One-pot synthesis of 2,2′-bisbenzofurans using cuprous chloride as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.03.040

A variety of novel 5,5′-disubstituted-2,2′-bisbenzofuran derivatives were synthesized by treatment of 4-substituted-2-(2- trimethylsilylethynyl)phenyl tert-butyldimethylsilyl ether analogues with CuCl as a catalyst in 62-82% isolated yields. This novel st

Full text of DOI:10.1016/j.tetlet.2013.03.040

Tetrahedron Letters 54 (2013) 2655–2657
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Tetrahedron Letters
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One-pot synthesis of 2,20-bisbenzofurans using cuprous chloride as a catalyst
Wen-Bin Pan b, Chin-Chau Chen a, Li-Lan Wei b, Li-Mei Wei b, , Ming-Jung Wu a,c,
⇑
⇑
a Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC
b Department of Applied Chemistry and Materials Science, Fooyin University, Kaohsiung, Taiwan, ROC
c Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
A variety of novel 5,50-disubstituted-2,20-bisbenzofuran derivatives were synthesized by treatment of 4-
substituted-2-(2-trimethylsilylethynyl)phenyl tert-butyldimethylsilyl ether analogues with CuCl as a cat-
alyst in 62–82% isolated yields. This novel strategy provides a straightforward and simple pathway for the
preparation of 2,20-bisbenzofuran derivatives of interest in life and material sciences.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 13 December 2012
Revised 1 March 2013
Accepted 8 March 2013
Available online 16 March 2013
Keywords:
One-pot synthesis
Cuprous chloride
2,20-Bisbenzofurans
Homocoupling/annulation
Benzofuran and its derivatives have attracted considerable
attention as synthetic targets due to their interesting proper-
ties.1–3 However, their dimers are much less studied, although they
are present in some molecules and natural products with biological
activities, including the inhibition of propyl endopeptidase4 and
protein phosphatase 1B (PTP-1B),5 antiprotozoal activities,6 and
antimicrobial effects.7 Moreover, 2,20-bis-(diphenylphosphino)-
3,30-bibenzo[b]furans have also been applied to diverse transition
metal catalyzed asymmetric reactions.8 Additionally, 3,30-bis(aryl-
benzofurans) have been reported as substrates for the synthesis of
benzonaphthofurans through photorearrangement reactions.9 Yet,
only few synthetic methodologies have been published for the con-
struction of 2,20-bisbenzofuran ring system in the literature; sev-
eral new approaches have been disclosed in recent years.10
Recently, Daugulis and co-workers reported a CuCl2-catalyzed
deprotonative dimerization of arenes to afford the 2,20-bisbenzofu-
ran in modest yield.11 In 2010, Wegner and co-workers also discov-
ered a novel pathway to access 3,30-bisbenzofuran analogues via a
gold-catalyzed domino cyclization–oxidative coupling reaction.12
Generally, the generation processes of bisbenzofurans usually in-
clude the homocoupling of two benzofuran units which need to
be activated prior to connection by metal-induced coupling reac-
tion, such as modified Castro reaction,13 copper-mediated palla-
multisteps,9 low isolated yields,12 and harsh reaction conditions.
Thus, the efficient and quick way to prepare 2,20-bisbenzofurans
from easily available starting material is a great challenge. Herein,
we described a copper-mediated successive homocoupling/annu-
lation reaction for the synthesis of 5,50-disubstituted-2,20-bis-
benzofurans under
a mild and efficient way with excellent
regioselectivity (Eq. 1):
TMS
CuCl
DMF
R
R
R
160oC
O
O
ð1Þ
OTBDMS
R = H, i-Pr, Et, Me, t-Bu, Cl, Br,
The synthesis of tert-butyldimethyl(2-((trimethylsilyl)ethy-
nyl)phenoxy)silane 3a starting from 2-iodophenol is presented in
Scheme 1. Protection reaction of 1a by TBDMSCl gained compound
2a in 92% yield, followed by Sonogashira–Heck–Cassar (SHC) cou-
pling reaction of 2a with trimethylsilylacetylene using Pd(PPh3)4 as
the catalyst that gave the precursor compound 3a in 92% yield.
