Efficient synthesis of functionalized dibenzofurans by domino 'twofold Heck/6π-electrocyclization' reactions of 2,3-di- and 2,3,5-tribromobenzofuran

Article abstract of DOI:10.1016/j.tetlet.2009.04.069

Functionalized dibenzofurans were prepared based on domino 'twofold Heck/6π-electrocyclization' reactions of 2,3-di- and 2,3,5-tribromobenzofuran.

Full text of DOI:10.1016/j.tetlet.2009.04.069

Tetrahedron Letters 50 (2009) 3929–3932
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of functionalized dibenzofurans by domino ‘twofold
Heck/6
p-electrocyclization’ reactions of 2,3-di- and 2,3,5-tribromobenzofuran
Munawar Hussain a, Nguyen Thai Hung a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized dibenzofurans were prepared based on domino ’twofold Heck/6
tions of 2,3-di- and 2,3,5-tribromobenzofuran.
p-electrocyclization’ reac-
Received 16 March 2009
Revised 15 April 2009
Accepted 17 April 2009
Available online 23 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzofurans
Catalysis
Domino reactions
Oxygen heterocycles
Palladium
Natural and non-natural benzofurans are of considerable phar-
macological relevance and occur in many natural products.1 For
example, synthetic amiodarone represents a potent antiarrythmic
and antianginal drug.2 7-Alkanoylbenzofurans and 7-alkanoyl-
2,3-dihydrobenzofurans occur in a number of natural products,
such as longicaudatin,3 the sessiliflorols A and B, flemistrictin E,
tovophenone C, vismiaguianone C or piperaduncin B.4 Dibenzofu-
rans are also present in a variety of pharmacologically active natu-
ral products. Examples include simple hydroxylated derivatives
2,6-dibromobenzofuran have been reported to regioselectively oc-
cur at position C-2. Bach and Bartels reported regioselective Negishi
and Kumada cross-coupling reactions of 2,3,5-tribromobenzofu-
ran.17 Herein, we report what are, to the best of our knowledge,
the first Heck reactions of 2,3-dibromo- and 2,3,5-tribromobenzofu-
ran. In this context, functionalized dibenzofurans were efficiently
prepared based on domino ’twofold Heck/6
p-electrocyclization’
reactions.18,19
Bach and Bartels reported that the direct bromination of
benzofuran (1), following the conditions reported by Antognazza
and co-workers ,20 resulted in the formation of a mixture of di-
and tribrominated products. Therefore, a useful and reliable
stepwise protocol was developed for the synthesis of 2,3-dib-
romobenzofuran (2a).15b In our hands, the direct reaction of 1 with
bromine (2.0 equiv) and KOAc (2.0 equiv) in CH2Cl2 (reflux, 4 h)
afforded 2,3-dibromobenzofuran (2a) in 84% yield (Scheme 1).
However, the reaction tends to be unreliable and depends on the
scale of the reaction and on minor changes of the conditions.
Bach and Bartels also reported a reliable stepwise synthesis of
(such as a- and c-cotonefuran, norascomatic acid and c-pyrufuran)
(Chart 1),5 aryl-substituted hydroxylated derivatives (e.g., candidu-
sin A and vialinin B),6 brominated derivatives (e.g., corallinafu-
ran),7 polycyclic derivatives (such as phlorofucofuroeckol A or
mallotusinin)8 and complex glycosylated derivatives (e.g., fulicin-
eroside).9 A number of synthetic approaches to dibenzofurans have
been reported.10
In recent years, it has been shown that polyhalogenated hetero-
cycles can be regioselectively functionalized in palladium(0)-cata-
lyzed cross-coupling reactions by selective activation of a single
halogen atom. The regioselectivity is controlled by electronic and
steric parameters.11 Recently, we have reported the synthesis of
aryl-substituted thiophenes,12 pyrroles13 and selenophenes14 based
on regioselective Suzuki reactions of tetrabromothiophene, tetrab-
romo-N-methylpyrrole and tetrabromoselenophene, respectively.
