmetrical bis-propargylic ester 1a undergoes a Cu(I)-catalyzed
process yielding the furyl dimer 2a (eq. 1).
Table 1. Cu(I)-Catalyzed Synthesis of Tri- and Tetrasubstituted
Furan Derivatives 4 and 6 from Propargyl Esters 1 and Silanes 3
and Germane 5a
This finding features a Cu(I)-chemoselective catalyzed reaction
cascade with a manifold interest: (i) the relevant furan ring4 is easily
available by a novel Cu(I)-catalyzed carbonyl-alkyne cyclization;
(ii) a new type of Cu(I)-carbene complex is likely to operate whose
reactivity could be exploited and, therefore, the cascade process
extended.
On the basis of these assessments we report an efficient synthesis
of tri- and tetrasubstituted furans5 as well as preliminary studies
on the reactivity of the proposed copper(I) 2-furylcarbene complex.6,7
When the Cu(I)-catalyzed cycloisomerization of 1a was con-
ducted in the presence of activated and unactivated alkenes no
cyclopropanation by the metal carbene occurred but dimerization
was found to be faster. On the contrary, we were pleased to find
that stirring 1a (R1 ) Ph) in CH2Cl2 (25 °C, 4 h) with
[Cu(CH3CN)4][BF4] (5 mol%) in the presence of triethyl silane 3a
(3 equiv) resulted in the formation of the furan derivative 4a in
57% yield after chromatographic purification (Scheme 1).8 Next,
we examined the suitability of an alkyl-substituted substrate like
1b (R1 ) npent) and found that, under the same reaction conditions,
the furan 4b was produced in 68% yield.9 Interestingly, the reaction
can be successfully extended to alkyl substrates since the presumed
Cu(I)-carbene species undergoes Si-H insertion in preference over
ꢀ-hydride elimination.10
a Yields of isolated product after column chromatography.
Thus, the reaction was found to tolerate a broad substitution range
for the alkyne terminus R1, including aryl, alkyl, trimethylsilyl, and
alkenyl groups (compounds 4a-d). Different R2-substituted esters,
including acetate, propanoate, pivalate, and acrylate, proved also
amenable to cyclization (compounds 4a-g). On the other hand,
the reaction proceeds efficiently with various silanes 3, for example,
tertiary silanes (trialkylsilanes and mixed dialkylarylsilanes) and
diethylsilane (compounds 4 g-j). The goal of synthesizing tetra-
substituted furans was exemplified by starting from 1 (R3 ) Me)
which produces furan 4k in acceptable yield (yield slightly higher
than that of the trisubstituted analogue 4h). We also found that the
proposed Cu(I) carbene intermediate derived from representative
The scope of this Cu(I)-catalyzed tandem reaction was next
investigated using substrates with substituents of varied nature and
various silicon and germanium hydrides (Table 1).
9
13528 J. AM. CHEM. SOC. 2008, 130, 13528–13529
10.1021/ja8058342 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cu(I)-Catalyzed Synthesis of Furan Derivatives 7 and 8
from Propargylic Esters 1a
(2) For a recent DFT study, see: (a) Correa, A.; Marion, N.; Fensterbank, L.;
Malacria, M.; Nolan, S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47,
718 For a recent report on gold intermediates, see: (b) Hashmi, A. S. K.
Angew. Chem., Int. Ed. 2008, 47, 6754.
(3) Barluenga, J.; Riesgo, L.; Vicente, R.; Lo´pez, L. A.; Toma´s, M. J. Am.
Chem. Soc. 2007, 129, 7772.
(4) Selected references showing the prominent role of the furan ring due to its
presence in many natural and biologically active products and to its potential
as synthetic intermediate: (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. in
Progress in Heterocyclic Chemistry; Gribble, G. W.; Gilchrist, T. L. Eds.;
Pergamon: Oxford, U.K., 2003; Vol. 15, p 167. (b) Keay, B. A.; Dibble,
P. W. In ComprehensiVe Heterocyclic Chemistry II; Katrizky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, U.K., 1997; Vol. 2, p
395. (c) Donnelly, D. M. X.; Meegan, M. J. ComprehensiVe Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K.,
1984; Vol. 4, p 657.
(5) For an overview covering the difficulties in accessing polysubstituted furans,
see: Kirch, S. F. Org. Biomol. Chem. 2006, 4, 2076.
(6) For a review on the synthetic applications of copper(I) carbene complexes
resulting from copper(I)-catalyzed decomposition of diazoesters, see:
Kirmse, W. Angew. Chem., Int. Ed. 2003, 42, 1088.
(7) The generation of a Cu(I) isoindazolylcarbene by CuCl-catalyzed azo-enyne
cyclization and the cyclopropanation to tetramethylethene has been
reported: (a) Kimball, D. B.; Herges, R.; Haley, M. M. J. Am. Chem. Soc.
2002, 124, 1572. (b) Shirtcliff, L. D.; Haley, M. H.; Herges, R. J. Org.
Chem. 2007, 72, 2411.
(8) The copper-catalyzed Si-H insertion into diazoesters and ketones has been
reported: Bagheri, V.; Doyle, M. P.; Taunton, J.; Claxton, E. E. J. Org.
Chem. 1988, 53, 6158.
(9) The reaction of the alkyl substituted diyne 1b with [Cu(CH3CN)4][BF4] (5
mol%, CH2Cl2, room temp) in the absence of triethylsilane 3a afforded
the corresponding dimer 2b in 85% yield.
