CuI-catalyzed domino process to 2,3-disubstituted benzofurans from 1-bromo-2-iodobenzenes and β-keto esters

Article abstract of DOI:10.1021/jo070729r

(Chemical Equation Presented) CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with β-keto esters in THF at 100°C leads to 2,3-disubstituted benzofurans. This domino transformation involves an intermolecular C-C bond formation and a subsequent intramolecular C-O bond formation process. Benzofurans with different substituents at the 5- and 6-position are accessible by employing the corresponding 1-bromo-2-iodobenzenes.

Full text of DOI:10.1021/jo070729r

CuI-Catalyzed Domino Process to 2,3-Disubstituted Benzofurans
from 1-Bromo-2-Iodobenzenes and â-Keto Esters
Biao Lu,† Bao Wang,‡ Yihua Zhang,‡ and Dawei Ma*,†
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and Center of Drug
DiscoVery, China Pharmaceutical UniVersity, Nanjing 210009, China
madw@mail.sioc.ac.cn
ReceiVed April 7, 2007
CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with â-keto esters in THF at 100 °C leads to 2,3-
disubstituted benzofurans. This domino transformation involves an intermolecular C-C bond formation
and a subsequent intramolecular C-O bond formation process. Benzofurans with different substituents
at the 5- and 6-position are accessible by employing the corresponding 1-bromo-2-iodobenzenes.
Introduction
The benzofuran moiety is abundant in both natural and
artificial molecules possessing potent biological activities.
Representative examples include amiodarone,1 a clinically
used drug for controlling intractable cardiac arrhythmias, and
compounds 22 and 3,3 two inhibitors of receptor kinases that
are promising candidates for the treatment of disorders
related to vasculogenesis or angiogenesis (see Figure 1).
Consequently, great efforts have been devoted to the develop-
ment of general methods for the assembly of substituted
benzofurans.4-6
Recently, we discovered that the L-proline assisted, CuI-
catalyzed coupling of â-keto esters with aryl halides can be
carried out under relatively mild conditions.7a Extension of this
work led to a convenient synthesis of 3-acyloxindols.8 Benzo-
furans can be elaborated from R-(2-halobenzyl)ketones via a
metal-catalyzed intramolecular cyclization.5,6 On the basis of
our previous results we decided to develop a domino process
FIGURE 1. Structures of some biologically important benzofuran
embodied molecules.
leading to benzofurans through coupling of 1-bromo-2-iodo-
benzenes with â-keto esters and subsequent intramolecular C-O
bond formation.6 The results of our investigations are disclosed
herein.
† Chinese Academy of Sciences.
‡ China Pharmaceutical University.
(1) (a) Singh, S. N.; Fletcher, R. D.; Fisher, S. G.; Singh, B. N.; Lewis,
H. D.; Deedwania, P. C.; Massie, B. M.; Colling, C.; Layyeri, D. N. Eng.
J. Med. 1995, 333, 77. (b) Ka´lai, T.; Va´rbio´, G.; Bogna´r, Z.; Pa´lfi, A.;
Hanto´, K.; Bogna´r, B.; O¨ sz, E.; Su¨megi, B.; Hideg, K. Bioorg. Med. Chem.
2005, 13, 2629.
Results and Discussion
(2) Romines, W. H.; Kania, R. S.; Lou, J.; Collins, M. R.; Cripps, S. J.;
He, M.; Zhou, R.; Palmer, C. L.; Deal, J. G. WO2003106462, 2003.
(3) Hong, Y.; Kania, R. S. U.S. Patent 5,137,395, 2005.
The initial experiment was conducted by heating a mixture
of 1-bromo-2-iodobenzene (4a), ethyl acetoacetate (5a) CuI,
10.1021/jo070729r CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/19/2007
J. Org. Chem. 2007, 72, 5337-5341
5337

Lu et al.