Sonogashira,15 Negishi15 and Stille16 coupling reactions of 2,3- and
Me
Me
OH
HO
OH
HO2C
HO
OMe
O
MeO
O
OMe
γ-Pyrufuran
Norascomatic acid
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Chart 1. Structures of some naturally occurring dibenzofurans.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.069

3930
M. Hussain et al. / Tetrahedron Letters 50 (2009) 3929–3932
Table 1
Br
Synthesis of 4a,d,e and 6a–c,e
i
4,6
R
(4) (%)a
(6)b (5)
Br
Br
O
O
a
b
c
d
e
Et
93
73
76
84
c
nBu
iBu
nHex
tBu
—
—
1
2a (84%)
c
ii
c
79
72
—
Br
75
Br
a
Yields of isolated products (based on 2a, T = 70 °C).
Yields of isolated products over two steps (based on 2a, T = 100 °C for the first
b
O
step).
c
2b (76%)
Experiment was not carried out.
Scheme 1. Bromination of benzofuran (1). Reagents and conditions: (i) Br2
(2.0 equiv), KOAc (2.0 equiv) CH2Cl2, reflux, 4 h; (ii) Br2 (4.5 equiv), KOAc (4.5 equiv),
CH2Cl2, reflux, 18 h.
plained by a domino ’twofold Heck/thermal 6p-electrocyclization’
reaction to give intermediate A which subsequently underwent a
double bond migration. The formation of an isomeric mixture sug-
gests that the double bond migration may proceed by a pericyclic
mechanism (1,5-hydrogen shift), since an ionic mechanism (in-
duced by protonation of the enol ether moiety of A) should have
resulted in the exclusive formation of B. Heating of a xylene solu-
tion of crude 5a–c,e in the presence of Pd/C afforded dibenzofurans
6a–c,e in 73–84% overall yields (based on 2a).
It is worth noting that, in contrast to Sonogashira and Stille
reactions, the Heck reaction proved to be not regioselective. The
reaction of 2a with only 1 equiv of acrylate 3e mainly resulted in
the formation of 4e and of starting material. This might be ex-
plained as follows. As other Pd(0)-catalyzed cross-coupling reac-
tions of 2a are known to regioselectively occur at position
C-2,15,16 it is expected (albeit not experimentally proven) that the
Heck reaction of 2a also first occurs at C-2. Due to the electron-
withdrawing character of the (tert-butoxycarbonyl)alkenyl group,
which is introduced at carbon C-2 in the first step, carbon C-3 be-
comes more electron deficient and, thus, more reactive with re-
spect to carbon C-3 of 2a. Alternatively, a neighbourhood effect
(chelation of the Pd(0) species by the alkenyl substituent located
at C-2) can be discussed.
2,3,5-tribromobenzofuran (2b) which was prepared from 5-bro-
mobenzofuran in 52% yield.15b We have found that 2b is available
in 76% yield by reaction of 1 with bromine (4.5 equiv) and KOAc
(4.5 equiv) in CH2Cl2 (reflux, 18 h).21
The Heck reaction of 2a with acrylates 3a,d,e (2.5 equiv) affor-
ded the 2,3-di(alkenyl)benzofurans 4a,d,e in good yields (Scheme
2, Table 1). The best yields were obtained when the reactions were
carried out using Pd(OAc)2 (5 mol %) and the biaryl monophos-
phine ligand SPhos (10 mol %) which was recently developed by
Buchwald and coworkers.22 The reactions were carried out in
DMF at 70 °C for 12 h.23 The employment of Pd(PPh3)4 was less
successful in terms of yield. The Pd(OAc)2/SPhos-catalyzed reaction
of 2a with acrylates 3a–c,e, carried out at 100 °C rather than at
70 °C, afforded the 1,2-dihydrodibenzofurans 5a–c,e as unsepara-
ble mixtures of isomers B and C. The formation of 5a–c,e can be ex-
CO2R
CO2R
The Heck reaction of 2a with styrene 3f directly afforded the
dibenzofuran 6f in 83% yield (Scheme 3). The dehydrogenation
spontaneously occurred under the reaction conditions and did
not require the use of Pd/C. Likewise, the Heck reaction of 2a with
acryl nitrile (3g) directly afforded 2,3-dicyanodibenzofuran (6g) in
74% yield.
