Flexible synthesis of fused benzofuran derivatives by rhodium-catalyzed [2 + 2 + 2] cycloaddition with phenol-linked 1,6-diynes

Article abstract of DOI:10.1021/ol900802d

A flexible and convenient synthesis of fused benzofuran derivatives has been achieved under mild reaction conditions by cationic rhodium(I)/ H8-BINAP complex-catalyzed [2 + 2 + 2] cycloadditions of phenol-linked 1,6-diynes with alkynes and nitriles.

Full text of DOI:10.1021/ol900802d

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2361-2364
Flexible Synthesis of Fused Benzofuran
Derivatives by Rhodium-Catalyzed
[2 + 2 + 2] Cycloaddition with
Phenol-Linked 1,6-Diynes
Yoshiyuki Komine, Akiyoshi Kamisawa, and Ken Tanaka*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo UniVersity
of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received April 13, 2009
ABSTRACT
A flexible and convenient synthesis of fused benzofuran derivatives has been achieved under mild reaction conditions by cationic rhodium(I)/
H8-BINAP complex-catalyzed [2 + 2 + 2] cycloadditions of phenol-linked 1,6-diynes with alkynes and nitriles.
Fused benzofuran derivatives are an important class of
compounds because of their utility in biologically active
Scheme 1
compounds including pharmaceutical ingredients.1 Therefore,
their convenient as well as flexible syntheses have attracted
much attention. Two methods for the construction of fused
benzofuran frameworks by metal-catalyzed or mediated
coupling reactions have been developed as shown in Scheme
1. One is the intramolecular O-arylation of hydroxybiphenyl
derivatives,2 and the other is the intramolecular dehaloge-
(1) For dibenzofuran derivatives, see: (a) Voigt, B.; Meijer, L.; Lozach,
O.; Scha¨chtele, C.; Totzke, F.; Hilgeroth, A. Bioorg. Med. Chem. Lett. 2005,
nation,3 dehydrohalogenation,4 dehydrocarboxylation,5 and
15, 823. For azadibenzofuran derivatives, see: (b) Oliveira, A. M. A. G.;
dehydrogenation6 of diaryl ether derivatives. However, these
reactions required harsh reaction conditions (high temperature
and basic or acidic conditions), and thus an alternative
Raposo, M. M. M.; Oliveira-Campos, A. M. F.; Machado, A. E. H.;
Puapairoj, P.; Pedro, M.; Nascimento, M. S. J.; Portela, C.; Afonso, C.;
Pinto, M. Eur. J. Med. Chem. 2006, 41, 367.
(2) (a) Liu, J.; Fitzgerald, A. E.; Mani, N. S. J. Org. Chem. 2008, 73,
2951. (b) Kawaguchi, K.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007, 72,
5119. (c) Martınez, A.; Ferna´ndez, M.; Estevez, J. C.; Estevez, R. J.;
Castedo, L. Tetrahedron 2005, 61, 1353. (d) Parmentier, M.; Gros, P.; Fort,
Y. Tetrahedron 2005, 61, 3261. (e) Yue, W. S.; Li, J. J. Org. Lett. 2002,
4, 2201.
(4) (a) Liu, Z.; Larock, R. C. Tetrahedron 2007, 63, 347. (b) Zhang,
Y.-M.; Razler, T.; Jackson, P. F. Tetrahedron Lett. 2002, 43, 8235.
(5) (a) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
4194. (b) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree, R. H.
Chem. Commun. 2008, 6312.
(3) Sanz, R.; Ferna´ndez, Y.; Castroviejo, M. P.; Perez, A.; Fanana´s, F. J.
J. Org. Chem. 2006, 71, 6291.
10.1021/ol900802d CCC: $40.75
Published on Web 05/08/2009
 2009 American Chemical Society

method that can be carried out under mild reaction conditions
(low temperature and neutral conditions) is highly desirable.