Our initial attempt for the oxidative dimerization/cyclization
reaction of 3a was treated with 10 mol % CuCl in DMF at room tem-
perature for 24 h, and no desired product 2,20-bisbenzofuran 4a
was observed (Table 1, entry 1). Upon heating the reaction mixture
in refluxing DMF, expected product 4a was afforded in 65% yield
(entry 2).16 To optimize the reaction conditions, we examined var-
ious reaction conditions for the tandem reaction of 3a by employ-
ing different copper salts and solvents. The results are summarized
in Table 1. Different copper-containing catalysts have been tested:
dium-promoted
coupling,14
or
BuLi/CuCl2
coupling.15
Unfortunately these protocols in preparing dimeric benzofurans
suffer from the use of expensive palladium or gold catalysts,12
⇑
Corresponding author.
E-mail address: sc009@mail.fy.edu.tw (L.-M. Wei).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.040

2656
W.-B. Pan et al. / Tetrahedron Letters 54 (2013) 2655–2657
TMS
outlined in Scheme 3. Iodination reactions of 4-substituted phenols
by chloramines T and NaI gave compounds 4-substituted-2-iod-
ophenols 1b–h along with low yield minor products of 4-substi-
tuted-2,6-diiodophenol compounds 1b0–h0 as outlined in
Scheme 4. Further protection reactions of 1b–h by TBDMSCl pro-
duced compounds 2b–h in 45–98% yields. Subsequent Sonogashira
coupling reactions of 2b–g afforded the substrates 3b–g in 87–97%
yields. However, the Sonogashira–Heck–Cassar (SHC) coupling
reaction of 2h gave unexpected monobenzofuran product, 5-ni-
tro-2-trimethylsilylbenzofuran 6, in 85% yield. This transformation
involves a Sonogashira coupling reaction and a subsequent intra-
molecular heteroannulation process (Scheme 5). Treatment of
3b–g in the presence of cuprous chloride induced these reactions,
5,50-disubstituted-2,20-bibenzofurans 4b–g were obtained in mod-
est to good yields. The results are presented in Scheme 6.
According to the preliminary research on the copper-catalyzed
cyclization and oxidative coupling reaction18 it may be reasonable
to consider that this deprotonative dimerization/annulation reac-
tion proceeds initial desilylation of the TMS group of the substrate
3a in the presence of copper salt, leading to the formation of Cu-
coordinated alkyne. Subsequently, Cu(I) acetylide intermediate
homocouples to produce 1,3-butadiyne 5 via the Glaser–Hay al-
kyne dimerization, wherein the deprotection of the TBDMS group
of 5 occurs, resulting in intramolecular 5-endo–dig cyclization of
a copper complex to furnish product 4a.
TMS
Pd(PPh3)4
CuI
n-BuNH2
ether, rt
TBDMSC
I
I
l
imidazole
CH2Cl2, rt
OH
OTBDMS
2a (92%)
OTBDMS
1a
3a (92%)
Scheme 1.
Cu(I) and Cu(II). CuCl was found to be superior to the others (en-
tries 2–5). When we used CuI as the catalyst, the reaction accom-
panied with homocoupling reaction product
5 in 18% yield
together with 4a in 15% yield (Scheme 2). Further investigating
the solvent effect, solvents, such as DMF, DMSO, CH3CN, toluene,
benzene, THF, and 1,4-dioxane, were used in this study (entries 2
and 6–11). We demonstrated that highly polar solvent DMF was
the best reaction medium, providing 4a in good yield (entry 2).
Other solvents, such as DMSO, CH3CN, toluene, benzene, THF, and
1,4-dioxane, showed no activity (entries 6–11). The chemical struc-
ture of the novel 2,20-bisbenzofuran 4a was characterized by spec-
troscopic analysis.17 It should be noted that the sequential process
proceeds in a regioselective manner.
With the optimum reaction conditions determined (entry 2), we
turn our attention to test the generality of this sequential dehy-
drogenative homocoupling/annulation reaction. Other substrates
3b–g bearing different substituents at the C-4 position of the phe-
nyl ring have also been synthesized (Scheme 3) and subjected to
the cascade reaction under the standard reaction conditions. The
synthesis of tert-butyldimethyl(2-((trimethylsilyl)ethynyl)phen-
oxy)silane 3b–g starting from 4-substituted iodophenols is
In conclusion, we have developed a CuCl-catalyzed tandem pro-
cess to convert simple 4-substituted-2-(2-trimethylsilylethy-
nyl)phenyl tert-butyldimethylsilyl ether analogues directly into
novel 5,50-disubstituted-2,20-bisbenzofuran derivatives. The
Table 1
Copper-catalyzed sequential oxidative homocoupling/cyclization reactions under various conditions
TMS
condition
O
O
OTBDMS
4a
3a
Entry
Additives (10 mol %)
Solvents
Temperature (°C)
Reaction time (h)
Productsa (yield, %)
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl2
DMF
DMF
DMF
DMF
rt
24
24
24
24
24
24
24
24
24
24
24
No reaction
65
Decomposed
55
15
Trace
No reaction
No reaction
No reaction
No reaction
No reaction
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
b
CuBr
CuIc
DMF
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMSO
CH3CN
Toluene
Benzene
THF
10
11
1,4-Dioxane
a
b
c
Isolated yields.