The Heck reaction of 2,3,5-tribromobenzofuran (2b) with acry-
lates 3b,e afforded the 2,3,5-tri(alkenyl)benzofurans 7a,b in good
yields (Scheme 4). The reactions were carried out in DMF at
70 °C for 12 h. The Pd(OAc)2/SPhos-catalyzed reaction of 2b with
O
4a,d,e
i
Br
CO2R
3a-e
Br
O
CO2R
CO2R
2a
ii
O
A
Me
CO2R
CO2R
Me
O
B
+
CO2R
Me
iii
CO2R
CO2R
3f
CO2R
i
O
Br
6f (83%)
CN
O
Br
O
C
5a-c,e
6a-c,e
O
i
CN
2a
CN
3g
O
Scheme 2. Synthesis of 4a,d,e and 6a–c,e. Reagents and conditions: (i) Pd(OAc)2
(5 mol %), SPhos (10 mol %), NEt3 (8.0 equiv), DMF, 70 °C, 12 h; (ii) Pd(OAc)2
(5 mol %), SPhos (structure see below, 10 mol %), NEt3, DMF, 100 °C, 48 h; isomeric
ratio B/C (assignment arbitrary): 5a (2:1.1), 5c (2:1), 5e (2:0.9); (iii) Pd/C (10 mol %),
xylene, reflux, 48 h.
6g (74%)
Scheme 3. Synthesis of 6f, g. Reagents and conditions: (i) Pd(OAc)2 (5 mol %), SPhos
(10 mol %), NEt3, DMF, 100 °C, 48 h.

M. Hussain et al. / Tetrahedron Letters 50 (2009) 3929–3932
3931
CO2R
Br
OMe
OMe
RO2C
i
Br
Br
Br
CO2R
1st attack
Br
O
11
O
O
CO2R
2b
Bach and Bartels (ref. 17), Kumada coupling
7a (R = nBu): 74%
7b (R = tBu): 77%
3b,e
ii
3e
1st attack
CO2R
RO2C
RO2C
Br
Br
CO2tBu
CO2R
CO2R
CO2R
RO2C
O
O
O
F
+
This work
iii
Chart 3. Regioselective reactions of 2b.
CO2R
8
CO2R
In conclusion, 2,3-dialkenylbenzofurans and functionalized
dibenzofurans were prepared based on domino ’twofold Heck/6
p-
O
electrocyclization’ reactions of 2,3-di- and 2,3,5-tribromobenzofu-
ran. The first attack of Pd(0) occurs at carbon C-2 which results in
a dramatic increase of the reactivity of C-3. Therefore, the Heck reac-
tion of 2,3-dibromobenzofuran proceeds with low regioselectivity.
9 (R = tBu): 71%
(based on 2b)
Scheme 4. Synthesis of 7a, b and 9. Reagents and conditions: (i) Pd(OAc)2 (5 mol %),
SPhos (10 mol %), NEt3 (8.0 equiv), DMF, 70 °C, 12 h; (ii) Pd(OAc)2 (5 mol %), SPhos
(10 mol %), NEt3, DMF, 100 °C, 48 h (isomeric ratio: 2:1, assignment arbitrary); (iii)
Pd/C (10 mol %), xylene, reflux, 48 h.
Acknowledgements
Financial support by State of Pakistan (H.E.C. scholarship for
M.H.), by the State of Mecklenburg-Vorpommern (scholarship for
M.H.) and by the State of Vietnam (M.O.E.T. scholarship N.T.H.) is
gratefully acknowledged.
acrylate 3e, carried out at 100 °C, afforded 8 as a mixture of two
isomers. Heating of a xylene solution of crude 8 in the presence
of Pd/C afforded the 5-alkenyldibenzofuran 9 in 71% yield. The
Heck reaction of 2b with acrylates 3b, e, carried out at >120 °C,
mainly resulted in the formation of the hydrogenated products
10a and 10b which were isolated as single isomers (Chart 2). How-
ever, the exact structure (isomer D or E) could not be unambigu-
ously assigned.