Our research group already demonstrated that cationic
rhodium(I)/biaryl bisphosphine complexes are highly effec-
tive catalysts for [2 + 2 + 2] cycloadditions, leading to
substituted benzenes and pyridines.7-10 In this paper, we
describe a flexible and convenient synthesis of fused ben-
zofuran derivatives by cationic rhodium(I)/H8-BINAP com-
plex-catalyzed [2 + 2 + 2] cycloadditions of phenol-linked
1,6-diynes11,12 with alkynes and nitriles (Scheme 2).13
Thus obtaining the targeted 1,6-diynes, a rhodium-
catalyzed [2 + 2 + 2] cycloaddition of 1,6-diyne 4a and
unsymmetrical monoyne 5a was attempted. Pleasingly, the
reaction proceeded to give the corresponding trisubstituted
dibenzofurans 6aa and 7aa in moerate yield by using a
cationic rhodium(I)/H8-BINAP complex as a catalyst,
although poor regioselectivity was observed (Table 1, entry
Table 1. Effect of Ligands on Yield and Regioselectivitya
Scheme 2
We first examined the synthesis of phenol-linked 1,6-
diynes. They could be readily prepared in three steps as
shown in Scheme 3. The reaction of a potassium salt of
entry
ligand
yield (%)b
6aa/7aa
1
2
3
4
H8-BINAP
BINAP
Segphos
dppb
56
35
33
16
39:61
34:66
61:39
31:69
a [Rh(cod)2]BF4 (0.0050 mmol), H8-BINAP (0.0050 mmol), 4a (0.10
mmol), 5a (0.20 mmol), and CH2Cl2 (2.0 mL) were used. b Determined by
1H NMR using 1,4-dimethoxybenzene as an internal standard.
Scheme 3
1). The use of other bisphosphine ligands significantly
decreased the product yields (entries 2-4).
The scope of dibenzofuran synthesis is shown in Table
2.15 Not only n-butyl-(4a) but also phenyl- and trimethylsilyl-
Table 2. Synthesis of Substituted Dibenzofurans by
RhodiumCatalyzed [2 + 2 + 2] Cycloadditionsa
2-iodophenol (1) with 1,1,2-trichloroethylene proceeded to
give aryl alkenyl ether 2 in 96% yield.14 Sonogashira
coupling between iodide 2 and terminal alkynes proceeded
to give phenol-linked 1,6-enynes 3 in excellent yields.
Treatment of 3 with n-butyl lithium at -40 °C formed
phenol-linked 1,6-diynes 4 in moderate to high yields.
entry
1
4 (R1)
5(R2, R3)
6/7 (% yield)b
(6) (a) Lee, B. D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022. (b) De Lombaert, S.; Blanchard, L.; Stamford, L. B.;
Tan, J.; Wallace, E. M.; Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.;
Moliterni, J.; Marcopoulos, N.; Savage, P.; Chou, M.; Trapani, A. J.; Jeng,
4a (n-Bu)
5a (Ph, CO2Et)
6aa (17)/7aa (32)
6ba/7ba (78, 6/7 )
66:34)
6ca (36)/7ca (36)
6bb (63)/7bb (19)
6bc (44)/7bc (24)
6bd (65)
2
4b (Ph)
4c (SiMe3) 5a (Ph, CO2Et)
5a (Ph, CO2Et)
3
A. Y. J. Med. Chem. 2000, 43, 488
(7) For our accounts, see: (a) Tanaka, K. Synlett 2007, 1977. (b) Tanaka,
K.; Nishida, G.; Suda, T. J. Synth. Org. Chem. Jpn. 2007, 65, 862
.
4
4b (Ph)
4b (Ph)
4b (Ph)
4a (n-Bu)
4c (SiMe3) 5d (CH2OH, CH2OH)
4b (Ph)
5b (Me, CO2Et)
5c (Me, CH2OH)
5d (CH2OH, CH2OH)
5d (CH2OH, CH2OH)
5
.
