Regioselective synthesis of 4,6,7-trisubstituted benzofurans from furfural imines and nonheteroatom stabilized alkynylcarbene complexes

Article abstract of DOI:10.1021/ja9063712

(Chemical Equation Presented) Nonheteroatom stabilized chromium alkynylcarbene complexes 3,6, generated in situ from Fischer cabene complexes 1, smoothly react with furan-2-ylmethanimines 4 to provide substituted 7-aminobenzofurans 5 in moderate to good y

Full text of DOI:10.1021/ja9063712

Published on Web 09/25/2009
Regioselective Synthesis of 4,6,7-Trisubstituted Benzofurans from Furfural
Imines and Nonheteroatom Stabilized Alkynylcarbene Complexes
Jose´ Barluenga,* Ara´nzazu Go´mez, Javier Santamar´ıa, and Miguel Toma´s
Instituto UniVersitario de Qu´ımica Organometa´lica “E. Moles”, Unidad Asociada al CSIC, UniVersidad de OViedo,
Julia´n ClaVer´ıa, 8, E-33006 OViedo, Spain
Received July 29, 2009; E-mail: barluenga@uniovi.es
Group 6 Fischer carbene complexes, discovered in 1964,1 have
demonstrated in the past decades high versatility for the synthesis
of carbo- and heterocycles as well as open chain compounds.2
Conversely, their nonheteroatom stabilized counterparts, first
reported by Casey in 1973,3 have received much less attention
mainly due to their low stability, particularly those having hydrogen
at the CR carbon.4,5 On the basis of this fact, we and others realized
that alkynyl carbenes would be much more promising from a
synthetic point of view. It was reported that alkynyl carbenes of
groups 6 and 7 behave as carbenoids in the homocoupling reaction
(dimerization)6 as well as in the cross-coupling reaction with
methoxyfuran.7 However, cyclization reactions of this class of metal
carbenes are restricted to an isolated intramolecular cyclopropa-
nation reported by Casey.6b
On the basis of the structural correspondence with R,ꢀ-unsatur-
ated (alkoxy)carbene complexes, we decided to investigate the
potential of nonstabilized alkynyl carbenes as a three-carbon synthon
in carbocyclization reactions. We report herein a new and highly
regioselective benzannulation reaction via the [3+3] carbocycliza-
tion of group 6 alkynylcarbene complexes 3 and furan-2-carbal-
dehyde imines 4, wherein the carbene ligand behaves as 1,3-dipole
species I (Figure 1).8 This benzannulation methodology would
represent a useful alternative to the well established annulation of
the furan ring. In this sense, the protocol reported here would
overcome the use of a pre-existing arene ring with the appropriate
substitution pattern, not always easily accessible for the benzofuran
synthesis. In spite of its importance for the construction of
functionalized six-membered rings, this type of carbocyclization
is rather uncommon in the literature due primarily to the lack of
appropriate pairs of C3 synthons.9
(see Supporting Information). Removal of the solvents and chro-
matographic purification afforded benzofurans 5a-h10 in moderate
to good overall yields. The reaction was found to be regioselective
affording a single or major (compounds 5c-e; >8:1) regiosiomer
(see Table 1). Interestingly, taking advantage of the versatile access
to metal carbenes 3, either regioisomer of 5 would be readily
available by simply exchanging their substituents R1/R2. In this way,
both regioisomers 5d and 5e were efficiently synthesized from
carbenes 3d (R1 ) Ph; R2 ) cC3H5) and 3e (R1 ) cC3H5; R2 )
Ph), respectively. Moreover, starting from the cross-conjugated
diynyl carbene 3f (R1 ) Ph-Ct C) permits attachment of the
alkynyl functionality at the C-4 of the benzofuran 5f. In the same
way, the 2-furaldehyde imine 4b (R3 ) allyl) afforded the
cycloadducts 5g,h, as single regioisomers, upon reaction with
carbenes 3a,b under the standard protocol. In turn, 5h underwent
efficient Pd-catalyzed N-allyl cleavage to provide the N-unsubsti-
tuted 7-aminobenzofuran 5i.11
Table 1. One-Pot Synthesis of Benzofurans 5 from Fischer
Carbene Complexes 1 via Nonheteroatom Stabilized Carbene
Complexes 3
Figure 1. [3+3] Carbocyclization of nonstabilized alkynyl carbenes.
Interestingly, the reaction could be carried out in a one-pot
manner starting from the corresponding (methoxy)carbene complex,
thus avoiding handling of the rather unstable (alkynyl)carbene
complex. Therefore, the yields given throughout this study are
referred to as (methoxy)carbenes 1. The protocol simply consists
of the generation of the nonstabilized metal carbene 3 by methoxy-
acetylide exchange of the oxygen-stabilized carbene 1 (see ref 6a
and Supporting Information) followed by the addition of the
substrate 4 (Table 1).