TABLE 1. Synthesis of Benzofuran 6a from 4a and 5aa
SCHEME 1
SCHEME 2
entry
ligand
solvent
temp (°C)
yield (%)b
1
2
3
4
5
6
7
8d
L-proline
L-proline
DMSO
THF
THF
40
70
70
100
100
100
100
70
0c
9
no
no
no
no
no
no
28
83
57
19
25
<3
THF
dioxane
DMSO
toluene
THF
a Reaction conditions: 4a (0.5 mmol), 5a (1.0 mmol), CuI
(50 µmol), ligand (0.1 mmol), K2CO3 (1.5 mmol), solvent (1.5 mL).
b Isolated yield. c 4a was recovered in 88% yield. d Cs2CO3 was used as a
base.
(Scheme 1).9 This result indicates that the intramolecular
cyclization of the cascade process aids the initial intermolecular
coupling.
L-proline and K2CO3 in DMSO at 40 °C (Table 1, entry 1).
Surprisingly, these standard conditions7a for coupling aryl
iodides and activated methylene compounds did not fur-
nish any coupling products, and 4a was recovered in
88% yield. After several attempts, it was found that by chang-
ing the solvent to THF and carrying out the reaction at
70 °C the desired benzofuran 6a can be isolated in 9% yield
(entry 2). Interestingly, removal of L-proline from the reac-
tion system gave a better result (entry 3), indicating that this
ligand does not benefit the current coupling reaction. The best
result was observed when the reaction temperature was in-
creased to 100 °C (entry 4). Using other solvents such as
dioxane, DMSO, and toluene under the same conditions
led to 6a in low yields (entries 5-7), demonstrating that the
cascade process is highly dependent upon the nature of the
solvent. In addition, switching the base to Cs2CO3 also gave a
poor result mainly because of the formation of some uniden-
tified side products (entry 8). It is noteworthy that, under these
optimized conditions, the reaction of 4-iodoanisole with 5a
resulted in 74% conversion, providing the coupling product 7
in 29% yield and its deacylation product 8 in 45% yield
We then explored the scope and limits of our newly deve-
loped domino process using various 1-bromo-2-iodoben-
zenes and â-keto esters; the results are summarized in
Table 2. From 5-methyl-1-bromo-2-iodobenzene (4b) benzo-
furan 6b was isolated, and its structure was confirmed by
X-ray analysis (see Supporting Information). This result
clearly illustrates that intermolecular coupling takes place at the
aryl iodide moiety, for 6b was obtained exclusively (entry 1).
The electronic nature of the substituents on the aromatic ring
of 4 has little influence on the reaction process, since
good yields were observed with both electron-rich and electron-
deficient 1-bromo-2-iodobenzenes (entries 1-5). Free hydroxyl
groups seem to interfere with the reaction process; this was
indicated by the fact that 4g resulted in a low yield, while its
silyl ether 4h delivered 6h in 75% yield (entries 7 and 8).
Furthermore, 4-substituted and 4,5-disubstituted 1-bromo-2-
iodobenzenes furnished the corresponding benzofurans in
reasonable yield (entries 9-11), demonstrating that varia-
tions at the 5,6 position of the benzofurans are compatible with
the present method. The relatively low yield obtained from
4-nitro-1-bromo-2-iodobenzene (4k), might be due to the
instability of the nitro group under the reaction conditions
(entry 11).
(4) For recent and selected examples, see: (a) Zhao, B.; Lu, X. Org.
Lett. 2006, 8, 5987. (b) Bellur, E.; Langer, P. J. Org. Chem. 2005, 70,
7686. (c) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761. (d)
Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 45,
6235. (e) Cruz, M. C.; Tamariz, J. Tetrahedron Lett. 2004, 45, 2377. (f)
Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004,
45, 907. (g) Macleod, C.; McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.;
Hamprecht, D. W.; Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003, 68,
387. (h) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191. (i) Kao, C.; Chern,
J. J. Org. Chem. 2002, 67, 6772. (j) Kraus, G. A.; Zhang, N.; Verkade, J.
G.; Nagarajan, M.; Kisanga, P. B. Org. Lett. 2000, 2, 2409. (k) Nan, Y.;
Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.