6c
7c
8c
9
(8) For the pioneering work on RhCl(PPh3)3-catalyzed [2 + 2 + 2]
cycloadditions of 1,6-diynes with monoynes, see: (a) Grigg, R.; Scott, R.;
Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1357. For the
6ad (48)
6cd (69)
5e (CH2OMe, CH2OMe) 6be (45)
stoichimetric reaction, see: (b) Müller, E. Synthesis 1974, 761
.
a [Rh(cod)2]BF4 (0.010 mmol), H8-BINAP (0.010 mmol), 4 (0.20
mmol), 5 (0.40 mmol), and CH2Cl2 (2.0 mL) were used. b Isolated yield.
c Solvent: THF.
(9) For a review of the rhodium-catalyzed [2 + 2 + 2] cycloadditions,
see: Fujiwara, M.; Ojima, I. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 7, p
129
.
2362
Org. Lett., Vol. 11, No. 11, 2009

substituted 1,6-diynes 4b and 4c could also participate in
this reaction (entries 1-3). With respect to monoynes, a
variety of functionalized monoynes 5b-e reacted with 4a-c
to give the corresponding trisubstituted dibenzofurans 6 and
7 in moderate to high yields (entries 4-9).
tion into [2 + 2 + 2] cycloadditions of those with nitriles,19,20
leading to substituted azadibenzofurans. Fortunately, acti-
vated nitrile 10a reacted with 1,6-diyne 4a to give the
corresponding meta-disubstituted azadibenzofuran 11aa in
good yield with excellent regioselectivity (Table 3, entry
Table 3. Effect of Ligands on Yield and Regioselectivitya
As we have recently reported that enol ethers can be used
as gaseous alkyne equivalents in the cationic rhodium(I)/
biaryl bisphosphine complex-catalyzed [2 + 2 + 2] cycload-
ditions,16,17 the use of enol ethers instead of monoynes was
investigated.15 The reaction of 4a with n-butyl vinyl ether
(8a) furnished monosubstituted dibenzofuran in moderate
yield (eq 1). In the reactions of 4a with 1,1-disubstituted
enol ether 8b and ketene acetal 8c, the corresponding meta-
disubstituted dibenzofurans were obtained with perfect
regioselectivities (eq 2).18
entry
ligand
yield (%)b
11aa/12aa
1
2
3
4
H8-BINAP
BINAP
Segphos
72
58
57
9
>98:2
>98:2
>98:2
>98:2
dppb
a [Rh(cod)2]BF4 (0.0050 mmol), H8-BINAP (0.0050 mmol), 4a (0.10
mmol), 10a (0.20 mmol), and CH2Cl2 (2.0 mL) were used. b Determined
1
by H NMR using 1,4-dimethoxybenzene as an internal standard.
1).21,22 The use of other bisphosphine ligands significantly
decreased the product yields (entries 2-4).
The present success in the [2 + 2 + 2] cycloadditions of
phenol-linked 1,6-diynes with monoynes or enol ethers,
leading to substituted dibenzofurans, prompted our investiga-
The scope of azadibenzofuran synthesis is shown in Table
4.15 Not only n-butyl- (entry 1) but also phenyl-substituted
(10) For recent reviews of transition-metal-catalyzed [2 + 2 + 2]
cycloadditions, see: (a) Tanaka, K. Chem. Asian J. 2009, 4, 508. (b) Shibata,
T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 1317. (c) Agenet, N.; Buisine,
O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. Organic Reactions;
RajanBabu, T. V., Ed.; John Wiley & Sons: Hoboken, 2007; Vol. 68, p 1.
(d) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209. (e)
Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (f)
Gandon, V.; Aubert, C.; Malacria, M. Curr. Org. Chem. 2005, 9, 1699. (g)
Table 4. Synthesis of Substituted Azadibenzofurans by
RhodiumCatalyzed [2 + 2 + 2] Cycloadditionsa
Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503
.
(11) [2 + 2 + 1] Cycloadditions of ynol ethers with Fe(CO)5 giving Fe
complexes of 3-oxocyclopentadienes and subsequent cycloadditions of those
with alkynes were reported; see: Imbriglio, J. E.; Rainier, J. D. Tetrahedron
Lett. 2001, 42, 6987
.
