Halopalladation/decarboxylation/carbon-carbon forming domino process: synthesis of 5-halo-6-substituted benzo[b]naphtho[2,1-d]furans

Article abstract of DOI:10.1021/ol8029752

A novel and general halopalladation/decarboxylation/carbon-carbon forming domino protocol is described for the synthesis of 5-halo-6-substituted benzo[b]naphtho[2,1-d]furans. The protocol represents the first example of trapping the σ-vinylpalladium inter

Full text of DOI:10.1021/ol8029752

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1139-1142
Halopalladation/Decarboxylation/
Carbon-Carbon Forming Domino
Process: Synthesis of
5-Halo-6-substituted
Benzo[b]naphtho[2,1-d]furans
Xiao-Cheng Huang,† Feng Wang,† Yun Liang,*,† and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research
(Ministry of Education), Hunan Normal UniVersity, Changsha 410081, China, and
College of Chemistry and Materials Science, Wenzhou UniVersity,
Wenzhou 325035, China
liangyun1972@126.com; jhli@hunnu.edu.cn
Received December 28, 2008
ABSTRACT
A novel and general halopalladation/decarboxylation/carbon-carbon forming domino protocol is described for the synthesis of 5-halo-6-
substituted benzo[b]naphtho[2,1-d]furans. The protocol represents the first example of trapping the σ-vinylpalladium intermediate, generated
from halopalladation of alkynes, by the decarboxylative coupling reaction.
Halopalladation of alkynes has been proven to be an
extremely important and convenient method for the construc-
Scheme 1
.
Mechanism of Halopalladation of Alkynes with Allyl
Halides
tion of both the carbon-carbon and carbon-halide bonds
in one step.1-4 Halopalladation of alkynes will generate a
versatile reactive σ-vinylpalladium intermediate A (Scheme
1).1 Until now, how to capture the σ-vinylpalladium inter-
mediate is still a highly challenging area because the capture
reagents are often limited to allyl halides, alkynes, conjugated
† Hunan Normal University.
dienes, and carbon monoxide. Recently, we found that the
σ-vinylpalladium intermediate could be trapped by some
nucleophilic ortho-groups in the arylalkyne moiety.3 This
prompted us to explore other nucleophilic groups for the
purpose. Accidently, we found that arylcarboxylates were
‡ Wenzhou University.
(1) For reviews, see: (a) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: New York, 1985. (b) Tsuji, J. Palladium
Reagents and Catalysts: InnoVations in Organic Synthesis; Wiley and Sons:
New York, 1995. (c) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: New York, 2000. (d) Lu, X. Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Inter-
science: New York, 2002; Vol. 2, pp 2267-2288. (e) Han, X. L.; Liu,
G. X.; Lu, X. Y. Chin. J. Org. Chem. 2005, 25, 1182. (f) Tang, S.; Wang,
(3) (a) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Li,
J.-H. Org. Lett. 2006, 8, 3017. (b) Tang, S.; Xie, Y.-X.; Li, J.-H.; Wang,
N.-X. Synthesis 2007, 1841. (c) Tang, S.; Yu, Q.-F.; Peng, P.; Li, J.-H.;
Zhong, P.; Tang, R.-Y. Org. Lett. 2007, 9, 3413.
N.-X.; Li, J.-H. Chin. J. Org. Chem. 2007, 27, 819
(2) Phillips, F. C. Z. Anorg. Allg. Chem. 1894, 6, 229
.
.
10.1021/ol8029752 CCC: $40.75
Published on Web 02/06/2009
2009 American Chemical Society