(5) (a) Carril, M.; SanMartin, R.; Tellitu, I.; Dom´ınguez, E. Org. Lett.
2006, 8, 1467. (b) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427. (c) Chen,
C.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964. (d) Willis, M. C.; Taylor,
D.; Gillmore, A. T. Org. Lett. 2004, 6, 4755.
(6) Pd-catalyzed benzofuran formation via coupling of some special
ketones and o-dihalobenzenes has been reported, see: (a) Terao, Y.; Satoh,
T.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 2345. (b)
Churruca, F.; SanMartin, R.; Tellitu, I.; Dom´ınguez, E.; Eur. J. Org. Chem.
2005, 2481. (c) Willis, M. C.; Taylor, D.; Gillmore, A. T. Tetrahedron
2006, 62, 11513.
From benzyl ester 5b, benzofuran 6m was isolated
in 71% yield (entry 12). Two olefin and benzene embodied
â-keto esters 5c and 5d also reacted well, delivering the
corresponding products in good yields (entries 13-15).
However, γ-i-propyl-substituted ester 5e only gave a mo-
derate yield (entry 16), while γ-phenyl ester 5f was
found to be unreactive (entry 17). This drawback may result
from the steric hindrance at the γ-position of the â-keto
ester.
When 1,4-dibromo-2,5-diiodobenzene (4m)10 was applied,
bisbenzofuran 9 was isolated in 44% yield, together with the
dehalogenation product 10 (Scheme 2). This result demonstrates
the potential usefulness of this process for the assembly of more
complex benzofurans.
(7) (a) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693. (b) Xie, X.;
Chen Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050. For related studies
from other groups, see: (c) Hennessy, E. J.; Buchwald, S. L. Org. Lett.
2002, 4, 269. (d) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607. (e) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett
2005, 2703. (f) Pei, L.; Qian, W. Synlett 2006, 1719.
(9) Similar conversion was reported by Parkinson and coworkers. See:
Zeevaart, J. G.; Parkinson, C. J.; Koning, C. B. Tetrahedron Lett. 2007,
48, 3289.
(10) Hart, H.; Harada, H.; Du, C.-J. F. J. Org. Chem. 1985, 50,
3104.
(8) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115.
5338 J. Org. Chem., Vol. 72, No. 14, 2007

Benzofuran Formation by Cu-Catalyzed Domino Process
TABLE 2. Synthesis of Substituted Benzofurans via a CuI-catalyzed Cascade Coupling Process of 1-Bromo-2-iodobenzenes with â-Keto
Estersa
a Reaction conditions: 1-bromo-2-iodobenzenes (4) (0.5 mmol), â-keto ester 5 (1.0 mmol), CuI (50 µmol), K2CO3 (1.5 mmol), THF (1.5 mL), 100 °C.
b Isolated yield. c 4a was recovered in about 90% yield.
Conclusion
to substituted benzofurans and a useful tool for the synthesis
of biologically active molecules.
In conclusion, we have developed a CuI-catalyzed domino
process11 for the assembly of 2,3-disubstituted benzofurans from
1-bromo-2-iodobenzenes and â-keto esters. A number of
functional groups are tolerated by our reaction conditions,
including vinyl, chloro, fluoro, nitro, carboxylate, ketone, and
silyl ether groups. Thus, our process represents a versatile access
Experimental Section
General Procedure for Copper-Catalyzed Domino Process
to Benzofuran. An oven-dried Schlenk tube was charged with CuI
(10 mg, 0.05 mmol), potassium carbonate (207 mg, 1.5 mmol),
J. Org. Chem, Vol. 72, No. 14, 2007 5339

Lu et al.
and 1-bromo-2-iodobenzenes (0.5 mmol). The tube was evacuated
and backfilled with argon (three times), and then ethyl acetoacetate
(130 mg, 1 mmol) and 1.5 mL of THF were added. The reaction
mixture in this sealed tube was stirred at 100 °C until the starting
aryl iodide was consumed. The cooled solution was partitioned
between ethyl acetate (40 mL) and saturated brine (10 mL). The
organic layer was isolated, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried over
Na2SO4 and concentrated in vacuum. The residue thus obtained
was purified by silica gel chromatography to give the product.