CuCl2 (1.1 equiv).
Reaction accompanied with homocoupling product.
TMS
CuI
OTBDMS
+
O
O
OTBDMS
OTBDMS
5 (18%)
3a
4a (15%)
Scheme 2.

W.-B. Pan et al. / Tetrahedron Letters 54 (2013) 2655–2657
2657
TMS
TMS
R
I
R
I
TBDMSCl
imidazole
CH2Cl2, rt
Pd(PPh3)4
CuI
R
OH
n-BuNH2
ether, rt
OTBDMS
OTBDMS
2
1
3
1b R = i-Pr
2b (94%)
2c (86%)
2d (74%)
2e (98%)
2f (88%)
2g (87%)
2h (45%)
3b (92%)
3c (88%)
3d (95%)
3e (97%)
3f (97%)
3g (87%)
1c R = C2H5
1d R = CH3
1e R = t-Bu
1f R = Cl
1g R = Br
1h R = NO2
Scheme 3.
R
I
OH
References and notes
R
R
I
chloramine T
NaI
DMF, rt
+
1. (a) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670; (b) Wallez,
V.; Poissonnier, S. D.; Chavatte, P.; Boutin, J. A.; Audinot, V.; Nicolas, J. P.;
Bennejean, C.; Delagrange, P.; Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45,
2788; (c) Carlsson, B.; Singh, B. N.; Temciuc, M.; Nilsson, S.; Li, Y. L.; Mellin, C.;
Malm, J. J. Med. Chem. 2002, 45, 623.
2. (a) Pacher, T.; Seger, C.; Engelmeier, D.; Vajrodaya, S.; Hofer, O.; Greger, H. J.
Nat. Prod. 2002, 65, 820; (b) Halabalaki, M.; Aligiannis, N.; Papoutsi, Z.;
Mitakou, S.; Moutsatsou, P.; Sekeris, C.; Skaltsounis, A. L. J. Nat. Prod. 2000, 63,
1672; (c) Banskota, A. H.; Tezuka, Y.; Midorikawa, K.; Matsushige, K.; Kadota, S.
J. Nat. Prod. 2000, 63, 1277.
OH
OH
I
1'
1
1b R = i-Pr (42%)
1b' (33%)
1c' (26%)
1d' (20%)
1e' (22%)
1f' (12%)
1g' (6%)
1c R = C2H5 (50%)
1d R = CH3 (69%)
1e R = t-Bu (71%)
1f R = Cl (73%)
1g R = Br (91%)
1h R = NO2 (90%)
3. Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W. X.; McDevitt, R.;
Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med.
Chem. 2000, 43, 1293.
1h' (trace)
Scheme 4.
4. (a) Kim, S. I.; Park, I. H.; Song, K. S. J. Antibiot. 2002, 7, 623; (b) Song, K. S.;
Raskin, I. J. Nat. Prod. 2002, 65, 76.
5. Dixit, M.; Tripathi, B. K.; Tamrakar, A. K.; Srivastava, A. K.; Kumar, B.; Goel, A.
Bioorg. Med. Chem. 2007, 15, 727.
6. Bakunova, S. M.; Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun,
R.; Hall, J. E.; Tidwell, R. R. J. Med. Chem. 2007, 50, 5807.
7. Kirilmis, C.; Koca, M.; Cukurovali, A.; Ahmedzade, M.; Kazaz, C. Molecules 2005,
10, 1399.
8. Andersen, N. G.; Parvez, M.; Keay, B. A. Org. Lett. 2000, 2, 2817.
9. Auzias, M.; Haussinger, D.; Neuburger, M.; Wegner, H. A. Org. Lett. 2011, 13,
474.
