Phosphazene base-catalyzed intramolecular cyclization for efficient synthesis of benzofurans via carbon-carbon bond formation

Article abstract of DOI:10.1039/b913588j

An organic superbase, phosphazene P4-^tBu, functioned as an active catalyst for intramolecular cyclization of o-alkynylphenyl ethers via carbon-carbon bond formation to provide an efficient synthetic method for 2,3-disubstituted benzofurans deri

Full text of DOI:10.1039/b913588j

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Phosphazene base-catalyzed intramolecular cyclization for efficient
synthesis of benzofurans via carbon–carbon bond formationw
Chikashi Kanazawa, Kengo Goto and Masahiro Terada*
Received (in College Park, MD, USA) 8th July 2009, Accepted 23rd July 2009
First published as an Advance Article on the web 7th August 2009
DOI: 10.1039/b913588j
An organic superbase, phosphazene P4-tBu, functioned as an
active catalyst for intramolecular cyclization of o-alkynylphenyl
ethers via carbon–carbon bond formation to provide an efficient
synthetic method for 2,3-disubstituted benzofurans derivatives
under mild reaction conditions without the need for a metal
catalyst.
enables efficient access to substituted benzofuran derivatives
without the need for a metal catalyst.
We began by investigating the catalytic cyclization reaction
of o-alkynylphenyl benzyl ether (1a) in the presence of a base
catalyst. As shown in Table 1, P4-tBu acts as an efficient and
unique catalyst in the present cyclization reaction.7 For
example, the reaction of 1a in the presence of P4-tBu
(10 mol%) in DMSO at 30 1C afforded the desired benzofuran
derivative (2a) in excellent yield (Table 1, entry 1). A screening
of other bases, such as KHMDS, nBuLi, and tBuONa, demon-
strated that these typical strong bases did not promote the
reaction at all, or as efficiently, under the same reaction
conditions (entries 2–4). The phosphazene base P1-tBu, which
is less basic than P4-tBu, was also ineffective (entry 5). Further
screening of other solvents revealed that their basicity is more
important in promoting the reaction efficiently than the
Alkynylbenzene derivatives having a nucleophilic site at the
ortho-position are widely utilized as efficient precursors for
constructing heterocyclic compounds. The intramolecular
cyclization reaction of o-alkynylphenols or o-alkynylphenyl
ethers via a carbon–oxygen bond (C–O) formation is one of
most simple and efficient methods for preparing benzofurans
(Scheme 1a),1–3 a very important class of heterocycles, as
versatile building blocks for naturally occurring and bio-
logically active compounds. A number of methodologies using
bases or transition metal catalysts have been established on
the basis of C–O cyclization. However, to the best of our
knowledge, there have been no previous reports on benzofuran
syntheses from alkynylbenzene derivatives via carbon–carbon
bond (C–C) cyclization (Scheme 1b),4,5 as an alternative
strategy (Scheme 1a). Herein we report catalytic intramolecular
cyclization of o-alkynylphenyl ethers via C–C forming
reactions to provide 2,3-disubstituted benzofuran derivatives
in high yields (Scheme 1b). The present unprecedented
cyclization was successfully demonstrated using an organic
superbase, phosphazene P4-tBu, as the catalyst.6 The method
8,9
polarity of the solvents employed;z the reaction proceeded
smoothly in basic solvents such as DMSO and DMF (entries 1
and 8), while in less basic solvents, such as THF or MeCN, the
reaction resulted in much less or nil product formation
(entries 6 and 7). The system with P4-tBu as the catalyst and
DMSO as the solvent accelerated the cyclization reaction
Table 1 Catalytic intramolecular cyclization of 1aa
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9c
P4-tBu
KHMDS
nBuLi
DMSO
DMSO
DMSO
DMSO
DMSO
THF
CH3CN
DMF
DMSO
95
20
No reaction
No reaction
No reaction
9
Scheme 1 Intramolecular cyclization of o-alkynylphenyl ethers.
tBuONa
P1-tBu
P4-tBu
P4-tBu
P4-tBu
P4-tBu
No reaction
89
Department of Chemistry, Graduate School of Science,
Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
E-mail: mterada@mail.tains.tohoku.ac.jp; Fax: +81-22-795-6602;
Tel: +81-22-795-6602
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of relevant compounds. See
DOI: 10.1039/b913588j
(95)d
a
Unless otherwise noted, all reactions were carried out using 10 mol%
c
of base at 30 1C for 1 h. b 1H NMR yield. 5 mol% of P4-tBu.
Isolated yield.
d
ꢀc
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efficiently10 and allowed the catalyst loading to be reduced to
5 mol% without compromising the chemical yield (entry 9).
overreaction between the nitrile moiety of 2k and intermediary
