2,3-Disubstituted 2,3,5-trisubstituted benzofurans by regioselective Pd-catalyzed cross-coupling reactions; a short synthesis of eupomatenoid-15

Article abstract of DOI:10.1055/s-2001-16052

2,3-Dibromobenzofuran (1) 2,3,5-tribromobenzofuran (2) undergo regioselective Sonogashira- Negishi-type cross-coupling reactions at the 2-position. Subsequent substitution reactions at C-3 are possible for the cross-coupling products obtained from compoun

Full text of DOI:10.1055/s-2001-16052

LETTER
1284
2,3-Disubstituted and 2,3,5-Trisubstituted Benzofurans by Regioselective Pd-
Catalyzed Cross-coupling Reactions; a Short Synthesis of Eupomatenoid-15
Thorsten Bach,* Marc Bartels
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(0)89/28913315; E-mail: thorsten.bach@ch.tum.de
Received 4 May 2001
coupling11 with both substrates 1 and 2 proceeded
Abstract: 2,3-Dibromobenzofuran (1) and 2,3,5-tribromobenzofu-
smoothly and with high regioselectivity (Scheme 1, Ta-
ran(2) undergo regioselective Sonogashira- and Negishi-type cross-
ble). Modified conditions were used according to which a
coupling reactions at the 2-position. Subsequent substitution reac-
tions at C-3 are possible for the cross-coupling products obtained
slight excess (1.5 equiv.) of diethylamine was employed
from compound 1. A regioselective functionalization of the 3,5-di- in THF as the solvent.12,13 Triethylamine was not suitable
bromobenzofurans derived from substrate 2 was achieved by an
as a base in this procedure.
halogen-metal exchange which occurred selectively at the 3-posi-
tion. In a conclusive reaction step cross-coupling reactions at C-5
were used to build up 2,3,5-trisubstituted benzofurans. As an exam-
HC CR, Et2NH
ple, the synthesis of eupomatenoid-15 (8) is described.
Br
3
Br
5
X
X
[PdCl2(PPh3)2, CuI]
2
Key words: catalysis, cross-coupling, heterocycles, palladium, re-
gioselectivity
Br
C CR
(THF)
25 °C
O
O
1
2
3
4
X = H
X = Br
Multi-substituted benzo[b]furan (benzofuran) rings are
structural motifs found in many interesting biologically
active compounds.1 Synthetic efforts to access benzo-
furans have been centered both on ring closure reactions
and on substitution reactions which occur at the pre-
formed benzofuran nucleus.2 Electrophilic aromatic sub-
stitution and metalation reactions are known to occur
regioselectively at the 2-position.2 The regioselectivity of
reactions in which other atoms than hydrogen are substi-
tuted have been studied scarcely.3,4 In connection with our
studies on regioselective Pd-catalyzed cross-coupling re-
actions of five-membered furans5 and thiazoles6 we be-
came interested in the analogous reactions of dibromo-
and tribromo-substituted benzofurans. We now report
our preliminary results in this area. It was found that an
initial Pd-catalyzed cross-coupling occurs preferentially
at the 2-position and that successive Pd- or Ni-catalyzed
reactions at less reactive positions are possible. For the
differentiation of the 3- vs. the 5-position a halogen-
metal exchange at low temperature proved more selective
than a Pd- or Ni-catalyzed process. The methodology
was applied to a short synthesis of the naturally occurring
2-(4’-methoxyphenyl)-3-methyl-5-(E)-propenylbenzofu-
ran (eupomatenoid-15).7
Scheme 1
Table Regioselective Sonogashira Cross-coupling of Various
Alkynes and Benzofurans 1 and 213
a Yield of isolated product after purification by flash chromatography
2,3-Dibromobenzofuran4 (1) and 2,3,5-tribromobenzo-
furan4,8 (2) are readily accessible starting materials which
were used in our preliminary studies. If successful, con-
secutive cross-coupling reactions should lead to 2,3-di-
substituted and 2,3,5-trisubstituted benzofurans. An all-
carbon 2,3,5-trisubstitution pattern appeared particularly
interesting as it is found in several biologically relevant
benzofurans, e.g. in the lignans isolated from Eupomatia
laurina and Eupomatia bennettii (eupomatenoids).7,9,10
We were pleased to find that the Sonogashira-type cross-
In general, the 2-substituted products 3 and 4 were the
sole substitution products isolated. No regioisomers were
observed. The comparably low yield in the reaction with
propargyl methyl ether (entries 7 and 8) did not come as a
surprise. This substrate had proved to be problematic in
previous cross-coupling reactions.5 Extensive hydro-de-
bromination and homo coupling were observed.
In a second set of experiments, aryl zinc compounds were
treated with benzofurans 1 and 2. Negishi coupling14 of
these substrates proved equally regioselective. As an
Synlett 2001, No. 8, 1284–1286 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2,3-Disubstituted and 2,3,5-Trisubstituted Benzofurans
1285