Ethyl 2-methylbenzofuran-3-carboxylate (6a): 1H NMR (300
MHz, CDCl3) δ 7.96 (m, 1H), 7.42 (m, 1H), 7.28 (m, 2H), 4.41
(q, J ) 7.2 Hz, 2H), 2.77 (s, 3H), 1.45 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 164.6, 163.6, 153.6, 126.3, 124.3, 123.7,
121.8, 110.8, 109.1, 60.3, 14.4 (2C); MS (EI) m/z 204 (M+), 175
(81), 159 (77), 103 (57), 77 (100), 51 (43); HRMS calcd for
C12H12O3 (M+) 204.0786, found 204.0779.
5.7 Hz, 2H), 2.74 (s, 3H), 1.44 (t, J ) 5.7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 164.5, 163.9, 153.8, 137.7, 125.7, 122.8, 121.6,
110.4, 109.3, 65.3, 60.3, 14.4, 14.3; MS (EI) m/z 234 (M+), 205
(75), 189 (56), 177 (20), 159 (20), 105 (28); HRMS calcd for
C13H14O4 (M+) 234.0892, found 234.0893.
Ethyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylbenzo-
1
furan-3- carboxylate (6h): H NMR (300 MHz, CDCl3) δ 7.89
(d, J ) 7.8 Hz, 1H), 7.45 (s, 1H), 7.22 (d, J ) 7.8 Hz, 1H), 4.85
(s, 2H), 4.41 (q, J ) 7.5 Hz, 2H), 2.77 (s, 3H), 1.46 (t, J ) 7.5 Hz,
3H), 0.97 (s, 9H), 0.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
164.6, 163.5, 153.9, 138.5, 125.1, 121.9, 121.3, 109.0, 108.4, 64.9,
60.2, 26.0, 18.4, 14.4 (2C), -5.20; MS (EI) m/z 348 (M+), 303
(7), 291 (49), 263 (4), 217 (100), 189 (15); HRMS calcd for
C19H28O4Si (M+) 348.1757, found 348.1757.
Ethyl 2-methyl-5-nitrobenzofuran-3-carboxylate (6i): 1H NMR
(300 MHz, CDCl3) δ 8.84 (s, 1H), 8.22 (d, J ) 9.0 Hz, 1H), 7.52
(d, J ) 9.0 Hz, 1H), 4.47 (q, J ) 7.2 Hz, 2H), 2.83 (s, 3H), 1.48
(t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 156.2,
145.0, 126.9, 120.3, 118.4, 118.3, 111.2, 111.0, 60.9, 14.5, 14.4;
MS (EI) m/z 249 (M+), 221 (80), 204 (100), 188 (7), 174 (24),
157 (56); HRMS calcd for C12H11NO5 (M+) 249.0637, found
249.0633.
Ethyl 5-methoxy-2-methylbenzofuran-3-carboxylate (6j): 1H
NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.31 (d, J ) 9.0 Hz, 1H),
6.87 (d, J ) 9.0 Hz, 1H), 4.41 (q, J ) 7.2 Hz, 2H), 2.75 (s, 3H),
3.87 (s, 3H), 1.45 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.5, 164.2, 156.7, 148.5, 127.1, 112.8, 111.2, 109.1, 104.4,
60.2, 55.9, 14.6, 14.4; MS (EI) m/z 234 (M+), 205 (90), 189 (45),
174 (10), 160(14), 63 (19); HRMS calcd for C13H14O4 (M+)
234.0892, found 234.0890.
