Synthesis of 2,3-disubstituted benzofurans by platinum olefin-catalyzed carboalkoxylation of o-alkynylphenyl acetals

Article abstract of DOI:10.1021/ja055202f

The PtCl₂-catalyzed cyclization reaction of o-alkynylphenyl acetals 1 in the presence of 1,5-cyclooctadiene produces 3-(α-alkoxyalkyl)benzofurans 2 in good to high yields. For example, the reaction of acetaldehyde ethyl 2-(1-octynyl)phenyl acetal (1a), acetaldehyde ethyl 2-(cyclohexylethynyl)phenyl acetal (1c), and acetaldehyde ethyl 2-(phenylethynyl)phenyl acetal (1f) in the presence of 2 mol % of platinum(II) chloride and 8 mol % of 1,5-cyclooctadiene in toluene at 30 °C gave the corresponding 2,3-disubstituted benzofurans 2a, 2c, and 2f in 91, 94, and 88% yields, respectively. Copyright

Full text of DOI:10.1021/ja055202f

Published on Web 10/08/2005
Synthesis of 2,3-Disubstituted Benzofurans by Platinum-Olefin-Catalyzed
Carboalkoxylation of o-Alkynylphenyl Acetals
Itaru Nakamura, Yuya Mizushima, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received August 1, 2005; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Table 1. Carboalkoxylation of 1a Catalyzed by the
Platinum-Olefin Systema
It is well known that the transition metal-catalyzed annulation
of o-alkynylarylamines, alcohols, and other derivatives produces
the corresponding heterocycles and carbocycles in high yields (eq
1).1 Furthermore, it is becoming popular that the 2,3-disubstituted
indoles and benzofurans shown in eq 2 can be synthesized from
o-alkynylanilines, phenols, and their derivatives through the external
addition of organopalladium species to the triple bond (eq 2).2
However, intramolecular annulation accompanied by migration of
the second functional group Y, attached to the first functional group
X, is rare (eq 3).3-6 This type of sequential addition of the two
functional groups is important from a synthetic point of view, since
2,3-disubstituted indoles (n ) 0, R at C2, Y at C3, X ) N) and
benzofurans (n ) 0, X ) O) constitute an often valuable structural
framework of biologically active natural products.7 Previously, the
synthesis of indoles (R at C2, allyl at C3, ref 3; or R at C2, acyl at
C3, ref 4) and benzofurans (R at C2, allyl at C3, ref 5; or R at C2,
propargyl/allenyl at C3, ref 6) was accomplished through reaction
of the type shown in eq 3. We report that the PtCl2-catalyzed
cyclization reaction of o-alkynylphenyl acetals 1 in the presence
of 1,5-cyclooctadiene (COD) produces 3-(R-alkoxyalkyl)benzo-
furans 2 in good to high yields (eq 4).8
olefin
yield of
2a/%b
recovery
entry
Pt
(mol %)
of 1a/%b
1
2
3
4
5
6
7
8
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2(cod)
COD (8)
none
93 (91)c
24
90
84
51
50
40
0
68
trace
16
48
50
1-hexene (16)
cyclooctene (16)
â-pinene (16)
norbornadiene (8)
styrene (16)
none
60
quant.
a The reaction of 1a (0.3 mmol) was carried out in the presence of 2
mol % of PtCl2 and olefin in toluene at 30 °C for 1 h. b The yield was
determined by 1H NMR using 1,4-dioxane as an internal standard. c Isolated
yield.
Table 2. Platinum-Catalyzed Carboalkoxylation of o-Alkynylphenyl
Acetals 1a
entry
1
R1
R2
R3
time/h
2
yield/%b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
1h
1i
n-Hex
(CH2)4Cl
cyclohexyl
t-Bu
p-(MeO)C6H4
Ph
p-(CF3)C6H4
n-Pr
Ph
Et
Et
Et
Et
Et
Et
Et
Me
Me
Bn
Bn
TBS
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
1
1
2.5
24
24
2a
2b
2c
2d
2e
2f
2g
2h
2i
91
92
94
trace
90
88
61
92
73
94
83
61
3
4 days
22
24
20
48
8c
9c
10d
11d
12e
1j
1k
1l
n-Pr
Ph
Ph
2j
2k
2l
4 days
a The reaction of 1 was carried out in the presence of 2 mol % of PtCl2
and 8 mol % of COD in toluene at 30 °C. b Isolated yield. c 20 mol % of
PtCl2 and 80 mol % of COD were used. d 10 mol % of PtCl2 and 40 mol
% of COD were used. e 100 mol % of PtCl2 and 80 mol % of COD were
used.
PtBr2, PtI2, K2PtCl4, PdCl2, NiCl2, Yb(OTf)3, [RhCl(cod)]2, and
Pd(PPh3)4, also did not promote the reaction. The reaction of 1a
using acetonitrile as solvent produced 2a in 60% yield along with
a small amount of unknown byproducts. The results of the reaction
of 1 are summarized in Table 2. The reaction of substrates bearing
4-chlorobutyl (1b) and cyclohexyl (1c) groups at the alkynyl
terminus proceeded very smoothly, while the reaction of 1d having
a tert-butyl group was sluggish (entries 2-4). The reaction of 1e,
which had an electron-rich aromatic group at the R1 position, gave
the desired product in a high yield, while the reaction of 1g, which
had an electron-deficient aromatic group, proceeded slowly, produc-
ing 2g in a moderate yield (entries 5-7). The reaction of the MOM
ethers (1h and 1i) and the BOM ethers (1j and 1k) proceeded
smoothly with use of slightly higher amounts of the platinum