A mechanistic proposal for the formation of the benzofuran
skeleton 5 from alkynyl carbenes 3 is outlined in Scheme 1. Thus,
the [3+3] cyclization process would be initiated by the nucleophilic
1,2-addition of the furan C-3 to the nonstabilized carbene complex
3 to form the intermediate Csp3-propargyl metalate II. This
Thus, 2-furaldehyde imine 4a (R3 ) Bu) was added to a blue-
colored solution of chromium alkynyl carbene 3a-f in THF at -80
°C and allowed to warm up until disappearance of the blue color
9
14628 J. AM. CHEM. SOC. 2009, 131, 14628–14629
10.1021/ja9063712 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
intermediate might equilibrate to the more stable Csp2-allenyl
metalate III which could evolve to the nonheteroatom stabilized
alkenyl carbene intermediate IV by proton transfer. Finally, a [2+2]
intramolecular cyclization (intermediate metallaazacyclobutane V)
followed by Cr-Hꢀ elimination and reductive metal elimination
would account for the formation of 5.
Finally, this work reveals that these apparently elusive alkynylcar-
bene complexes can be easily handled and might be synthetically
useful.
Acknowledgment. We are grateful to Ministerio de Educacio´n
of Spain (CTQ2007-61048) and Principado de Asturias (IB08-088)
for supporting this research. A.G. thanks Ministerio de Educacio´n
and European Union (Fondo Social Europeo) for a predoctoral
fellowship.
Scheme 1. Mechanistic Proposal for the Formation of Benzofurans
5a-h
Supporting Information Available: Data for 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Fischer, E. O.; Maasbo¨l, A. Angew. Chem. 1964, 76, 645.
(2) Selected reviews: (a) De Meijere, A.; Schirmer, H.; Duetsch, M. Angew.
Chem., Int. Ed. 2000, 39, 3964. (b) Herndon, J. W. Tetrahedron 2000, 56,
1257. (c) Barluenga, J.; Santamar´ıa, J.; Toma´s, M. Chem. ReV. 2004, 104,
2259. (d) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E. J.
Organomet. Chem. 2005, 690, 539. (e) Go´mez-Gallego, M.; Manchen˜o,
M. J.; Sierra, M. A. Acc. Chem. Res. 2005, 38, 44. (f) Herndon, J. W.
Coord. Chem. ReV. 2009, 253, 86. (g) Santamar´ıa, J. Curr. Org. Chem.
2009, 13, 31. (h) Metal Carbenes in Organic Synthesis; Do¨tz, K. H., Ed.;
Topics in Organometallic Chemistry; John Wiley & Sons: New York, 2004;
Vol. 13.
(3) Casey, C. P.; Burkhardt, T. J. J. Am. Chem. Soc. 1973, 95, 5833.
(4) (a) Casey, C. P.; Burkhardt, T. J.; Bunnell, C. A.; Calabrese, J. C. J. Am.
Chem. Soc. 1977, 99, 2127. (b) Casey, C. P.; Polichnowski, S. W. J. Am.
Chem. Soc. 1977, 99, 6097. (c) Casey, C. P.; Polichnowski, S. W.; Tuinstra,
H. E.; Albin, L. D.; Calabrese, J. C. Inorg. Chem. 1978, 17, 3045. (d)
Iwasawa, N.; Maeyama, K.; Saitou, M. J. Am. Chem. Soc. 1997, 119, 1486.
(5) For previous studies on CR-H nonheteroatom stabilized carbene complexes
in our group, see: Barluenga, J.; Ballesteros, A.; Bernardo de la Ru´a, R.;
Santamar´ıa, J.; Rubio, E.; Toma´s, M. J. Am. Chem. Soc. 2003, 125, 1834.
(6) (a) Barluenga, J.; de Sa´a, D.; Go´mez, A.; Ballesteros, A.; Santamar´ıa, J.;
de Prado, A.; Toma´s, M.; Sua´rez-Sobrino, A. L. Angew. Chem., Int. Ed.
2008, 47, 6225. For dimerizations involving group 7 carbene complexes,
see: (b) Casey, C. P.; Kraft, S.; Powell, D. R. J. Am. Chem. Soc. 2000,
122, 3771. (c) Casey, C. P.; Kraft, S.; Powell, D. R. J. Am. Chem. Soc.
2002, 124, 2584. (d) Casey, C. P.; Dzwiniel, T. L. Organometallics 2003,
22, 5285. (e) Casey, C. P.; Dzwiniel, T. L.; Kraft, S.; Guzei, I. A.
Organometallics 2003, 22, 3915. (f) Ortin, Y.; Sournia-Saquet, A.; Lugan,
N.; Mathieu, R. Chem. Commun. 2003, 1060.