Bach and Bartels reported that the Kumada coupling of 2-aryl-
3,5-dibromobenzofuran 11, derived from 2b, occurs at carbon
atom C-5 (Chart 3).17 We have found that the Heck reaction of
2b with 2 equiv of acrylate 3e resulted in functionalization of car-
bon atoms C-2 and C-3 and in reduction of C-5 to give 4e. This re-
sult can be explained by the following assumption which has not
yet been experimentally proven: the first reaction of 3e with 2b oc-
curs at position C-2 to give intermediate F (Chart 3). The reactivity
of carbon C-3 is increased by the neighbourhood effect of the (tert-
butoxycarbonyl)alkenyl substituent located at carbon C-2 (vide su-
pra). Therefore, the second attack occurs at carbon C-3 rather than
at C-5.
References and notes
1. (a) Miyata, O.; Takeda, N.; Morikami, Y.; Naito, T. Org. Biomol. Chem. 2003, 1,
254; (b) Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.; Pan, X. Tetrahedron Lett. 2004,
45, 6235; (c) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004,
43, 6144; (d) Hagiwara, H.; Sato, K.; Nishino, D.; Hoshi, T.; Suzuki, T.; Ando, M.
J. Chem. Soc., Perkin Trans. 1 2001, 2946; Review: (e) Butin, A. V.; Gutnow, A. V.;
Abaev, V. T.; Krapivin, G. D. Molecules 1999, 4, 52; (f) Fuerst, D. E.; Stoltz, B. M.;
Wood, J. L. Org. Lett. 2000, 22, 3521; (g) Schneider, B. Phytochemistry 2003, 64,
459; (h) Katritzky, A. R.; Kirichenkok, K.; Ji, Y.; Steel, P. J.; Karelson, M. ARKIVOC
2003, vi, 49.
2. (a) Wendt, B.; Ha, H. R.; Hesse, M. Helv. Chim. Acta 2002, 85, 2990; (b) Carlsson,
B.; Singh, B. N.; Temciuc, M.; Nilsson, S.; Li, Y. L.; Mellin, C.; Malm, J. J. Med.
Chem. 2002, 45, 623; and references cited therein (c) Kwiecien, H.; Baumann, E.
J. Heterocycl. Chem. 1997, 1587; (d) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc.
1984, 106, 4218; (e) Matyus, P.; Varga, I.; Rettegi, T.; Simay, A.; Kallay, N.;
Karolyhazy, L.; Kocsis, A.; Varro, A.; Penzes, I.; Papp, J. G. Curr. Med. Chem. 2004,
1, 61; (f) Wong, H. N. C.; Pei, Yu; Yick, C. Y. Pure Appl. Chem. 1999, 71, 1041.
3. Longicaudatin: (a) Joshi, A. S.; Li, X.-C.; Nimrod, A. C.; ElSohly, H. N.; Walker, L.
A.; Clark, A. M. Planta Med. 2001, 67, 186; For related natural products, see: (b)
Sigstad, E.; Catalan, C. A. N.; Diaz, J. G.; Herz, W. Phytochemistry 1993, 33, 165;
(c) Drewes, S. E.; Hudson, N. A.; Bates, R. B. J. Chem. Soc., Perkin Trans.1 1987,
2809.
4. Sessiliflorol A: (a) Chan, J. A.; Shultis, E. A.; Carr, S. A.; DeBrosse, C. W.;
Eggleston, D. S. J. Org. Chem. 1989, 54, 2098; Sessiliflorol B: (b) Marston, A.;
Zagorski, M. G.; Hostettmann, K. Helv. Chim. Acta 1988, 71, 1210; (c) Drewes, S.
E.; Hudson, N. A.; Bates, R. B.; Linz, G. S. Tetrahedron Lett. 1984, 25, 105;
Flemistrictin E: (d) Subrahmanyam, K.; Rao, J. M.; Vemuri, V. S. S.; Babu, S. S.;
Roy, C. P.; Rao, K. V. J. Ind. J. Chem., Sect B 1982, 21, 895; Tovophenone C: (e) Seo,
E.-K.; Wall, M. E.; Wani, M. C.; Navarro, H.; Mukherjee, R.; Farnsworth, N. R.;
Kinghorn, A. D. Phytochemistry 1999, 52, 669; Vismiaguianone C: (f) Seo, E.-K.;
Wani, M. C.; Wall, M. E.; Navarro, H.; Mukherjee, R.; Farnsworth, N. R.;
Kinghorn, A. D. Phytochemistry 2000, 55, 35; Piperaduncin B: (g) Joshi, A. S.; Li,
X.-C.; Nimrod, A. C.; ElSohly, H. N.; Walker, L. A.; Clark, A. M. Planta Med. 2001,
67, 186; See also: (h) Bohlmann, F.; Zdero, C. Chem. Ber. 1976, 109, 1436.
