A novel entry to functionalized benzofurans and indoles via palladium(0)-catalyzed arylative dearomatization of furans

Article abstract of DOI:10.1021/ol300008d

A novel entry to functionalized benzofurans and indoles from furans in moderate to good yields has been developed. This protocol involves palladium(0)-catalyzed dearomatizing intramolecular arylation of the furan ring, formation of a π-allylic palladium complex, furan ring opening, and a β-hydride elimination sequence.

Full text of DOI:10.1021/ol300008d

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1098–1101
A Novel Entry to Functionalized
Benzofurans and Indoles via
Palladium(0)-Catalyzed Arylative
Dearomatization of Furans
Biaolin Yin,*,† Congbi Cai,† Guohui Zeng,† Ruoqi Zhang,† Xiang Li,† and
Huanfeng Jiang†
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou, Guangdong, 510640, China
blyin@scut.edu.cn
Received January 3, 2012
ABSTRACT
A novel entry to functionalized benzofurans and indoles from furans in moderate to good yields has been developed. This protocol involves
palladium(0)-catalyzed dearomatizing intramolecular arylation of the furan ring, formation of a π-allylic palladium complex, furan ring opening,
and a β-hydride elimination sequence.
Dearomatization of aromatic compounds has attracted
considerable attention because it provides a simple method
toachievefunctionalizedalicyclicsyntheticbuildingblocks
which can be utilized as intermediates for the preparation
of natural products and bioactive compounds.1,2 Of par-
ticular interest is the dearomatization of furans due to their
low Dewar resonance energy of 4.3 kcal mol and because
furan rings contain masked functionalities of olefin, diene,
enol ether, and 1,4-dicarbony. Accordingly, their partial
dearomatization allows the reactivity of the remaining
unsaturation to be intensively exploited. To date, there are
a number of different methods that, with unequal scope,
allow the dearomatization of the furan ring and which have
been used extensively in the synthesis of numerous bioactive
molecules.3 Among these methods, there are only a few
examples of transition-metal-catalyzed dearomatizing pro-
cesses being used for organic synthesis. These examples are
limited to the highly toxic metals omsium4 and chromium5
or noble metals such as gold.6 Over the past decades,
(3) For recent examples of the dearomatization of furan ring, see: (a)
McDermott, P. J.; Stockman, R. A. Org. Lett. 2005, 7, 27. (b) Zhou, X.;
Wu, W.; Liu, X.; Lee, C.-S. Org. Lett. 2008, 10, 5525. (c) Jackson, K. L.;
Henderson, J. A.; Morris, J. C.; Motoyoshi, H.; Phillips, A. J. Tetra-
hedron Lett. 2008, 49, 2939. (d) Abrams, J. N.; Babu, R. S.; Guo, H.; Le,
D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem. 2008, 73,
1935. (e) Bi, J.; Aggarwal, V. K. Chem. Commun. 2008, 1, 120. (f) Liu, L.;
Gao, Y.; Che, C.; Wu, N.; Wang, D. Z.; Li, C.-C.; Yang, Z. Chem
Commun. 2009, 662. (g) Pavlakos, E.; Georgiou, T.; Tofi, M.;
Montagnon, T.; Vassilikogiannakis, G. Org. Lett. 2009, 11, 455. (h) Dong,
J.-Q.; Wong, H. N. C. Angew. Chem., Int. Ed. 2009, 48, 2351.
(4) (a) Chen, H.; Hodges, L. M.; Liu, R.; Stevens, W. C.; Sabat, M.,
Jr.; Harman, W. D. J. Am. Chem. Soc. 1994, 116, 5499. (b) Chen, H.; Liu,
R.; Myers, W. H.; Harman, W. D. J. Am. Chem. Soc. 1998, 120, 509.
Reviews: (c) Harman, W. D. Chem. Rev. 1997, 97, 1953. (d) Smith, P. L.;
Chordia, M. D.; Harman, W. D. Tetrahedron 2001, 57, 8203.
(1) For selected recent reviews, see: (a) Ortiz, F. L.; Iglesias, M. J.;
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Fernandez, I.; Sanchez, C. A.; Gomez, G. R. Chem. Rev. 2007, 107, 1580.
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(b) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467. (c)
Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235.
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(d) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
(2) For selected recent references, see: (a) Garcıa-Fortanet, J.;
Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 6676. (b)
Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132,
11416. (c) Lee, S.; Chataigner, I.; Piettre, S. R. Angew. Chem., Int. Ed.
2011, 50, 472. (d) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.; Ye,
K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455 and references
cited therein. (e) Rudolph, A.; Bos, P. H.; Meetsma, A.; Minnaard, A. J.;
Feringa, B. L. Angew. Chem., Int. Ed. 2011, 50, 5834. (f) Green, J. C.;
Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133, 1603. (g) Rousseaux, S.;
Garcıa-Fortanet, J.; Sanchez, M. A. D. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2011, 133, 9282 and references cited therein. (h) Peng, B.;
Zhang, S.; Yu, X.; Feng, X.; Bao, M. Org. Lett. 2011, 13, 5402.
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Chem.;Eur. J. 2003, 9, 5725.
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Chen, Y.; Li, G.; Liu, Y. Adv. Synth. Catal. 2011, 353, 392.
r
10.1021/ol300008d
Published on Web 02/08/2012
2012 American Chemical Society