catalyst (entries 8-11); the reaction of 1h using 2 mol % of PtCl2
and 8 mol % of COD proceeded very slowly and it took 5 days,
giving 2h in 50% yield along with 50% yield of recovered 1h.9
The reaction of acetaldehyde ethyl o-(1-octynyl)phenyl acetal
1a in the presence of 2 mol % of PtCl2 and 8 mol % of COD in
toluene proceeded at 30 °C, and 1 h later 3-(1-ethoxyethyl)-2-
hexylbenzofuran 2a was produced in 91% yield (Table 1, entry 1).
The use of COD as an additive is very important for facilitating
this migration, as shown in Table 1. The reaction in the absence of
COD gave 2a in 24% yield (entry 2). The reaction using 1-hexene
or cyclooctene, instead of COD, gave 2a in a similar yield, while
the use of â-pinene, norbornadiene, or styrene resulted in lower
yields (entries 3-7). Interestingly, PtCl2(cod) did not promote the
reaction at all (entry 8). Other transition metal complexes, such as
9
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J. AM. CHEM. SOC. 2005, 127, 15022-15023
10.1021/ja055202f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Plausible Mechanism
Scheme 2. Synthesis of Vibsanol Precursor 11 via
Carboalkoxylationa
The reaction of TBS ether 1l was promoted by the use of a
stoichiometric amount of the platinum catalyst (entry 12). The
reaction of 1m bearing a THP group did not proceed at all. The
benzyl ether 2k and TBS ether 2l were converted to the corre-
sponding aldehyde 3 and alcohol 4 in good yields, respectively (eqs
5 and 6).
a Reagents and conditions: (a) BOMCl, NaH, THF, 0 °C, quantitative;
(b) [4-(1-ethoxyethyl)-3-methoxyphenyl]acetylene, Pd(PPh3)4,CuI, Et3N,
THF, room temperature, 64%; (c) 20 mol % PtCl2, 80 mol % COD, toluene,
30 °C, 76%.
(Scheme 2). Accordingly, a formal synthesis of 8 was accomplished
through platinum-olefin-catalyzed carboalkoxylation methodology.
In conclusion, we are in a position to synthesize 3-(R-alkoxy-
alkyl)-2-substitued benzofurans in an efficient and atom-eco-
nomic manner. The present result suggests that a cation-stabil-
izing group Y may undergo transition metal-catalyzed intramo-
lecular 1,3-transfer from X to the C3 position of the heterocycles
containing X. We are now investigating the full scope of this type
of transformation.
Supporting Information Available: Experimental details and NMR
spectra of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(5) Palladium(0)-catalyzed endo-cyclization: (a) Cacchi, S.; Fabrizi, G.; Moro,
L. Synlett 1998, 741. (b) Monterio, N.; Balme, G. Synlett 1998, 746. PtCl2-
catalyzed exo-cyclization: (c) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am.
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A plausible mechanism for the platinum-catalyzed reaction of 1
is illustrated in Scheme 1. Platinum chloride is coordinated by the
triple bond of the substrate 1. Nucleophilic attack of the oxygen
atom of the phenyl acetal moiety of 5 would give the cyclized
intermediate 6. Migration of the R-alkoxyalkyl group of 6 to the
carbon bonded to platinum atom would produce the intermediate
7. Elimination of platinum chloride gives the product 2. COD
probably works as an activating agent to disconnect Pt-Cl bonds
of polymeric platinum chloride and to generate a reactive platinum
catalyst.10 However, since PtCl2(cod) itself did not promote the
present reaction at all, a real active species might be a platinum
oligomer (Table 1, entry 8).
We applied the present reaction for the synthesis of vibsanol 8,
which was isolated from Viburnum awabuki. It is well known that
(8) After submitting this paper, we became aware that research closely related
to our work was going on in Fu¨rstner’s laboratory. Fu¨rstner, A.; Davies,
P. W. J. Am. Chem. Soc. 2005, 127, 15024.
(9) The reaction of N-methoxymethyl-N-tosyl-2-(1-pentynyl)aniline in the
presence of catalytic amounts of PtCl2 and COD gave the monosubstituted
indole, 2-propyl-N-tosylindole, in 9% yield. A similar migration did not
work well for a nitrogen analogue (X ) N, Y ) CH2OCH3 in eq 3)
(10) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima, Y.;
Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423.
(11) Fukuyama, Y.; Nakahara, M.; Minami, H.; Kodama, M. Chem. Pharm.
Bull. 1996, 44, 1418.
8 works as an inhibitor of lipid peroxidation.11,12 The precursor of
carboalkoxylation, o-alkynylaryl benzyl acetal 10, was synthesized
from the o-iodophenol 9, prepared from iodovaniline according to
the reported procedures.12 The carboalkoxylation of 10 proceeded
smoothly, giving the desired vibsanol precursor 11 in 76% yield
(12) (a) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999, 40, 4211.
(b) Sasai, A.; Aoyama, T.; Shioiri, T. Heterocycles 2000, 52, 643.
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