(10) The extremely ease with which most transition metal alkyl carbenes suffer
ꢀ-hydride elimination is well documented, see for example: (a) Taber, D. F.;
Herr, R. J.; Pack, S. K.; Geremia, J. M. J. Org. Chem. 1996, 61, 2908 In
some cases the use of low reaction temperatures and sterically demanding
carboxylates proved to be useful in order to avoid ꢀ-hydride elimination.
For recent successful Rh(I)-catalyzed reactions of R-alkyl-R-diazoesters
with alkynes and alkenes, see: (b) Panne, P.; Fox, J. M. J. Am. Chem. Soc.
2007, 129, 22. Panne, P.; DeAngelis, A.; Fox, J. M. Org. Lett. 2008, 10,
2987.
(11) In all the cases examined, the dimer resulting from the competing carbene
ligand dimerization was detected in less than 10% yield.
(12) Unfortunately, all attempts to perform the reaction with Bu3SnH resulted
only in extensive decomposition and no furane derivative was ever isolated.
(13) In this coupling process CuBr proved to be superior to the cationic complex
in terms of chemical yield.
a Yield of isolated product after column chromatography. b A 80:20
mixture of Z/E isomers was obtained. c A 85:15 mixture of Z/E isomers
was obtained.
propargylic substrates is smoothly intercepted by triethylgermanium
5 to provide (furan-2-ylmethyl)germane derivatives (compounds
6a-c).11,12
Furthermore, the heterocoupling reaction to create a carbon-carbon
double-bond was investigated by running the Cu(I)-catalyzed
cycloisomerization of 1 in the presence of 2.5 equiv of ethyl
diazoacetate (EDA) (Table 2). Gratifyingly, the heterocoupling
event occurred cleanly in the presence of CuBr (5 mol%) to furnish
ethyl 3-(furan-2-yl)prop-2-enoates 7a,b (Z/E mixtures) along with
variable amounts of maleate and fumarate esters.13,14 This new
heterocoupling reaction proceeds in high yields (76-82%) and
moderate steroselectivity allowing the preparation of furan deriva-
tives bearing a vinyl moiety at C-2.
Finally, the sequence cycloisomerization/carbene oxidation would
allow the preparation of 2-acylfurans.15 This goal was achieved
directly by stirring at room temperature the bis-propargylic system
1 in the presence of CuCl (5 mol %) under air, as it is illustrated
in Table 2 for the tri- and tetrasubstituted 2-pentanoyl and
2-benzoylfurans 8a,b.
In conclusion, we have developed a regioselective Cu(I)-
catalyzed synthesis of highly substituted furans from readily
available bis-propargylic esters.16 The multistep process is consistent
with the intermediacy of a 2-furyl copper(I) carbene complex which
allows for further variable functionalization or coupling at C-2.17
This unprecendented approach to copper(I) 2-furylcarbene com-
plexes18 has made possible the exploration of its capability for C-X
(X ) Si, Ge) and CdY (Y ) C, O) bond formation. Hopefully
this work will open the way to study the potential of these copper
carbene species.
(14) During the study of the optimization and scope of this process we found
that the treatment of diyne 1d with diethyl diazomalonate in the presence
of CuBr (5 mol %) did not produce the heterocoupling product. In this
case the diazo derivative acts just as a modulating ligand giving rise to the
Knoevenagel adduct 9 in 65% yield. Furthermore, the treatment of
compound 9 with triethylsilane 3a ([Cu(CH3CN)4][BF4], 5 mol %, CH2Cl2,
room temp) or EDA (CuBr, 5 mol %, CH2Cl2, room temp) afforded the
furan derivatives 4e (92%) and 7b (89%), respectively.
(15) The oxidation of the gold(I) carbene intermediate formed by 1,2-pivaloyloxy
rearrangement of propargylic esters has been achieved using sulfoxides as
the stoichiometric oxidants: Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.;
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838.
(16) The metal-catalyzed reactions of bis-propargylic esters are extremely rare.
For an isolated example involving (1,1-diethynylmetyl) acetates, see: Kato,
K.; Teraguchi, R.; Kusakabe, T.; Motodate, S.; Yamamura, S.; Mochida,
T.; Akita, H. Synlett 2007, 63.
(17) Nonmetal 2-furfurylidenes from diazocompounds cannot be trapped due
to rapid ring-opening rearrangement; see: (a) Sun, Y.; Wong, M. W. J.
Org. Chem. 1999, 64, 9170 For successful trapping of 2-furyl carbenes
derived from photocyclization of 1,2-diketones conjugated with eneyne,
see: (b) Nakatani, K.; Adachi, K.; Tanabe, K.; Saito, I. J. Am. Chem. Soc.
1999, 121, 8221.
Acknowledgment. Financial support for this work is acknowl-
edged (Grants CTQ2004-08077, CTQ2007-61048, and IB 05-136).
L.R. thanks the Ministerio de Educacio´n y Ciencia for a predoctoral
fellowship.
Supporting Information Available: Experimental procedures and
spectral and analytical data for compounds 1, 4, and 6-8. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) For generation of 2-furylcarbenes of other transition metals by cyclization
of 1-buten-3-ynylketones, see: (a) Miki, K.; Nishino, F.; Ohe, K.; Uemura,
S. J. Am. Chem. Soc. 2002, 124, 5260. (b) Miki, K.; Yokoi, T.; Nishino,
F.; Kato, Y.; Washitake, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 2004, 69,
1557. (c) Miki, K.; Uemura, S.; Ohe, K. Chem. Lett. 2005, 34, 1068.
References
(1) Reviews: (a) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006,
348, 2271. (b) Marco-Contelles, J.; Soriano, E. Chem.sEur. J. 2007, 13,
1350. (c) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
(d) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
JA8058342
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13529