10. (a) Shen, Y. D.; Wu, H. Q.; An, L. K.; Huang, Z. S.; Bu, X. Z.; Gu, L. Q. Chin. Chem.
Lett. 2005, 16, 1581; (b) Dixit, M.; Sharon, A.; Maulik, P. R.; Goel, A. Synlett 2006,
1497; (c) Kumar, B.; Dixit, M.; Singh, S. P.; Raghunadan, R.; Maulik, P. R.; Goel,
A. Tetrahedron Lett. 2009, 50, 4335.
TMS
Pd(PPh3)4
CuI
O2N
I
O2N
TMS
O
n-BuNH2
ether, rt
OTBDMS
2h
6 (85%)
Scheme 5.
TMS
11. Do, H. Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052.
12. Auzias, M. G.; Neuburger, M.; Wegner, H. A. Synlett 2010, 2443.
13. Bakunov, S. A.; Bakunova, S. M.; Bridges, A. S.; Wenzler, T.; Barszcz, T.;
Werbovetz, K. A.; Brun, R.; Tidwell, R. R. J. Med. Chem. 2009, 52, 5763.
14. Yang, L. Y.; Chang, C. F.; Huang, Y. C.; Lee, Y. J.; Hu, C. C.; Tseng, T. H. Synthesis
2009, 1175.
R
R
R
CuCl, DMF
160oC, 24h
OTBDMS
O
O
3
4
4b (62%)
3b R = i-Pr (92%)
3c R = C2H5 (88%)
3d R = CH3 (95%)
3e R = t-Bu (97%)
3f R = Cl (97%)
3g R = Br (87%)
15. Benincori, T.; Brenna, E.; Sannicolo, F.; Trimacro, L.; Antognazza, P.; Cesarotti,
E.; Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244.
4c (82%)
4d (75%)
4e (73%)
4f (65%)
4g (65%)
16. General procedure for the preparation of 5,50-disubstituted-2,20-bisbenzofurans: A
slurry
of
the
4-substituted-2-(2-trimethylsilylethynyl)phenyl
tert-
butyldimethylsilyl ether 3a (0.67 mmol) and CuCl (10 mol %) in dry DMF
(10 mL) at 160 °C was stirred for 24 h. After cooling to room temperature,
saturated NaCl(aq) solution was added to the reaction mixture, and extracted
with EtOAc. The combined organic layer was dried over anhydrous MgSO4(s)
After filtration and removal of the solvent, the residue was purified by flash
chromatography to give the product 4a (65%).
.
Scheme 6.
17. Compound 4a (65%) as a white solid: mp = 193–194 °C; 1H NMR (400 MHz,
CDCl3) d 7.65 (dq, 2H, J = 7.6, 0.8 Hz), 7.56 (dd, 2H, J = 8.0, 0.8 Hz), 7. 36 (td, 2H,
J = 7.2, 1.2 Hz), 7. 29 (td, 2H, J = 7.6, 1.2 Hz), 7.17 (d, J = 0.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 155.1, 147.7, 128.5, 125.1, 123.3, 121.4, 111.3, 103.7;
EI(MS) m/z (rel. intensity) 234 (M+, 100), 178 (11), 176 (25); HRMS (ESI-TOF)
Calcd for C16H10O2, 234.0681, Found: 234.0686; Anal. Calcd for C16H10O2: C,
82.04; H, 4.30. Found: C, 81.79; H, 4.98.
18. (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. A. J. Am. Chem. Soc. 2001, 123,
2074; (b) Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72,
7783; (c) Bai, Y.; Zeng, J.; Ma, J.; Liu, W.; Gorityala, B. K.; Liu, X. W. J. Comb.
Chem. 2010, 12, 696; (d) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.;
Pak, J. J. Tetrahedron Lett. 1997, 38, 7483; (e) Nishihara, Y.; Ikegashira, K.;
Hirabayashi, K.; Ando, J.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780; (f)
Nishihara, Y.; Takemura, M.; Mori, A.; Osakada, K. J. Organomet. Chem. 2001,
620, 282.
notable features of this cascade reaction are its mild reaction con-
ditions, synthetic simplicity, excellent yields, high regioselectivity,
and usage of less expensive CuCl as a catalyst. The application of
this methodology to the preparation of pharmaceutical or material
interest molecules, 2,20-bisbenzofuran analogues, is currently un-
der investigation.
Acknowledgment
We thank the National Science Council of the Republic of China
for the financial support of this program.