palladium(0) catalysis of organic halides and reactions that
occur via π-allyl palladium complexes have received tremen-
dous interest as a consequence of the resulting CꢀC and
Cꢀheteroatom bonds.7 However, palladium (0)-catalyzed
dearomatization of a furan ring involving these two species
to provide access to novel heterocyclic compounds has
seldom been reported.
using a diverse range of nucleophiles gave rise to several
conjugated enol ethers.10 With this outcome considered,
it was envisioned that the intramolecular palladium(0)-
catalyzed R-arylation of a furan ring could also be used to
form a π-allylic palladium complex B under suitable
conditions (Scheme 1b). The exploration and further
transformations of complex B would be particularly useful
for the construction of functionalized heterocyclic com-
pounds. For example, if methyloxy or methylamine were
tethered between the furan and phenyl ring, after an
elimination step, fuctionalized benzofurans and indoles
could be obtained. Herein are presented the detailed results
of this investigation into the novel use of palladium(0)-
catalyzed arylative dearomatization of furan rings, which
has resulted in fuctionalized benzofurans and indoles, two
important classes of heterocycles presented in many phar-
maceuticals and natural products.11,12
Scheme 1. Palladium-Catalyzed Arylation of Conjugated
Dienes
Palladium(0)-catalyzed reactions of aryl halides or
vinylic halides with dienes produce a π-allylic palladium
complex A which then undergoes a hydride elimination to
form a substituted diene or reacts with mild nucleophiles
such as amines and stabilized carbanions to form allylated
products (Scheme 1a).8 Furan rings have usually been
characterized as a special class of dienes in organic syn-
thesis. For example, furan rings undergo a DielsꢀAlder
reaction with dienophiles during the construction of dif-
ferent bicyclic or tricyclic skeletons.9 Acid-catalyzed dear-
omatizing nucleophilic substitutions of 2-furylcarbinol
Figure 1. 2-(2-Bromo-phenoxy-methyl)-furans 1 used in this
study.
Scheme 2. Strategy for Pd(0)-Catalyzed Dearomatization of
Furan and Potential Challenges
(7) For some recent books on palladium catalysis in organic syn-
thesis, see: (a) Tsuji, J. Palladium Reagents and Catalysts;Innovation in
Organic Synthesis; John Wiley & Sons: New York, 1995. (b) Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2002; Vols. 1 and 2. (c) Tsuji, J. Palladium
Reagents and Catalysts;New Perspectives for the 21st Century; John
Wiley & Sons: New York, 2004.
€
(8) (a) Andersson, P. G.; Backvall, J.-E. J. Am. Chem. Soc. 1992, 114,
8696. (b) Yeh, M.-C. P.; Tsao, W.-C.; Tu, L.-H. Organometallics 2005,
€
24, 5909. (c) Karlsson, E. A.; Backvall, J.-E. Chem.;Eur. J. 2008, 14,
9175.
(9) For selected recent examples of furan dearomatization through
DielsꢀAlder cycloadditions, see: (a) Chen, C.-H.; Rao, P. D.; Liao, C.-C.
J. Am. Chem. Soc. 1998, 120, 13254. (b) Xiong, H.; Hsung, R. P.; Berry,
C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174. (c) Kaelin,
D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 6937.
(d) Domingo, L. R.; Aurell, M. J. J. Org. Chem. 2002, 67, 959.
(10) (a) Yin, B.-L.; Yang, Z.-M.; Hu, T.-S.; Wu, Y.-L. Synthesis2003,
1995. (b) Chen, L.; Xu, H.-H.; Yin, B.-L.; Xiao, C.; Hu, T.-S.; Wu, Y.-L.
J. Agric. Food Chem. 2004, 52, 6719. (c) Yin, B.-L.; Wu, Y.-L.; Lai, J.-Q.
Eur. J. Org. Chem. 2009, 2695. (d) Robertson, J.; Naud, S. Org. Lett.
2008, 10, 5445. (e) Yin, B.-L.; Lai, J.-Q.; Zhang, Z.-R.; Jiang, H.-F. Adv.
Synth. Catal. 2011, 353, 1961. (f) Palmer, L. I.; Read de Alaniz, J. Angew.
Chem., Int. Ed. 2011, 50, 7167.
Org. Lett., Vol. 14, No. 4, 2012
1099

