A facile two-step synthesis of 2-arylbenzofurans based on the selective cross McMurry couplings

Article abstract of DOI:10.1021/jo7019652

(Chemical Equation Presented) A novel two-step synthesis of 2-arylbenzofurans has been developed. It involves a selective cross McMurry coupling of a salicylaldehyde or substituted salicylaldehyde with an aromatic aldehyde and a sequential oxidative cyclization of the resulting ortho-vinylphenols. Utilizing this synthetic protocol, a variety of 2-arylbenzofurans including cicerfuran (5) have been efficiently synthesized.

Full text of DOI:10.1021/jo7019652

SCHEME 1
A Facile Two-Step Synthesis of
2-Arylbenzofurans Based on the Selective Cross
McMurry Couplings
Xin-Fang Duan,* Jing Zeng, Zhan-Bin Zhang, and
Guo-Fu Zi
Department of Chemistry, Beijing Normal UniVersity,
Beijing 100875, China
xinfangduan@Vip.163.com
ReceiVed September 6, 2007
palladium-catalyzed O-arylation of o-halobenzyl ketones,6 and
(v) intramolecular McMurry couplings7 or Wittig reactions.8
Recently, we have initiated a program to achieve the general
and selective cross McMurry couplings between two carbonyl
compounds.9 We reported that, in the presence of a series of
groups such as -OH, -NH2, etc., a selective cross McMurry
coupling between diaryl or aryl ketones with various ketones
was achieved.9 We now disclose a novel two-step synthetic
strategy for 2-arylbenzofurans using the selective cross McMurry
couplings between two aromatic aldehydes as a pivotal step,
namely, (a) a selective cross McMurry coupling of salicyl-
aldehyde or substituted salicylaldehyde with an aromatic alde-
hyde yielding an o-vinylphenol, and (b) a sequential oxidative
A novel two-step synthesis of 2-arylbenzofurans has been
developed. It involves a selective cross McMurry coupling
of a salicylaldehyde or substituted salicylaldehyde with an
aromatic aldehyde and a sequential oxidative cyclization of
the resulting ortho-vinylphenols. Utilizing this synthetic
protocol, a variety of 2-arylbenzofurans including cicerfuran
(5) have been efficiently synthesized.
Benzofurans and their analogues constitute a major group of
naturally occurring compounds.1 Their broad range of biological
activities and significant pharmacological potentials have gener-
ated extensive and enduring efforts toward the syntheses of these
important heterocyclic compounds.2 Major reported synthetic
strategies involve (Scheme 1) (i) oxidative cyclization of
o-vinylphenols,3 (ii) dehydrative cyclization of R-phenoxy
ketones,4 (iii) cyclization of o-ynylphenol,5 (iv) copper- or
(4) (a) Shen, Q.; Peng, Q.; Shao, J.-L.; Liu, X.-L.; Huang, Z.-H.; Pu,
X.-Z.; Ma, L.; Li, Y.-M.; Chan, A. S. C.; Gu, L.-Q. Eur. J. Med. Chem.
2005, 40, 1307. (b) Mashraqui, S. H.; Patil, M. B.; Sangvikar, Y.; Ashraf,
M.; Mistry, H. D.; Daub, E. T. H.; Meetsma, A. J. Heterocycl. Chem. 2005,
42, 947. (c) Santini, C.; Berger, G. D.; Han, W.; Mosley, R.; MacNaul, K.;
Berger, J.; Doebber, T.; Wu, M.; Moller, D. E.; Tolman, R. L.; Sahoo, S.
P. Bioorg. Med. Chem. Lett. 2003, 13, 1277. (d) Jørgensen, M.; Krebs, F.
C.; Bechgaard, K. J. Org. Chem. 2000, 65, 8783.
(5) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006,
8, 2803. (b) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489. (c) Yue,
D.-W.; Yao, T.-L.; Larock, R. C. J. Org. Chem. 2005, 70, 10292. (d) Yao,
T.-L.; Yue, D.-W.; Larock, R. C. J. Org. Chem. 2005, 70, 9985 and
references therein.
(6) (a) Carril, M.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett.
2006, 8, 1467. (b) Chen, C.-Y.; Dormer, P. G. J. Org. Chem. 2005, 70,
6964. (c) Churruca, F.; SanMartin, R.; Tellitu, I.; Dominguez, E. Eur. J.
Org. Chem. 2005, 12, 2481. (d) Willis, M. C.; Taylor, D.; Gillmore, A. T.
Org. Lett. 2004, 6, 4755.
(7) For the preparation of 2,3-disubstituted benzofuran via the intramo-
lecular McMurry couplings, see: (a) Rele, S.; Talukdar, S.; Banerji, A.;
Chattopadhyay, S. J. Org. Chem. 2001, 66, 2990. (b) Fu¨rstner, A.; Hupperts,
A. J. Am. Chem. Soc. 1995, 117, 4468. (c) Fu¨rstner, A.; Hupperts, A.; Rock,
A.; Janssen, E. J. Org. Chem. 1994, 59, 5215. (d) Fu¨rstner, A.; Jumbam,
D. N. Tetrahedron 1992, 48, 5991. (e) Banerji, A.; Nayak, S. K. Chem.
Commun. 1990, 150. The preparation of 2- or 3-monosubstituted benzofurans
by this methodology is quite few; see ref 7d, p 5994.
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, p
259. (b) ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: London, 1984; Vol. 4, p 531. (c) Cagniant,
P.; Cagniant, D. In AdVances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic Press: New York, 1975; Vol. 18, p 337.
(2) (a) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog.
Heterocycl. Chem. 2005, 17, 142. (b) Hou, X.-L.; Yang, Z.; Wong, H. N.
C. Prog. Heterocycl. Chem. 2003, 15, 167. (c) Dell, C. P. Sci. Synth. 2001,
10, 11. (d) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67.
(3) For I2-mediated cyclization, see: (a) Pan, C.-F.; Yu, J.; Zhou, Y.-
Q.; Wang, Z.-Y.; Zhou, M.-M. Synlett 2006, 1657. (b) Kim, K. M.; Ryu,
E. K. Heterocycles 1995, 41, 219. For the cyclization using DDQ, see: (c)
Takeshi, K.; Koji, I. Heterocycles 2005, 65, 1641. (d) Fujita, M.; Qi, G.-
Z.; Verkerk, U. H.; Dzwiniel, T. L.; McDonald, R.; Stryker, J. M. Org.
Lett. 2004, 6, 2653. (e) Nicolaides, D. N.; Fylaktakidou, K. C.; Litinas, K.
E.; Adamopoulos, S. G. J. Heterocycl. Chem. 1998, 35, 91. (f) Imafuku,
K.; Fujita, R. Chem. Express 1991, 6, 323. (g) Merlini, L.; Cardillo, G.;
Cricchio, R. Tetrahedron 1971, 27, 1875. For other reagents, see: (h) Aslam,
S. N.; Stevenson, P. C.; Phythian, S. J.; Veitch, N. C.; Hall, D. R.
Tetrahedron 2006, 62, 4214. (i) Lattanzi, A.; Senatore, A.; Massa, A.;
Scettri, A. J. Org. Chem. 2003, 68, 3691. (j) Masutani, K.; Irie, R.; Katsuki,
T. Chem. Lett. 2002, 36.
(8) (a) Yuan, Y.; Men, H.-B.; Lee, C. J. Am. Chem. Soc. 2004, 126,
14720. (b) Katerina, C.; Miloslav, N.; Pavel, P.; Jiri, S. Collect. Czech.
Chem. Commun. 2000, 65, 1939. (c) Jean, G.; Nicole, B.; Pierre, D. J.
Heterocycl. Chem. 1990, 27, 10. (d) Hercouet, A.; Lecorre, M. Tetrahedron
Lett. 1979, 20, 2145.
(9) Duan, X.-F.; Zeng, J.; Lu¨, J.-W.; Zhang, Z.-B. J. Org. Chem. 2006,
71, 9873.
10.1021/jo7019652 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/21/2007
J. Org. Chem. 2007, 72, 10283-10286
10283