5. (a) Kokubun, T.; Harborne, J. B. Phytochemistry 1995, 40, 1649; (b) Burden, R. S.;
Kemp, M. S.; Wiltshire, C. W.; Owen, J. D. J. Chem. Soc., Perkin Trans. 1 1984,
1445.
CO2R
CO2R
RO2C
RO2C
O
O
D
E
CO2R
CO2R
6. (a) Kobayashi, A.; Takemura, A.; Koshimizu, K.; Nagano, H.; Kawazu, K. Agric.
Biol. Chem. 1982, 46, 585; (b) Ma, B.-J.; Liu, J.-K. Z. Naturforsch. B 2005, 60, 565;
(c) Takahashi, A.; Kudo, R.; Kusano, G.; Nozoe, S. Chem. Pharm. Bull. 1992, 40,
3194; (d) Xie, C.; Koshino, H.; Esumi, Y.; Onose, J.-i.; Yoshikawa, K.; Abe, N.
Bioorg. Med. Chem. Lett. 2006, 16, 5424.
10a,b (R = nBu, tBu)
Chart 2. Products formed at temperatures higher than 120 °C.

3932
M. Hussain et al. / Tetrahedron Letters 50 (2009) 3929–3932
7. Kitamura, M.; Koyama, T.; Nakano, Y.; Uemura, D. Chem. Lett. 2005, 34, 1272.
8. (a) Jaegers, E.; Hillen-Maske, E.; Steglich, W. Z. Naturforsch. B 1987, 42, 1349; (b)
Anh, M.-J.; Yoon, K.-D.; Min, S.-Y.; Lee, J. S.; Kim, J. H.; Kim, T. G.; Kim, S. H.; Kim,
N.-G.; Huh, H.; Kim, J. Biol. Pharm. Bull. 2004, 27, 544; (c) Liu, K. C. S. C.; Lin, M.-
T.; Lee, S.-S.; Chiou, J.-F.; Ren, S.; Lien, E. J. Planta Med. 1999, 65, 43; (d)
Yoshikawa, M.; Xu, F.; Morikawa, T.; Ninomiya, K.; Matsuda, H. Bioorg. Med.
Chem. Lett. 2003, 13, 1045.
saturated solution of Na2S2O3 and NaHCO3. The organic and the aqueous layers
were separated and the latter was extracted with CH2Cl2 (3ꢀ40 mL). The
combined organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by column chromatography (flash silica gel,
pure heptanes) to yield 2b as a colourless solid (33.5 g, 76%).
22. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358. and references
cited therein.
9. Rezanka, T.; Hanus, L. O.; Kujan, P.; Dembitsky, V. M. Eur. J. Org. Chem. 2005,
2708.