Initially the transformation of 2-(2-bromo-phenoxy-
methyl)-furans (1) (Figure 1), which were prepared via
the Mitsunobu reaction of 2-furylcarbinols with phenols,
into benzofurans was studied. The success of this dearo-
matization strategy (Scheme 2, Path c) relies on the careful
selection of the substrate 1 and choosing suitable reaction
conditions to suppress the C3 arylation of the furan ring13
(Path a) and the CꢀO bond cleavage to form the π-allylic
palladium complex D (Path b). With these considerations,
the reaction conditions were optimized using furan 1a as a
model. With Pd(PPh3)4 (5 mol %), PPh3 (10 mol %), and
Cs2CO3 (1.5 equiv) in dioxane at 140 °C for 24 h, furan 1a
was transformed into (E)-3-benzofuran-3-yl-propenal 2a
in 17% yield (Table 1, entry 1). An evaluation of the effect
as a palladium source or diphosphines as ligands (entries
12ꢀ13). It was therefore concluded that the optimal
combination for this reaction was to use dioxane as the
solvent, Pd(PPh3) (5% mol) as the catalyst, PPh3 as the
ligand (10%), and K2CO3 (2 equiv) as the base.
Table 1. Optimization of the Reaction Conditionsa,b
yield
entry
[Pd]
base (equiv)
solvent
(%)c
1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Cs2CO3 (1.5)
K3PO4 (1.5)
KOt-Bu (1.5)
K2CO3 (1.5)
DBU (1.5)
TEA (1.5)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
DMF
17
2
trace
trace
34
3
4
5
trace
NDd
61
6
7
K2CO3 (2)
K2CO3 (3)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (1.5)
K2CO3 (1.5)
8
51
9
46
10
11
12
13
23
DMSO
31
dioxane
dioxane
39e
25f
a Reaction conditions: [Pd] (5 mol %), ligand (10 mol %), base
(1 mmol), and furan 1a (0.5 mmol) in solvent (5 mL) at 140 °C for 24 h.
b Unless otherwise noted, the ligand was PPh3. c The yield was deter-
mined by NMR methods using 1,3,5-trimethylbenzene as an internal
standard. d ND: not detected. e With dppp (1,3-bis(diphenylphosphino)-
propane) as the ligand. f With dppf (1,10-bis(diphenylphosphino)
ferrocene) as the ligand.
Figure 2. Scope of the Pd-catalyzed dearomatization of furans
under the following reaction conditions: Pd(PPh3)4 (5 mol %),
PPh3 (10 mol %), K2CO3 (1 mmol), and 1 (0.5 mmol) in 1,4-
dioxane (5 mL) at 140 °C for 24 h. The percentages correspond
to the isolated yields. aND: not detected.
of the base revealed a significant increase in yield to 34%
when Cs2CO3 (1.5 equiv) was substituted for K2CO3 (entry
4). Increasing the amount of K2CO3 to 2 equiv further
increased the yield to 61% (entry 7). However an excess of
K2CO3 (3 equiv) gave a slightly lower yield (entry 8). By
screening the solvent used, it was determined that dioxane
was optimal (entries 9ꢀ11). Finally, it was noted that no
yield improvement occurred when switching to Pd2(dba)3
To investigate the scope of the reaction, a series of furan
1 withvariable R1, R2, and R3 groups were used to produce
a range of benzofurans 2 under the optimized reaction
conditions. The resulting compounds illustrated in Figure 2
indicate that contribution of the electrons from the
substituent groups (R3) on the phenyl rings have a signifi-
cant influence on the reaction. Electron-donating R3 groups
generally promoted higher yields. However 1e which had a
4-CF3 group on its phenyl ring did not provide the desired
product 2e; instead it produced a complicated reaction
system. A possible explanation for this failure might lie in
(11) For reviews on the synthesis of benzofurans by transition-metal-
catalyzed transformations, see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2004, 104, 3079. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006,
106, 4644.
(12) For a review on the synthesis of indoles, see: Cacchi, S.; Fabrizi,
G. Chem. Rev. 2011, 111, 215.
(13) For a review on C3 direct arylation of heteroaromatic com-
pounds with aryl halides by CꢀH bond activation, see: Roger, J.;
Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20.
1100
Org. Lett., Vol. 14, No. 4, 2012