TABLE 1. The Influence of the Equivalent of Low Valent
Titanium on the Cross McMurry Reactions between Salicylaldehyde
and Aryl Aldehyde
TABLE 2. The Oxidative Cyclization of o-Vinylphenols to
2-Arylbenzofurans
time
(h)
yieldb
(%)
entry
aldehydea
Ti (equiv)
1
2
3
4
5
6
7
8
9
1a + 2a
1a + 2a
1a + 2a
1a + 2a
1a + 2a
1a + 2b
1a + 2b
1a + 2b
1a + 2b
1a + 2b
TiCl4-Zn-Py (5)
TiCl4-Zn-Py (4)
TiCl4-Zn-Py (2.5)
TiCl4-Zn (4)
3.5
5
6
5
6
3
5.5
6
6
6
43 (3aa)
50.2 (3aa)
58 (3aa)
51 (3aa)
60 (3aa)
60 (3ab)
73 (3ab)
74 (3ab)
72 (3ab)
75 (3ab)
TiCl4-Zn (2.5)
TiCl4-Zn-Py (5)
TiCl4-Zn-Py (4)
TiCl4-Zn-Py (2.5)
TiCl4-Zn (4)
10
TiCl4-Zn (2.5)
a The mole ratios of 1a to 2a, 2b were 1:1.2. b Yield of isolated
product.
cyclization of the o-vinylphenol to afford the corresponding
2-arylbenzofuran. Because the reagents are readily available and
the protocols simple to carry out, this new synthetic methodol-
ogy represents a convenient and effective approach toward a
variety of 2-arylbenzofurans.
Initially, we performed the McMurry coupling of salicylal-
dehyde (1a) with benzaldehyde (2a) and 4-methoxybenzalde-
hyde (2b) using 5 equiv of low valent titanium (TiCl4-Zn-
Py) according to our reported procedure.9 It was observed that
the coupling proceeded significantly faster than those between
ketones9 with isolated yields of the cross couplings products
ranging from 43 to 60%, respectively (Table 1, entries 1 and
6). The yields increased to 58 and 74% when 2.5 equiv of low
valent titanium was used (Table 1, entries 3 and 8). We observed
a yellow precipitate forming during the course of the reaction.
Ordinarily, the couplings occur as a black mixture using TiCl4-
Zn as a low valent titanium source. The yields were similar to
those using TiCl4-Zn-Py (Table 1, entries 4, 5, 9, and 10).
Here, optimal conditions for cross McMurry couplings of
salicylaldehyde or substituted salicylaldehyde (1) with aryl
aldehyde (2) employed 2.5 equiv of TiCl4-Zn with a 1:1.2 mol
ratio of 1 to 2.
a Isolated yield.
obtained the oxidative cyclization product via m-CPBA/TsOH.
With the above optimized conditions for the two reactions,
we prepared a variety of 2-arylbenzofurans through this two-
step synthetic strategy in order to establish the generality of
this approach (Table 3). This method proved to be a flexible
and convergent protocol for 2-arylbenzofurans. Besides 2-phenyl
or substituted phenyl benzofurans, 2-heteroaromatic substituted
benzofurans were also conveniently and efficiently synthesized
(Table 3, entries 3, 4, and 7). The oxidative cyclization
proceeded smoothly, and high yields were achieved. In regards
the selective cross McMurry reaction, the following features
are highlighted: (1) the hydroxyl group of 1a-f is important
to the selective cross coupling as it not only enhances the
selective cross coupling over homocoupling but also facilitates
the isolation of the products; (2) the presence of electron-
donating groups, such as methoxy and piperidinyl, seems
beneficial to the enhancement of the selectivity cross coupling
The oxidative cyclization of o-vinylphenols was tested using
three reagents: (A) DDQ,3c-g (B) m-CPBA/TsOH,3h and (C)
I2/K2CO3.3c-g The results are outlined in Table 2. Although
DDQ is commonly utilized to carry out the oxidative cyclization,
we observed that the other two reagents were equally effective.
Additionally, the workup of the DDQ reaction required greater
effort than the other two methods. The reported cyclization via
m-CPBA/TsOH was performed in two steps:3h epoxidation by
m-CPBA followed by TsOH-catalyzed cyclization. In our lab,
we improved the procedure and performed the two reactions in
one pot. We found that this method was suitable for the
o-vinylphenol without an electron-donating group such as MeO-
(Table 2, entry 1). The method employing I2/K2CO3 was highly
effective and simple for the oxidative cyclization in most cases.
We were able to achieve the oxidative cyclization of o-
vinylphenols using I2/K2CO3 in most cases that were attempted.
For the o-vinylphenols without electron-donating groups, we
10284 J. Org. Chem., Vol. 72, No. 26, 2007