example, three reactions of the tribromo-substituted arene
2 are depicted in Scheme 2. The aryl zinc chloride 5 was
prepared from the corresponding bromide by halogen-
metal exchange (2.1. equiv. tert-BuLi, 78 °C, THF) and
subsequent transmetalation (1 equiv. ZnCl2, 78 °C
r.t., THF).
Br
Br
Br
t BuLi, MeI
OMe
OMe
−78 °C (THF)
O
O
6a
54%
7
MgCl
[NiCl2(dppe)]
[I2]
OMe
66 °C (THF)
25 °C (THF)
quant.
O
Br
Z
ClZn
Z
Y
78%
Eupomatenoid-15 (8)
[PdCl2(PPh3)2]
Br
+
2
Y
(THF)
25 °C
O
Scheme 3
5
a
b
c
Y = OMe, Z = H
6
66%
69%
65%
Y = OTBDMS, Z = H
Y = Z = OCH2O
Further studies are under way to prove the general appli-
cability of this route for the synthesis of 2,3,5-trisubstitut-
ed benzofurans. In addition, we continue to study cross-
coupling reactions which may lead to a differentiation of
the 3- vs 5-position in compounds 6. Results of these stud-
ies will be reported in due course.
Scheme 2
Attempts to differentiate between the 3- and 5-position of
3,5-dibromobenzofurans 4 and 6 by a Pd-catalyzed cross-
coupling remained unsuccessful so far. In reactions con- Acknowledgement
ducted with MeZnCl and benzofuran 6a under more dras-
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 260 and grant Ba 1372/4-2) and the Fonds der Chemischen In-
dustrie.
tic condition we observed product mixtures. In the course
of these studies conditions were discovered which al-
lowed for a complete two-fold methyl-debromination of
compound 6a [6 equiv. MeZnCl, 0.1 equiv. PdCl2(dppf),
THF, reflux, 18 h]. In addition, methyl-debromination re-
actions of compounds 3 at the 3-position were achieved
by cross-coupling with MeZnCl.
References and Notes
(1) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67-76 and
references cited therein.
(2) Dell, C. P. in Science of Synthesis (Houben-Weyl); Vol. 10;
Thomas, E. J., Ed.; Thieme: Stuttgart, 2001, pp. 11-86.
Friedrichsen, W. in Comprehensive Heterocyclic Chemistry
II; Vol. 2; Katrizky, A. R.; Rees, C. W.; Scriven, E. F. V.,
Eds.; Pergamon: Oxford, 1996, pp. 351-393.
Röhrkasten, R.; Konrad M. In Houben-Weyl, 4th ed.; Vol. E
6b 1; Kreher, R., Ed.; Thieme: Stuttgart, 1994, pp. 33-162.
Donnelly, D. M. X.; Meegan, M. J. In Comprehensive
Heterocyclic Chemistry; Vol. 4; Katrizky, A. R.; Rees, C. W.,
Eds.; Pergamon: Oxford, 1984, pp. 657-712.
Cagniant, F.; Cagniant, D. Adv. Heterocycl. Chem. 1975, 18,
337-482.
The halogen-metal exchange reaction15 which can be car-
ried out at much lower temperature than any cross-cou-
pling was considered a viable alternative for the selective
substitution of one bromine atom in compounds 6. Indeed,
treatment of benzofuran 6a with tert-butyl lithium at
78 °C and subsequent quenching with water gave the
hydrodebrominated products in a ratio of 4:1. The prefer-
ential position at which the bromine-lithium exchange had
taken place was the 3-position and the major isomer con-
sequently was the 2-aryl-5-bromobenzofuran. Quenching
with methyl iodide was less selective presumably because
an equilibration takes place prior to the methylation. Still,
we succeeded in isolating the desired major product 3-me-
thylbenzofuran 7 in 54% yield (Scheme 3). In order to
convert this 5-bromobenzofuran into the natural product
eupomatenoid-15 (8) a final substitution at the 5-position
was required. Some optimization revealed that the Ni-cat-
alyzed cross-coupling of propenyl magnesium chloride
was a reliable and high-yielding method for the desired
transformation. As the Grignard reagent we used was not
stereochemically pure, a subsequent equilibration10 was
necessary to establish the correct E-configuration of the
product. The total yield of eupomatenoid-1516 starting
from the readily available 2,3,5-tribromobenzofuran 2
amounted to 27%.
Mustafa, A. In The Chemistry of Heterocyclic Compounds;
Vol. 29; Weissberger, A.; Taylor, E. C., Eds.; Wiley: New
York, 1973, pp. 1-142.
(3) Cugnon de Sevricourt, M.; Robba, M. Bull. Soc. Chim. Fr.
1977, 142-144.
(4) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org.
Chem. 1996, 61, 6244-6251.
(5) Bach, T.; Krüger, L. Tetrahedron Lett. 1998, 39, 1729-1732.
Bach, T.; Krüger, L. Synlett 1998, 1185-1186.
Bach, T.; Krüger, L. Eur. J. Org. Chem. 1999, 2045-2057.
(6) Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707-1710.
Bach, T.; Heuser, S. Angew. Chem. 2001, 113, in press.
(7) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1627-
1633.
(8) Cugnon de Sevricourt, M.; Robba, M. Bull. Soc. Chim. Fr.
1977, 139-141.
(9) McCredie, R. S.; Ritchie, E.; Taylor, W. C., Aust. J. Chem.
1969, 22, 1011-1032.
Bowden, B. F.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1972,
25, 2659-2669.
Synlett 2001, No. 8, 1284–1286 ISSN 0936-5214 © Thieme Stuttgart · New York