Ethyl 5-fluoro-2-methylbenzofuran-3-carboxylate (6k): 1H
NMR (300 MHz, CDCl3) δ 7.61 (dd, J ) 6.3, 2.4 Hz, 1H), 7.35
(dd, J ) 6.3, 3.9 Hz, 1H), 6.99 (m, 1H), 4.41 (q, J ) 6.9 Hz, 2H),
2.76 (s, 3H), 1.45 (t, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 165.3, 164.1, 159.8 (d, J ) 189.9 Hz), 149.8, 127.3 (d, J ) 9.0
Hz), 111.9 (d, J ) 21.0 Hz), 111.4 (d, J ) 7.7 Hz), 109.4 (d, J )
2.4 Hz), 107.7 (d, J ) 21.0 Hz), 60.4, 14.5, 14.4; MS (EI) m/z 222
(M+), 193 (100), 177 (100), 165 (6), 149 (24), 120 (12); HRMS
calcd for C12H11O3F (M+) 222.0692, found 222.0687.
Compound 6l: 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 6.91
(s, 1H), 5.99 (s, 2H), 4.38 (q, J ) 7.2 Hz, 2H), 2.71(s, 3H), 1.43
(t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 162.6,
148.6, 145.9, 145.2, 119.7, 109.4, 101.4, 100.6, 93.1, 60.2, 14.4
(2C); MS (EI) m/z 248 (M+), 219 (100), 203 (18), 174 (16), 101
(15), 53 (19); HRMS calcd for C13H12O5 (M+) 248.0685, found
248.0675.
Benzyl 2-methylbenzofuran-3-carboxylate (6m): 1H NMR (300
MHz, CDCl3) δ 7.93 (m, 1H), 7.50-7.28 (m, 6H), 7.26 (m, 2H),
5.41 (s, 2H), 2.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3,
164.0, 153.6, 136.2, 128.7, 128.5, 128.2, 126.2, 124.3, 123.8, 121.8,
110.8, 108.9, 66.1, 14.5; MS (EI) m/z 266 (M+), 248 (11), 175
(40), 159 (42), 91 (100), 77 (13); HRMS calcd for C17H14O3 (M+)
266.0943, found 266.0945.
Ethyl 2-(but-3-enyl)benzofuran-3-carboxylate (6n): 1H NMR
(300 MHz, CDCl3) δ 7.98 (m, 1H), 7.44 (m, 1H), 7.29 (m, 2H),
5.89 (m, 1H), 5.09 (m, 1H), 5.00 (m, 1H), 4.41 (q, J ) 7.2 Hz,
2H), 3.29 (t, J ) 7.5 Hz, 2H), 2.56 (m, 2H), 1.47 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 164.3, 153.7, 128.8,
126.2, 124.4, 123.7, 121.9, 115.7, 110.9, 109.0, 60.3, 31.8, 27.8,
14.4; MS (EI) m/z 244 (M+), 215 (8), 203 (34), 175 (100), 91 (53),
55 (36); HRMS calcd for C15H16O3 (M+) 244.1099, found 244.1105.
Ethyl 2,6-dimethylbenzofuran-3-carboxylate (6b): Mp: 65-
1
67 °C; H NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 7.8 Hz, 1H),
7.23 (s, 1H), 7.11 (d, J ) 7.8 Hz, 1H), 4.40 (q, J ) 6.9 Hz, 2H),
2.75 (s, 3H), 2.46 (s, 3H), 1.44 (t, J ) 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 164.6, 163.0, 154.0, 134.5, 125.1, 123.7, 121.2,
110.0, 109.0, 60.2, 21.6, 14.4, 14.3; MS (EI) m/z 218 (M+), 189
(100), 171 (60), 145 (30), 115 (50), 91 (32); HRMS (EI) calcd for
C13H14O3 (M+) 218.0943, found 218.0944.