TABLE 3. Preparation of 2-Arylbenzofuran Using the Selective Cross McMurry Reactions
a The mole ratios of 1a-1f to 2a-2k were 1:1.2. b Yield of isolated product.
(Table 3, entries 2, 6, 8, 9, and 13-15), an effect also observed
for the homocoupling of diaryl ketone;10 (3) to achieve a
selective cross coupling, the rates of two carbonyl compounds
in the McMurry reaction should not be significantly different;
otherwise the coupling of the two carbonyl compounds will
result in predominantly homocoupling products. In our hands,
the couplings of salicylaldehyde with butyraldehyde, cyclo-
pentanecarboxaldehyde, and cyclohexanone did not signifi-
cantly afford their respective cross coupling products. We
observed that the homocouplings of butyraldehyde, cyclo-
pentanecarboxaldehyde, and cyclohexanone were complete in
approximately 1 h, and hardly any cross coupling products were
observed.
cicerfuran is more convenient and effective compared to
previously reported procedures,11a,b for the reagents are readily
available and the procedures are simple. Moreover, the overall
yield of 60% is significantly higher than those reported
(<20%).11a,b
In conclusion, we developed a facile two-step synthetic
strategy for 2-arylbenzofurans. The key step is a selective cross
McMurry coupling between a salicylaldehyde or substituted
salicylaldehyde and an aromatic aldehyde. This synthetic
approach further extends the scope of the cross McMurry
reaction and provides a novel approach toward the facile
syntheses of 2-arylbenzofurans.
Utilizing the synthetic approach outlined above, we achieved
a total synthesis of a naturally occurring benzofuran compound,
cicerfuran (5),11 as illustrated in Scheme 2. Our synthesis of
(11) (a) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.; Veitch, N. C.;
Hall, D. R. Tetrahedron 2006, 62, 4214. (b) Novak, Z.; Timari, G.; Kotschy,
A. Tetrahedron 2003, 59, 7509. (c) Stevenson, P. C.; Veitch, N. C.
Phytochemistry 1998, 48, 995. (d) Stevenson, P. C.; Veitch, N. C.
Phytochemistry 1998, 48, 947.
(10) Chung, M. K.; Qi, G. Z.; Stryker, J. M. Org. Lett. 2006, 8, 1491.
J. Org. Chem, Vol. 72, No. 26, 2007 10285