(12) For rhodium(I)-catalyzed [2 + 2 + 2] cycloadditions of diynes with
alkynyl ethers, see: (a) Clayden, J.; Moran, W. J. Org. Biomol. Chem. 2007,
5, 1028. (b) Alayrac, C.; Schollmeyer, D.; Witulski, B. Chem. Commun.
2009, 1464
.
(13) For the pioneering works on the syntheses of substituted indolines
and carbazoles by RhCl(PPh3)3-catalyzed [2 + 2 + 2] cycloadditions using
nitrogen-bridged 1,6-diynes, see: (a) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. 1999, 38, 2426. (b) Witulski, B.; Alayrac, C. Angew. Chem., Int.
Ed. 2002, 41, 3281. (c) See also ref 12b. For cobalt or iron-mediated formal
[2 + 2 + 2] cycloadditions using nitrogen-bridged 1,6-diynes, see: (d)
Rainier, J. D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7275. (e) Rainier,
J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037. For iridium(I)/PPh3-catalyzed
analogous [2 + 2 + 2] cycloadditions of silicon-bridged 1,6-diynes with
monoynes, leading to substituted siloles, see: (f) Matsuda, T.; Kadowaki,
S.; Goya, T.; Murakami, M. Org. Lett. 2007, 9, 133
(14) For the synthesis of an O-ethynyl-2-naphthol derivative, see:
Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987, 52, 2919
.
.
(15) Homo-[2 + 2 + 2] cycloadditions of 1,6-diynes 4 proceeded other
a [Rh(cod)2]BF4 (0.010 mmol), H8-BINAP (0.010 mmol), 4 (0.20
mmol), 10 (0.40 mmol), and CH2Cl2 (2.0 mL) were used. b Isolated yield.
than the desired cross-[2 + 2 + 2] cycloadditions.
(16) Hara, H.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 2537
.
(17) For the pioneering work on a transition-metal-catalyzed [2 + 2 +
2] cycloaddition of a 1,6-diyne with an enol ether, see: Kezuka, S.; Tanaka,
S.; Ohe, T.; Nakaya, Y.; Takeuchi, R. J. Org. Chem. 2006, 71, 543
.
(18) In the reaction of 4a and 8b, the choice of biaryl bisphosphine
ligands did not affect the product yield and regioselectivity. [Yields of 9ab
determined by 1H NMR using 1,4-dimethoxybenzene as an internal standard:
34% (H8-BINAP), 34% (BINAP), 33% (Segphos)].
1,6-diyne 4b could participate in this reaction furnishing the
corresponding meta-disubstituted azadibenzofuran in good
yield with excellent regioselectivity (entry 2).21,22 On the
Org. Lett., Vol. 11, No. 11, 2009
2363

other hand, the reaction of trimethylsilyl-substituted 1,6-diyne
4c with 10a furnished desilylated product 13ca along with
ortho-disubstituted product 12ca in moderate yield (entry 3).
With respect to nitriles, a variety of activated (10b-d) and
unactivated (10e and 10f) nitriles reacted with 4a-c to give
the corresponding meta-disubstituted azadibenzofurans 11 or
desilylated product 13ce in fair to high yields with excellent
regioselectivities (entries 4-10).21,22
In conclusion, we have achieved a flexible and convenient
synthesis of fused benzofuran derivatives by cationic rhod-
ium(I)/H8-BINAP complex-catalyzed [2 + 2 + 2] cycload-
ditions with phenol-linked 1,6-diynes. Applications of the
present catalysis in the synthesis of ladder-type and helically
chiral molecules are currently underway in our laboratory.