Ethyl 6-chloro-2-methylbenzofuran-3-carboxylate (6c): 1H
NMR (300 MHz, CDCl3) δ 7.84 (d, J ) 8.1 Hz, 1H), 7.42 (s, 1H),
7.26 (d, J ) 8.1 Hz, 1H), 4.40 (q, J ) 7.2 Hz, 2H), 2.75 (s, 3H),
1.43 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.1,
164.0, 153.6, 130.1, 125.0, 124.4, 122.3, 111.3, 109.1, 60.4, 14.4
(2C) ; MS (EI) m/z 238 (M+), 209 (100), 193 (47), 175 (19), 164
(17), 102 (25); HRMS calcd for C12H11O3Cl(M+) 238.0397, found
238.0395.
Ethyl 2-methyl-6-(trifluoromethyl)benzofuran-3-carboxylate
1
(6d): H NMR (300 MHz, CDCl3) δ 8.05 (d, J ) 8.1 Hz, 1H),
7.69 (s, 1H), 7.55 (d, J ) 8.4 Hz, 1H), 4.43 (q, J ) 7.2 Hz, 2H),
2.80 (s, 3H), 1.45 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.0, 163.8, 152.7, 129.4, 126.7 (q, J ) 33.8 Hz), 125.7, 122.2,
120.7 (q, J ) 3.8 Hz), 109.3, 108.3 (q, J ) 4.2 Hz), 60.6, 14.6,
14.4; MS (EI) m/z 272 (M+), 243 (60), 227 (100), 199 (20), 151
(41), 102 (12); HRMS (EI) calcd for C13H11O3F3 (M+) 272.0660,
found 272.0665.
Ethyl 6-acetyl-2-methylbenzofuran-3-carboxylate (6e): 1H
NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 8.02 (d, J ) 8.1 Hz, 1H),
7.93 (d, J ) 8.1 Hz, 1H), 4.43 (q, J ) 7.2 Hz, 2H), 2.82 (s, 3H),
2.67 (s, 3H), 1.46 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 197.3, 166.8, 163.9, 153.4, 133.8, 130.8, 124.2, 121.5, 111.0,
109.5, 60.6, 26.8, 14.7, 14.4; MS (EI) m/z 246 (M+), 231 (100),
217 (7), 203 (45), 157 (14), 43 (27); HRMS calcd for C14H14O4
(M+) 246.0892, found 246.0892.
Ethyl 6-(methoxycarbonyl)-2-methylbenzofuran-3-carboxy-
1
late (6f): H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 8.00 (m,
2H), 4.43 (q, J ) 6.9 Hz, 2H), 3.95 (s, 3H), 2.81 (s, 3H), 1.46 (t,
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 166.4,
163.9, 153.1, 130.6, 126.4, 125.2, 121.4, 112.4, 109.4, 60.5, 52.2,
14.7, 14.4; MS (EI) m/z 262 (M+), 233 (87), 217 (62), 203 (68),
188 (7), 157 (23); HRMS calcd for C14H14O5 (M+) 262.0841, found
262.0846.
Ethyl 6-(hydroxymethyl)-2-methylbenzofuran-3-carboxylate
1
(6g): H NMR (300 MHz, CDCl3) δ 7.87 (d, J ) 7.8 Hz, 1H),
7.42 (s, 1H), 7.25 (d, J ) 7.8 Hz, 1H), 4.76 (s, 2H), 4.39 (q, J )
Ethyl 2-(but-3-enyl)-5-methoxybenzofuran-3-carboxylate (6o):
1H NMR (300 MHz, CDCl3) δ 7.49 (d, J ) 2.7 Hz, 1H), 7.33 (d,
J ) 9.3 Hz, 1H), 6.89 (dd, J ) 9.0, 2.7 Hz, 1H), 5.89 (m, 1H),
5.09 (m, 1H), 5.01 (m, 1H), 4.42 (q, J ) 7.2 Hz, 2H), 3.87 (s, 3H),
3.27 (t, J ) 7.6 Hz, 2H), 2.55 (m, 2H), 1.45 (t, J ) 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 167.0, 164.4, 156.7, 148.6, 136.9,
127.0, 115.6, 113.0, 111.3, 109.0, 104.5, 60.2, 55.9, 31.9, 28.0,
(11) For recent examples of Cu-catalyzed domino processes, see: (a)
Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (b)
Martin, R.; Rodr´ıguez, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006,
45, 7079. (c) Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 2274. (d) Altenhoff, G.; Glorius, F. AdV. Synth.