was found that treatment of 2-furanmethanamines
(3aꢀ3e) under the same reaction condition as those used
for furan 1 produced very high yields of five functionalized
indoles (5aꢀ5e).
Scheme 3. Synthesis of Indoles
In summary, a novel entry to functionalized benzofur-
ans and indoles starting from furans has been developed.
The protocol involves palladium(0)-catalyzed dearomatiz-
ing C2 arylation of the furan ring, the formation of a
π-allylic palladium complex, furan ring opening, and a
β-hydride elimination. This research demonstrates the
possibility of carbopalladation of the double bond of the
furan ring, in the same way as a common double bond, and
expands the synthetic application of five-membered aro-
matic rings as building blocks. Further studies on the
reaction scope and trapping the π-allylic palladium
complex with intermolecular nucleophiles to synthesize
structurally novel spiro-compounds are currently under-
way. The results will be reported in due course.
the better leaving ability of the 4-CF3-phenoxyl group
resulting in the cleavage of the CꢀO bond in the presence
of the Pd(0) catalyst. With respect to the substitution on the
furan ring, some electron-neutral groups (R1 = H, Me, Ph)
were well tolerated. When R1 was TBS, or methoxycarbonyl
groups, the reactions were proven to be unsuccessful (2s, 2t).
It should also be noted that the yields of enals (R1 = H)
were generally lower than those of the corresponding enones
(R1 = Me or Ph) possibly as a result of the partial
decomposition of the enals under basic reaction conditions.
The focus of the study then switched to the possibility of
synthesizing functionalized indoles using the same reaction
conditions as in the case of benzofurans (Scheme 3).14 It
Acknowledgment. This work was support by the Fun-
damental Research Funds for the Central Universities
(2012ZZ043), the National Natural Science Foundation of
China (No. 21072062), and the Natural Science Foundation
of Guangdong Province, China (10351064101000000).
Supporting Information Available. Details on general
1
experimental methods, and copies of H and 13C NMR
spectra of all the new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) For a similar synthesis of functionalized indoles using aryl iodide
under microwave irradiation, see: Kaim, L.; Grimaud, L.; Wagschal, S.
Chem. Commun. 2011, 47, 1887.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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