1286
T. Bach, M. Bartels
LETTER
Picker, K.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1973, 26,
1111-1119.
Read, R. W.; Taylor, W. C. Aust. J. Chem. 1979, 32, 2317-
2321.
for another 17 h at ambient temperature. Diethylether (20 mL)
was added and the solution was washed with 0.1% aqueous
hydrochloric acid (3 10 mL) and once with brine (10 mL).
The solvent was evaporated and the residue was purified by
column chromatography (eluent: pentane). 432 mg of
compound 3a (78%) were obtained. 1H NMR (CDCl3, 250
MHz): = 1.32 (s, 9 H), 7.18-7.42 (m, 4 H). 13C NMR (62.9
MHz, CDCl3): = 28.5 (s), 30.5 (q), 68.3 (s), 102.0 (d) 109.1
(s), 111.3 (d), 119.7 (d), 123.6 (d) 126.2 (d), 127.6 (s), 137.7
(s), 153.3 (s).
(10) For other synthetic approaches to eupomatenoids, see:
Ahmed, R.; Stevenson, R. Phytochemistry 1975, 14, 2710-
2712.
McKittrick, B. A.; Stevenson, R. J. Chem. Soc. Perkin Trans.
1 1983, 475-482.
Watanabe, M.; Date, M.; Kawanishi, K.; Hori, T.; Furukawa,
S. Chem. Pharm. Bull. 1991, 39, 41-48.
Engler, T. A.; Chai, W. Tetrahedron Lett. 1996, 37, 6969-
6970.
(14) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340-348.
Negishi, E.-i.; Liu, F. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, pp. 1-47.
(15) Schulze, V.; Brönstrup, M.; Böhm, V. P. W.; Schwerdtfeger,
P.; Schimeczek, M.; Hoffmann, R. W. Angew. Chem. Int. Ed.
Engl. 1998, 37, 824-826 and refs. cited therein.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470.
Sonogashira, K. In Comprehensive Organic Synthesis; Vol. 3;
Trost, B. M., Ed.; Pergamon: Oxford, 1991, pp. 521-549.
Sonogashira, K. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, pp. 203-229.
(16) 1H NMR (CDCl3, 250 MHz) data of compound 8: = 1.91
(dd, J = 6.4 Hz, J = 1.8 Hz, 3 H), 2.43 (s, 3 H), 3.87 (s, 3 H),
6.24 (dq, J = 15.9 Hz, J = 6.4 Hz, 1 H), 6.52 (dq, J = 15.9 Hz,
J = 1.8 Hz; 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 7.28 (dd, J = 8.5
Hz, J = 1.5 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 1 H), 7.44 (d, J = 1.5
Hz, 1 H), 7.74 (d, J = 8.8 Hz, 2 H).
(12) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.
(13) Represenative procedure: 2,3-Dibromobenzofuran (2.0 mmol,
552 mg), copper iodide (0.2 mmol, 38 mg) and PdCl2(PPh3)2
(0.1 mmol, 70 mg) were dissolved in 10 mL of THF. N,N-
Diethylamine (3.0 mmol, 220 mg, 0.31 mL) was added to the
stirred mixture at room temperature. A solution of tert-
butylacetylene (3.0 mmol, 246 mg) in 5 mL of THF was then
added within 1 h by syringe. The reaction mixture was stirred
Article Identifier:
1437-2096,E;2001,0,08,1284,1286,ftx,en;G08201ST.pdf
Synlett 2001, No. 8, 1284–1286 ISSN 0936-5214 © Thieme Stuttgart · New York