an available alternative to the traditional capture reagents to
trap the σ-vinylpalladium complexes.5 In the presence of
PdCl2 and CuX2 (X ) Cl, Br), a variety of 2-(2-(2-substituted
ethynyl)phenyl)-benzofuran-3-carboxylates could undergo an
intramolecular decarbonylative coupling reaction to capture
the σ-vinylpalladium intermediate in situ. In this paper, we
report our preliminary results on the first example of trapping
the σ-vinylpalladium intermediate by the decarboxylative
coupling reaction (eq 1). It is noteworthy that the products,
polycyclic aromatic furans, are prominent structural units
found in a wide range of natural products, pharmaceuticals,
and materials as well as important intermediates in organic
synthesis.6
Table 1. Screening Optimal Conditionsa
entry
R
CuX2 (equiv)
solvent
benzene
toluene
ClCH2CH2Cl
CH3CN
t (h) yield (%)b
1
2
3
4
5
6
7
8
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuCl2 (1)
CuCl2 (5)
s
16 69 (2a)
23 70 (2a)
6
60 (2a)
Ethyl 2-(2-(2-phenylethynyl)phenyl)benzofuran-3-carbox-
ylate (1a) was treated with PdCl2 and CuCl2 to screen the
optimal reaction conditions, and the results are summarized
in Table 1. Initially, a set of solvents were examined, and
benzene was found to be the most effective solvent (entries
1-6). Treatment of substrate 1a with PdCl2 and CuCl2 in
benzene afforded the corresponding target product 2a in a
69% yield (entry 1). Identical results were obtained using
toluene as the solvent (entry 2). However, other solvents,
such as ClCH2CH2Cl, CH3CN, THF, and cyclohexane,
decreased the yield to some extent (entries 3-6). Subse-
quently, the amount of CuCl2 was tested (entries 7-9). We
found that 1 equiv of CuCl2 reduced the yield to 55% (entry
7), and 5 equiv of CuCl2 provided the same yield as that of
3 equiv of CuCl2 (entry 8). However, a trace amount of 2a
was observed without either CuCl2 or PdCl2 (entries 9 and
11). It is worth noting that no reaction is observed using
LiCl instead of CuCl2 (entry 10), and room temperature gives
a low yield after 24 h (entry 12). The screening results
demonstrated that two analogs, i-propyl 2-(2-(2-phenylethy-
24 20 (2a)
16 24 (2a)
23 54 (2a)
24 55 (2a)
16 70 (2a)
24 trace (2a)
16 0 (3a)
24 trace (2a)
24 16 (2a)
16 59 (2a)
16 65 (2a)
16 35 (3a)
16 59 (3a)
THF
cyclohexane
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
MeCN
9
10
LiCl (3)
11c
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuCl2 (3)
CuBr2 (3)
CuBr2 (3)
12d Et (1a)
13
14
15
16e
i-Pr (1b)
Bn (1c)
Et (1a)
Et (1a)
a Reaction conditions: 1 (0.3 mmol), PdCl2 (10 mol %), and CuCl2 (3
equiv) in solvent (5 mL) at 100 °C. b Isolated yield. c Without PdCl2. d At
room temperature. e PdBr2 (10 mol %) instead of PdCl2.
nyl)phenyl)benzofuran-3-carboxylate (1b) or benzyl 2-(2-
(2-phenylethynyl)phenyl)-benzofuran-3-carboxylate (1c), were
also suitable for the halopalladation/decarbonylation/carbon-
carbon forming reaction with PdCl2 and CuCl2 in moderate
yields (entries 13 and 14). To our delight, the reaction of
substrate 1a with PdBr2 and CuBr2 was conducted success-
fully in MeCN to afford the corresponding 5-bromo-6-
phenylbenzo[b]-naphtho[2,1-d]furan (3a) in 59% yield (entry
16).
(4) For other papers on the halopalladation reactions using PdX2/CuX2
as a catalytic system, see: (a) Ba¨ckvall, J. E.; Nordberg, R. E. J. Am. Chem.
Soc. 1980, 102, 393. (b) Ji, J.; Zhang, C.; Lu, X. J. Org. Chem. 1995, 60,
1160. (c) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (d) Li, J.-H; Jiang,
H.-F.; Feng, A.-Q.; Jia, L.-Q. J. Org. Chem. 1999, 64, 5984. (e) Li, J.-H.;
Jiang, H.-F.; Chen, M.-C. J. Org. Chem. 2001, 66, 3627. (f) Li, J.-H.; Liang,
Y.; Xie, Y.-X. J. Org. Chem. 2004, 69, 8125. (g) Li, J.-H.; Tang, S.; Xie,
Y.-X. J. Org. Chem. 2005, 70, 477. (h) Ma, S.; Wu, B.; Zhao, S. Org. Lett.
2003, 5, 4429. (i) Ma, S.; Wu, B.; Jiang, X.; Zhao, S. J. Org. Chem. 2005,
70, 2568. (j) Ma, S.; Wu, B.; Jiang, X. J. Org. Chem. 2005, 70, 2588. (k)
Huang, J.; Zhou, L.; Jiang, H. Angew. Chem., Int. Ed. 2006, 45, 1945.
(5) For selected reviews and papers on Pd-catalyzed decarboxylative
coupling reactions, see: (a) Goossen, L. J.; Goossen, K.; Rodríguez, N.;
Blanchot, M.; Linder, C.; Zimmermann, B. Pure Appl. Chem. 2008, 80,
1725. (b) Goossen, L. J.; Rodríguez, N.; Goossen, K. Angew. Chem., Int.
Ed. 2008, 47, 3100, and references cited therein. (c) Tatamidani, H.; Yokota,
K.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 5615. (d) Goossen,
L. J.; Knauber, T. J. Org. Chem. 2008, 73, 8631. (e) Goossen, L. J.;
Zimmermann, B.; Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103. (f)
Goossen, L. J.; Rodríguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130,
15248. (g) Goossen, L. J.; Rudolphi, F.; Oppel, C.; Rodríguez, N. Angew.
Chem., Int. Ed. 2008, 47, 3043. (h) Maehara, A.; Tsurugi, H.; Satoh, T.;
Miura, M. Org. Lett. 2008, 10, 1259. (i) Nakano, M.; Tsurugi, H.; Satoh,
T.; Miura, M. Org. Lett. 2008, 10, 1851. (j) Forgione, P.; Brochu, M.-C.;
St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem.
Soc. 2006, 128, 11350.
As shown in Table 2, we examined the scope of the
halopalladation/decarboxylation/carbon-carbon bond form-
ing process with respect to ethyl carboxylate substrates under
the standard conditions. Substituents at the terminal alkynic
moiety of 2-(2-(ethynyl)phenyl)benzofuran-3-carboxylates
were first evaluated in the presence of PdX2 and CuX2 (X
) Cl, Br) (entries 1-13). While carboxylates 1d-1f bearing
electron-rich aryl groups were treated with PdX2 and CuX2
(X ) Cl or Br) in good yields (entries 1-6), substrates
1g-1k, having either electron-deficient aryl or alkyl groups,
reduced the yields to some extent (entries 7-12). Ethyl 2-(2-
(2-o-tolylethynyl)phenyl)benzofuran-3-carboxylate (1e), for
instance, underwent the tandem reaction with PdCl2 and
(6) (a) Harvey, R. G. Polycyclic Aromatic Hydeocarbons; Wiley-VCH:
New York, 1996. (b) Harvey, R. G. In Handbook of EnVironmental
Chemistry; Hutzinger, D., Neilson, A., Eds.; Springer: Berlin, Heidelberg,
1997; Vol. 3,part 1, ch. 1. (c) Watson, M. D.; Fechtenkotter, A.; Mullen,
K. Chem. ReV. 2001, 101, 1267. (d) Law, K. Y. Chem. ReV. 1993, 93, 449.
(e) Jung, M. E. Tetrahedron 1976, 32, 3. (f) Molander, G. A. Acc. Chem.
Res. 1998, 31, 603. (g) Tiwari, S. S.; Srivastava, S. C. J. Med. Chem. 1967,
10, 983.
1140
Org. Lett., Vol. 11, No. 5, 2009