A possible mechanism for the highly regioselective [2 +
2 + 2] cycloadditions of phenol-linked 1,6-diynes 4 with
enol ethers 8 and nitriles 10 is shown in Scheme 4. Oxidative
Scheme 4
Acknowledgment. This work was supported partly by a
Grant-in-Aid for Scientific Research (No. 20675002) from
MEXT, Japan. We are grateful to Takasago International
Corporation for the gift of H8-BINAP and Segphos, and
Umicore for generous supports in supply of a rhodium
complex.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900802D
(20) For recent reviews involving the synthesis of nitrogen heterocycles
by transition-metal-catalyzed [2 + 2 + 2] cycloadditions, see: (a) Varela,
J. A.; Saa´, C. Synlett 2008, 2571. (b) Hess, W.; Treutwein, J.; Hilt, G.
Synthesis 2008, 3537. (c) Heller, B.; Hapke, M. Chem. Soc. ReV. 2007, 36,
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Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (f) Varela, J. A.;
Saa´, C. Chem. ReV. 2003, 103, 3787.
coupling of two alkyne moieties of 4 with rhodium leads to
rhodacyclopentadiene intermediate A. Regioselective inser-
tions of the double bond of 8 and the cyano group of 10
between the sterically less demanding rhodium-carbon bond
furnish intermediates B and C, respectively. The electroni-
cally negative sp2 carbon atom ꢀ to the methoxy group of 8
and the nitrogen atom of 10 preferentially form the bonds
with the cationic rhodium. Reductive eliminations furnish
dibenzofuran 9 and azadibenzofuran 11, respectively.
Finally, the reaction of 4a with isocyanate 14 was
investigated, which revealed that the expected 2-pyridone-
fused benzofuran 15 was obtained in good yield as a single
regioisomer (eq 3).15,23 The observed high regioselectivity
can be explained by preferential bond formation of nitrogen
atom of 14 with the cationic rhodium, which is similar to
the mechanism shown in Scheme 4.
(21) Similar regioselectivities were observed in ruthenium- and cobalt-
catalyzed [2 + 2 + 2] cycloadditions of unsymmetrical 1,6-diynes with
nitriles. For Ru(II), see: (a) Yamamoto, Y.; Kinpara, K.; Ogawa, R.;
Nishiyama, H.; Itoh, K. Chem.-Eur. J. 2006, 12, 5618. (b) Yamamoto,
Y.; Kinpara, K.; Nishiyama, H.; Itoh, K. AdV. Synth. Catal. 2005, 347,
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S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (d)
Yamamoto, Y.; Okuda, S.; Itoh, K. Chem. Commun. 2001, 1102. (e)
Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6189.
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AdV. Synth. Catal. 2008, 350, 143. (g) Kase, K.; Goswami, A.; Ohtaki, K.;
Tanabe, E.; Saino, N.; Okamoto, S. Org. Lett. 2007, 9, 931. (h) Hrdina, R.;
Stara`, I.; Dufkova`, L.; Mitchel, S.; Cisarova`, I.; Kotora, M. Tetrahedron
2006, 62, 968. (i) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.;
Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew. Chem., Int. Ed.
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(22) The regioisomeric ortho-disubstituted azadibenzofurans 12 were
not generated at all or generated in only trace amounts (<3% yields).
(23) For cationic rhodium(I)/biaryl bisphosphine complex-catalyzed [2
+ 2 + 2] cycloadditions of alkynes with isocyanates, see: (a) Tanaka, K.;
Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737. (b) Tanaka, K.; Takahashi,
Y.; Suda, T.; Hirano, M. Synlett 2008, 1724. For neutral rhodium(I)
complex-catalyzed [2 + 2 + 2] cycloadditions of alkynes with isocyanates,
see: (c) Flynn, S. T.; Hasso-Henderson, S. E.; Parkins, A. W. J. Mol. Catal.
1985, 32, 101. (d) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782.
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+ 2 + 2] cycloadditions of alkynes with nitriles, see: (a) Tanaka, K.; Suzuki,
N.; Nishida, G. Eur. J. Org. Chem. 2006, 3917. (b) Wada, A.; Noguchi,
K.; Hirano, M.; Tanaka, K. Org. Lett. 2007, 9, 1295. (c) Tanaka, K.; Hara,
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(d) Cioni, P.; Diversi, P.; Ingrosso, G.; Lucherini, A.; Ronca, P. J. Mol.
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