We have also made a single test to evaluate the influence of the
metal on the regioselectivity of the reaction (Scheme 2). Fortunately,
when the tungsten carbene 6, formed from the corresponding
tungsten (methoxy)carbene complex, reacted with 2-furaldehyde
imine 4a under the standard reaction conditions, the benzofuran
derivative 5j was obtained in 43% yield along with minor amounts
of its regioisomer 5c (5j/5c > 20:1). In this case, the process should
involve the intermediate VI, analogous to III (Scheme 1), by
conjugate addition of the imine to the carbene. Therefore the
regioselectivity found with chromium carbenes can be reversed by
simply using a metal with higher steric demand, like tungsten, which
makes more difficult the 1,2-addition and directs the process through
the 1,4-addition pathway.12
(7) Barluenga, J.; Garc´ıa-Garc´ıa, P.; de Sa´a, D.; Ferna´ndez-Rodr´ıguez, M. A.;
Bernardo de la Ru´a, R.; Ballesteros, A.; Aguilar, E.; Toma´s, M. Angew.
Chem., Int. Ed. 2007, 46, 2610.
(8) Furfural itself fails to react with complexes 3 up to room temperature. At
that temperature CR-H insertion into THF along with decomposition of 3
was observed.
Scheme 2. Reverse Regioselectivity with Tungsten Carbene
Complex 6
(9) For recent examples, see: (a) Ghosh, S. K.; Buchanan, G. S.; Long, Q. A.;
Wei, Y.; Al-Rashid, Z. F.; Skelenicka, H. M.; Hsung, R. P. Tetrahedron
2008, 64, 883. (b) Hussain, I.; Nguyen, V. T. H.; Yawer, M. A.; Dang,
T. T.; Fischer, C.; Reinke, H.; Langer, P. J. Org. Chem. 2007, 72, 6255.
(c) For a review, see: Feist, H.; Langer, P. Synthesis 2007, 327.
(10) The structure of 5 was established by 1D- and 2D-NMR experiments.
(11) Appropriately, N-substituted 7-aminobenzofurans have been reported as
antitumoral agents. See: (a) Lambert, C. M. P.; Ple, P. PCT Int. Appl
2002030924. (b) Hennequin, L. F. A.; Gibson, K. H.; Foote, K. M. PCT
Int. Appl. 2003047583. (c) Hennequin, L. F. A. PCT Int. Appl. 2004041811.
(12) We have already experienced the preference of tungsten over chromium
for the conjugate addition to alkynyl(methoxy)carbene complexes. See:
(a) Barluenga, J.; Toma´s, M.; Rubio, E.; Lo´pez-Pelegr´ın, J. A.; Garc´ıa-
Granda, S.; Pertierra, P. J. Am. Chem. Soc. 1996, 118, 695. (b) Barluenga,
J.; Toma´s, M.; Lo´pez-Pelegr´ın, J. A.; Rubio, E. Tetrahedron Lett. 1997,
38, 3981.
(13) For selected examples, see: (a) Kraus, G. A.; Zhang, N.; Verkade, J. G.;
Nagarajan, M.; Kisanga, P. B. Org. Lett. 2000, 2, 2409. (b) Kno¨lker, H. J.;
Krahl, M. P. Synlett 2004, 528. (c) Yue, D.; Yao, T.; Larock, R. C. J. Org.
Chem. 2005, 70, 10292. (d) Carril, M.; San Mart´ın, R.; Tellitu, I.;
Dom´ınguez, E. Org. Lett. 2006, 8, 1467. (e) Okitsu, T.; Nakazawa, D.;
Taniguchi, R.; Wada, A. Org. Lett. 2008, 10, 4967.
(14) Some benzofuran syntheses of limited generality involving the construction
of the arene ring have been reported. (a) Do¨tz, K. H.; Dietz, R. Chem. Ber.
1978, 111, 2517. (b) Wulff, W. D.; McCallum, J. S.; Kunng, F. A. J. Am.
Chem. Soc. 1988, 110, 7419. (c) Barluenga, J.; Toma´s, M.; Rubio, E.;
Lo´pez-Pelegr´ın, J. A.; Garc´ıa-Granda, S.; Pe´rez-Priede, M. J. Am. Chem.
Soc. 1999, 121, 3065. (d) Zhang, Y.; Candelaria, D.; Herndon, J. W.
Tetrahedron Lett. 2005, 46, 2211.
In conclusion, presented here is the first synthetic application of
group 6 nonheteroatom stabilized carbene complexes in carbocy-
clization reactions. Specifically, a facile and regioselective entry
into substituted benzofurans is achieved by the [3+3] benzoannu-
lation reaction of 2-furaldehyde imines and metal alkynylcarbene
complexes. Moreover, this work features access to N-unsubstituted
7-aminobenzofurans, a heterocyclic motif found in compounds with
antitumor activity. It should be noted that the procedure reported
herein involves the construction of the arene ring, while most
general methods to synthesize the benzofuran ring are based on
the annulation of the furan ring onto a preexisting arene nucleous.13,14
Due the simplicity of the reaction and the readily availability of
the starting materials, this benzoannulation reaction seems amenable
for selectively accessing other classes of polycyclic structures.
JA9063712
9
J. AM. CHEM. SOC. VOL. 131, NO. 41, 2009 14629