23. General procedure for the synthesis of dibenzofurans 6a–c,e and 9a: In a pressure
tube a DMF suspension (5 mL) of Pd(OAc)2 (12 mg, 0.05 mmol, 2.5 mol % per Br
atom of the substrate) and dicyclohexyl (20,60-dimethoxybiphenyl-2-
yl)phosphine (SPhos) (41 mg, 0.10 mmol) was purged with argon and the
mixture was stirred at 20 °C to give a yellowish to brownish clear solution. To
the stirred solution were added 2a or 2b (1.0 mmol), NEt3 (1.1 mL, 8.0 mmol)
and the acrylate 3 (1.25 equiv per Br atom of the substrate). The reaction
mixture was stirred at 100 °C for 48 h. The solution was cooled to 20 °C, poured
into H2O and CH2Cl2 (25 mL each), and the organic and the aqueous layers
were separated. The latter was extracted with CH2Cl2 (3ꢀ25 mL). The
combined organic layers were washed with H2O (3ꢀ20 mL), dried (Na2SO4)
and concentrated in vacuo. To the crude material were added xylene (3 mL)
and Pd/C (30 mg, 10 mol %). The solution was stirred under reflux for 48 h
under argon atmosphere. The reaction mixture was filtered and the filtrate was
concentrated in vacuo. The residue was purified by chromatography (flash
silica gel, heptanes/EtOAc) to give 6a–c,e or 9a. Diisobutyl dibenzo[b,d]furan-
2,3-dicarboxylate (6c): Starting with 2a (276 mg, 1.0 mmol), 6c was prepared as
a brownish highly viscous oil (305 mg, 84%). 1H NMR (250 MHz, CDCl3): d 0.94
(d, 6H, J = 6.8 Hz, 2CH3), 0.95 (d, 6H, J = 6.78 Hz, 2CH3), 1.93–2.10 (m, 2H, 2CH),
4.10 (d, 4H, J = 6.8 Hz, 2CH2O), 7.30–7.37 (m, 1H, ArH), 7.43–7.56 (m, 2H, ArH),
7.82 (s, 1H, ArH), 7.91–7.95 (m, 1H, ArH), 8.27 (s, 1H, ArH). 13C NMR (62 MHz,
CDCl3): d 19.2 (4CH3), 27.7, 27.8 (CH), 71.9, 72.0, (CH2O), 112.1, 112.5, 121.4,
122.0 (CH), 123.6 (C), 124.1 (CH), 126.3, 127.3 (C), 128.7 (CH), 131.8, 156.6,
157.5 (C), 167.5, 167.6 (CO). IR (KBr): v = 3072, 2959, 2873 (m), 1719 (s), 1636,
1602, 1577 (w), 1454, 1393, 1376, 1350, 1306 (m), 1274, 1239, 1219, 1778,
1111, 1100, 1060 (s), 1011, 983 (m), 945, 900, 848, 881, 767 (w), 746 (m), 722,
694, 602, 564 cmꢁ1. MS (EI, 70 eV): m/z (%) = 368 ([M]+, 9), 312 (4), 256 (62),
239 (100), 212 (13), 195 (10). HRMS (EI, 70 eV): calcd for C22H24NO5 [M]+:
368.16183; found: 368.16179.
10. See for example: (a) Sanz, R.; Fernández, Y.; Castroviejo, M. P.; Pérez, A.;
Fañanás, F. J. J. Org. Chem. 2006, 71, 6291; (b) Serra, S.; Fuganti, C. Synlett 2003,
2005; (c) Wu, M.-J.; Lee, C.-Y.; Lin, C.-F. Angew. Chem., Int. Ed. 2002, 41, 4077.
11. Review: Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
12. Dang, T. T.; Rasool, N.; Dang, T. T.; Reinke, H.; Langer, P. Tetrahedron Lett. 2007,
48, 845.
13. Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P. Tetrahedron Lett. 2008,
49, 1698.
14. Dang, T. T.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109.
15. (a) Bach, T.; Bartels, M. Synlett 2001, 1284; (b) Bach, T.; Bartels, M. Synthesis
2003, 925.
16. Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968.
17. Bach, T.; Bartels, M. Tetrahedron Lett. 2002, 43, 9125.
18. De Meijere and coworkers reported twofold Heck reactions of 1,2-
dibromocycloalk-1-enes and related substrates and subsequent
6
p-
electrocyclization: Voigt, K.; von Zezschwitz, P.; Rosauer, K.; Lansky, A.;
Adams, A.; Reiser, O.; de Meijere, A. Eur. J. Org. Chem. 1998, 1521. and
references cited therein.
19. For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem.
1993, 105, 137. Angew. Chem., Int. Ed. Engl. 1993, 32, 131; (b) Tietze, L. F. Chem.
Rev. 1996, 96, 115.
20. Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P. J. Org. Chem.
1996, 61, 6244.
21. Synthesis of 2,3,5-tribromobenzofuran (2b): To a CH2Cl2 solution (100 mL) of
benzofuran (1) (10 mL, 125 mmol) and KOAc (55.1 g, 562.5 mmol) was added
dropwise a CH2Cl2 solution (50 mL) of Br2 (28.9 mL, 562.5 mmol) at 20 °C and
the solution was heated under reflux for 18 h. To this solution was added a