droxymethyl groups resulted in a low yield (entry 12). It is
noted that the reactions of substrates 1d or 1i can be
conducted efficently in toluene (entries 2 and 10). Gratify-
ingly, the standard conditions were compatible with the
thiophen-2-yl group, providing a moderate yield (entry 13).
It was found that two groups, OMe and F, on the 2-aryl
moiety were perfectly tolerated under the standard conditions
(entries 14-17). Ethyl 2-(5-methoxy-2-(2-phenylethynyl)phe-
nyl)benzofuran-3-carboxylate (1m), for example, underwent
the reaction with PdCl2 and CuCl2 smoothly in 69% yield
(entry 14). Remarkably, naphtho[2,1-b]furan-1-carboxylates
1q and 1r were suitable substrates providing good yields
under the same conditions (entries 18 and 19).
Table 2. Halopalladation/Decarboxylation/Carbon-Carbon
a
Forming Reactions of 1 with PdX2 and CuX2
The reaction of 2-(2-(2-phenylethynyl)phenyl)-benzofuran
(3) was also tested under the standard conditions, and a mixture
was observed by GC-MS analysis (eq 2). In the presence of
PdCl2 and CuCl2, 30% of substrate 3 was consumed after 24 h
to provide a mixture of the desired product 2a and another
hydroarylation product 4 in 16% total yield.
Two possible mechanisms as outlined in Scheme 2 were
proposed for the present reaction on the basis of the
previously reported mechanism.1-5 Complexation of PdX2
with the carbon-carbon triple bond affords intermediate B,
followed by trans-addition to give intermediate C, the
σ-vinylpalladium intermediate.1-3 Intermediate C undergos
Scheme 2. A Working Mechanism
a Reaction conditions: 1 (0.3 mmol), PdCl2 (10 mol %), CuCl2 (3 equiv)
in benzene (5 mL) at 100 °C. b Isolated yield. c In toluene. d PdBr2 (10 mol
%) and CuBr2 (3 equiv) in MeCN (5 mL).
CuCl2 in 82% yield (entry 3) and with PdBr2 and CuBr2 in
89% yield (entry 4). The reaction of substrate 1g, bearing
an electron-deficient NO2 group, with PdCl2 and CuCl2
afforded the target product 2g in only 48% yield (entry 7).
The alkyl groups, including octyl, hexyl, and 2-cyclohexenyl
at the alkyne moiety, also provided the corresponding
products in moderate yields (entries 8-11), and the hy-
Org. Lett., Vol. 11, No. 5, 2009
1141