carbanion species (entry 4).y A variety of R4 substituents were
tolerated at the alkynyl terminus in the present cyclization
reaction (entries 5–8). The corresponding products were
obtained in good yield, irrespective of the electronic properties
of the aryl groups (entries 5 and 6). It is noteworthy that
substrates having both alkenyl and alkyl groups were good
candidates for the present catalytic reactions (entries 7 and 8).
Finally, we applied the present catalytic method to a
vinylogous analogue of 1a, that is, o-alkynylphenyl allyl ether
(1p) (eqn (1)), and 3, which has a methine carbon at the alkoxy
group (eqn (2)). Unfortunately, the reaction of the vinylogous
1p yielded an oligomeric product under standard reaction
conditions. However, this problem could be circumvented by
addition of excess water11 and the desired product (2p) was
obtained in good yield (eqn (1)). On the other hand, the
reaction of 3 yielded geometrical mixtures of 3-benzylidene-
2,3-dihydrobenzofurans (4) with a quaternary carbon atom
(eqn (2)). In the reaction of 3a (R3 = Ph), relatively harsh
conditions, including high catalyst loading, high temperature,
and prolonged reaction, were required to obtain the corres-
ponding product (4a) in good yield. Without any additive,
moderate (E)-selectivity (E : Z = 2 : 1) was observed, while
Having identified suitable reaction conditions and
a
promising catalyst, P4-tBu, we next investigated the scope
and limitations of the present cyclization reaction (Table 2).
Both electron-donating and electron-withdrawing aryl groups
were tolerated for the substituents (R3) at the alkoxy terminus
(entries 1 and 2), although higher reaction temperature and
catalyst loading were required in the reaction of 1c bearing the
electron-donating p-methoxyphenyl substituent (entry 2). In
contrast, the sterically demanding 1-naphthyl substituent was
applicable without any difficulties (entry 3). Further investi-
gation of the R4 substituent at the alkynyl terminus revealed
that the electron-donating p-methoxyphenyl and the sterically
hindered 1-naphthyl substituents promoted the attainment of
the corresponding benzofurans in high yields (entries 4 and 5).
However, the reaction of the alkyl substituted 1g resulted in a
complex mixture (entry 6).
Table 2 P4-tBu-catalyzed intramolecular cyclization of various 1a
t
addition of excess BuOH resulted in the formation of the
opposite (Z)-isomer as the major product (E : Z = 1 : 3.5),
albeit with low chemical yield.7,11 In contrast, the reaction of
3b (R3 = CO2Et) proceeded smoothly under the standard
reaction conditions to give (Z)-4b predominantly (E : Z = 1 : 4).
The (Z)-selectivity could be improved (E : Z = 1 : 25) by
adding excess ethanol, although elevated temperature and a
prolonged reaction period were required to achieve high
chemical yield.7,11
Entry
1
R3
R4
2
Yieldb (%)
1c
2d
3
4
5
1b
1c
1d
1e
1f
p-O2NC6H4
p-MeOC6H4
1-Naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
2b
2c
2d
2e
2f
62
72
89
91
p-MeOC6H4
1-Naphthyl
nPr
86
e
6
1g
2g
a
Unless otherwise noted, all reactions were carried out using 5 mol%
b
of P4-tBu at 30 1C for 1–3 h in DMSO (1.0 M). Isolated yield.
c
d
10 mol% of P4-tBu. 15 mol% of P4-tBu. At 100 1C for 6 h.
Complex mixture.
e
ð1Þ
The present catalytic cyclization can also be applied to
o-alkynylphenyl ethers having carbonyl groups at the alkoxy
terminus (R3). As shown in Table 3, the P4-tBu catalyst
exhibited excellent performance for these substrates and
the corresponding products were obtained in high yields
(entries 1–3), with the exception of the nitrile substituent,
which gave the product (2k) in low yield as a result of
ð2Þ
Table 3 Intramolecular cyclization of 1 having carbonyl groups at
the alkoxy terminusa
Entry
1
R3
R4
2
Yieldb (%)
1
2
3
4
5
6
7
8c
1h
1i
1j
1k
1l
1m
1n
1o
CO2Et
CO2 Bu
COPh
CN
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Ph
Ph
Ph
2h
2i
2j
2k
2l
2m
2n
2o
86
70
76
14
88
87
83
59
t
A plausible mechanism of the P4-tBu-catalyzed cyclization is
depicted in Fig. 1. Deprotonation of 1 by P4-tBu to generate
anion A, followed by 5-exo intramolecular cyclization, would
give vinyl anion intermediate B.10 Subsequent protonation of
B would take place by the conjugate acid [P4-tBuH]+, as
supported by the catalytic reaction proceeding smoothly even
in DMF (Table 1, entry 8), although DMSO or the substrate
(1), having a carbonyl group at the alkoxy terminus, cannot be
p-MeOC6H4
p-CF3C6H4
1-Cyclohexenyl
nPr
a
Unless otherwise noted, all reactions were carried out using 5 mol%
b
of P4-tBu at 30 1C for 1–2 h in DMSO (1.0 M). Isolated yield.
c
15 mol% of P4-tBu. At 100 1C for 6 h.
ꢀc
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Chem. Commun., 2009, 5248–5250 | 5249