Catal. 2004, 346, 1661. (e) Nordmann, G.; Buchwald, S. L. J. Am. Chem.
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5340 J. Org. Chem., Vol. 72, No. 14, 2007

Benzofuran Formation by Cu-Catalyzed Domino Process
14.4; MS (EI) m/z 274 (M+), 245 (4), 233 (92), 205 (100), 189
(19), 91 (28); HRMS calcd for C16H18O4 (M+) 274.1205, found
274.1201.
60.3, 14.7, 14.5; MS (EI) m/z 330 (M+), 301 (67), 285 (20), 273
(50), 256 (15), 149 (11); HRMS calcd for C18H18O6 (M+) 330.1103,
found 330.1104.
Ethyl 6-chloro-2-phenethylbenzofuran-3-carboxylate (6p): 1H
NMR (300 MHz, CDCl3) δ 7.86 (d, J ) 8.7 Hz , 1H), 7.43 (m,
1H), 7.27-7.19 (m, 6H), 4.37 (q, J ) 7.2 Hz, 2H), 3.45 (m, 2H),
3.05 (m, 2H), 1.41 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.5, 163.8, 153.6, 140.4, 130.3, 128.5 ,128.3, 126.3, 124.9,
124.5, 122.5, 111.5, 109.0, 60.5, 34.0, 30.2, 14.4; MS (EI) m/z 328
(M+), 282 (40), 237 (50), 209 (78), 193 (9), 91(100); HRMS (EI)
calcd for C19H17O3Cl (M+) 328.0866, found 328.0864.
Methyl 6-acetyl-2-isopropylbenzofuran-3-carboxylate (6q): 1H
NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 8.02 (d, J ) 8.4 Hz, 1H),
7.95 (m, 1H), 4.05 (m, 1H), 3.97 (s, 3H), 2.67 (s, 3H), 1.39 (d, J
) 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 197.3, 174.7, 164.3,
153.3, 133.8, 130.7, 124.1, 121.8, 111.3, 107.3, 51.6, 27.8, 26.8,
20.5; MS (EI) m/z 260 (M+), 245 (55), 229 (7), 185 (21), 171 (23),
115 (12); HRMS calcd for C15H16O4 (M+) 260.1049, found
260.1050.
1
Ethyl 5-bromo-2-methylbenzofuran-3-carboxylate (10): H
NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.35 (m, 1H), 7.27 (m,
1H), 4.42 (q, J ) 5.4 Hz, 2H), 2.76 (s, 3H), 1.45 (t, J ) 5.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 164.7, 163.9, 152.3, 128.2,
127.2, 124.5, 117.1, 112.2, 108.8, 60.5, 14.4 (2×C); MS (EI) m/z
284 (M+, 81Br), 282 (M+, 79Br), 255 (83), 253 (82), 175 (64), 157
(29), 102 (52); HRMS (EI): calcd for (M+, 79Br) C12H11O3Br
281.9892, found 281.9895.
Acknowledgment. We are grateful to the Chinese Academy
of Sciences, National Natural Science Foundation of China
(Grants 20621062 and 20572119) for our financial support.
1
Supporting Information Available: Copies of H NMR and
13C NMR spectra for all new products; X-ray crystallographic data
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound 9: 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 2H), 4.43
(q, J ) 6.9 Hz, 4H), 2.80 (s, 6H), 1.47 (t, J ) 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 164.6, 164.4, 151.2, 123.9, 109.1, 102.8,
JO070729R
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