anion exchange with Cu to produce intermediate D. Inter-
mediate E is formed from decarboxylation of intermediate
D.5 Subsequently, intramolecular transmetalation of inter-
mediate E takes place to give intermediate F. Finally,
reductive elimination of intermediate F yields both the target
product and Pd(0) species. The Pd(0) species are oxidized
by CuX2 to regenerate the active PdX2 species. Another
possible pathway is a Heck-like mechanism. Insertion of the
vinylpalladium species C into benzofuran via a Heck-like
process forms intermediate G, which subsequently undergoes
decarboxylative ꢀ-carbo-elimination to give the desired
product.
We deduced that three roles of CuX2 are played in the
process: (1) as a halide source; (2) as a cocatalyst to react
with carbonyls generating the Cu intermediate in the decar-
bonylation process; and (3) as a cocatalyst to cleave the
C-Pd σ-bond and regenerate the active PdX2 species in the
halopalladation reaction. Study of the real function of CuX2
is in progress.
domino process. In the presence of PdCl2 and CuX2, a variety
of 2-(2-(2-substitutedethynyl)phenyl)benzofuran-3-carboxy-
lates underwent the reaction to afford 5-halo-6-substituted
benzo[b]naphtho[2,1-d]furans in moderate to good yields.
It is noteworthy that these products with a halide (Cl or
Br) provide an attractive and useful route to introduce new
groups for the synthesis of new natural products. Work
to apply the reaction in organic synthesis is currently
underway.
Acknowledgment. We thank the Specialized Research
Fund for the Doctoral Program of Higher Education (No.
20060542007), National Natural Science Foundation of
China (No 20572020), New Century Excellent Talents in
University (No. NCET-06-0711), and Fok Ying Tung
Education Foundation (No. 101012) for financial support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 2 and 3;
typical procedure. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have developed a new and general
protocol for the synthesis of polycyclic aromatic furans by
a halopalladation/decarboxylation/carbon-carbon forming
OL8029752
1142
Org. Lett., Vol. 11, No. 5, 2009