SCHEME 2. Total Synthesis of Cicerfuran
anhydrous Na2SO4. The organic layer was concentrated, and the
crude material was purified by flash chromatography to give the
desired products.
Experimental Section
General Procedure for Cross McMurry Reactions. Under an
Ar atmosphere, a four-necked flask equipped with a magnetic stirrer
was charged with zinc powder (0.8 g, 12 mmol) and 40 mL of
THF. The mixture was cooled to -5 ∼ 0 °C, and TiCl4 (0.65 mL,
6 mmol) was added by a syringe slowly with the temperature kept
under 0 °C. The suspension was warmed to room temperature and
stirred for 0.5 h, then heated at reflux for 2.5 h. The mixture was
again cooled to -5 ∼ 0 °C, and the solution of two aldehydes (in
1:1.2 mol ratio, 2.4 mmol) in THF (15 mL) was added slowly.
After addition, the reaction mixture was heated at reflux until the
carbonyl compounds were consumed (monitored by TLC). The
reaction was quenched with 10% aqueous NaHCO3 solution and
taken up CH2Cl2. The organic layer was collected and concentrated.
The crude material was purified by flash chromatography to give
the desired products.
General Procedure for the Oxidative Cyclization of o-
Vinylphenols Using I2/K2CO3. To a solution of o-vinylphenol (2
mmol) in THF (20 mL) was added anhydrous K2CO3 (1.53 g, 11.1
mmol) and was stirred for 10 min. I2 (2.82 g, 11.1 mmol) was added,
and the mixture was stirred at ambient temperature until the
o-vinylphenol was consumed. The mixture was poured into
saturated aqueous NaHCO3 (30 mL) and treated with saturated
aqueous NaHSO3 to remove the unreacted iodine. The mixture was
extracted with EtOAc, and the organic layer was dried over
anhydrous Na2SO4. The organic layer was concentrated, and the
crude material was purified by flash chromatography to give the
desired products.
Acknowledgment. We gratefully acknowledge the National
Nature Science Foundation of China (Grant 20672014) and Drs.
Noriyuki Kawahata and Yao Ma for revising this manuscript
and their helpful advice.
General Procedure for the Oxidative Cyclization of o-
Vinylphenols Using m-CPBA/TsOH. To a solution of o-vinylphe-
nol (5 mmol) in chloroform (100 mL) was added m-chloroperben-
zoic acid (1.8 g, 8.5 mmol). The mixture was stirred at 35-40 °C
until the o-vinylphenol was completely oxidized (monitored by
TLC). Then a few crystals of p-toluenesulfonic acid were added,
and the resulting mixture was again stirred at 35-40 °C until the
epoxide was consumed (monitored by TLC). The mixture was
washed with saturated aqueous NaHCO3 (100 mL), and the organic
layer was washed with 2 × 200 mL purified water and dried over
Supporting Information Available: Typical experimental
procedures and characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO7019652
10286 J. Org. Chem., Vol. 72, No. 26, 2007