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ruled out as the proton source. The protonation provides the
intermediate C while also regenerating P4-tBu for further
catalytic cycles. Heteroaromatization of C finally gives the
benzofuran (2).
of Synthesis, ed. E. J. Thomas, Georg Thieme Verlag, Stuttgart,
2000, vol. 10, p. 11.
2 For recent studies on intramolecular cyclization reactions of
´
´
o-alkynylphenols, see: (a) C. Martınez, R. Alvarez and
J. M. Aurrecoechea, Org. Lett., 2009, 11, 1083; (b) Z. Liang,
S. Ma, J. Yu and R. Xu, Tetrahedron, 2007, 63, 12877;
(c) B. M. Trost and A. McClory, Angew. Chem., Int. Ed., 2007,
46, 2074; (d) R. Bernini, S. Cacchi, I. D. Salve and G. Fabrizi,
Synthesis, 2007, 873; (e) M. Nakamura, L. Ilies, S. Otsubo and
E. Nakamura, Angew. Chem., Int. Ed., 2006, 45, 944; (f) Y. Hu,
K. J. Nawoschik, Y. Liao, J. Ma, R. Fathi and Z. Yang, J. Org.
Chem., 2004, 69, 2235; (g) Y. Hu, Y. Zhang, Z. Yang and R. Fathi,
J. Org. Chem., 2002, 67, 2365. See also: (h) G. Zeni and
R. C. Larock, Chem. Rev., 2006, 106, 4644.
3 For intramolecular cyclization reactions of o-alkynylphenyl ether
derivatives, see: (a) F. Manarin, J. A. Roehrs, R. M. Gay,
R. Brandao, P. H. Menezes, C. W. Nogueira and G. Zeni,
J. Org. Chem., 2009, 74, 2153; (b) I. Nakamura, Y. Mizushima,
U. Yamagishi and Y. Yamamoto, Tetrahedron, 2007, 63, 8670;
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¨
15024; (d) I. Nakamura, Y. Mizushima and Y. Yamamoto, J. Am.
Chem. Soc., 2005, 127, 15022; (e) S. Cacchi, G. Fabrizi and
L. Moro, Tetrahedron Lett., 1998, 39, 5101–5104;
(f) N. Monteiro and G. Balme, Synlett, 1998, 746; (g) S. Cacchi,
G. Fabrizi and L. Moro, Synlett, 1998, 741.
4 For benzofuran syntheses starting from o-carbonylphenyl ether
derivatives, see: (a) J. Li, T. S. Rush, III, W. Li, D. DeVincentis,
X. Du, Y. Hu, J. R. Thomason, J. S. Xiang, J. S. Skotnicki,
S. Tam, K. M. Cunningham, P. S. Chockalingam, E. A. Morris
and J. I. Levin, Bioorg. Med. Chem. Lett., 2005, 15, 4961;
(b) K. K. Park and J. Jeong, Tetrahedron, 2005, 61, 545;
(c) G. A. Kraus, N. Zhang, J. Verkade, M. Nagarajan and
P. Kisanga, Org. Lett., 2000, 2, 2409.
5 Rh-catalyzed dihydropyran synthesis through C–C formation:
D. Shikanai, H. Murase, T. Hata and H. Urabe, J. Am. Chem.
Soc., 2009, 131, 3166.
Fig. 1 Plausible catalytic cycles.
6 (a) R. Schwesinger and H. Schlemper, Angew. Chem., Int. Ed.
Engl., 1987, 26, 1167; (b) R. Schwesinger and C. Hasenfratz,
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Chem., 1996, 1055.
In conclusion, we have demonstrated a novel efficient
synthetic method for substituted benzofurans starting from
o-alkynylphenyl ethers. The use of P4-tBu as the catalyst in
DMSO as a solvent is crucial for the present unprecedented
reaction, which enables cyclization via carbon–carbon bond
formation. Further application of the present method is in
progress with the aim of developing efficient syntheses of not
only heterocyclic compounds but also carbocyclic varieties.
We acknowledge Research Fellowships from the Japan
Society for the Promotion of Science for Young Scientists (C.K.).
7 Recently we found that a catalytic amount of P4-tBu efficiently
accelerated the 5-exo specific intramolecular cyclization reaction of
o-alkynylbenzamides, providing isoindolinone derivatives having
the exo-vinylidene moiety, in which the presence/absence of a
protic additive, water in this case, was found to be crucial in
controlling the geometry at the exo-double bond, see:
C. Kanazawa, M. Terada, to be submitted.
8 For normalized donor numbers (DNN), see: Y. Murcus, J. Solution
Chem., 1984, 13, 599.
Notes and references
z Normalized donor numbers (DNN) of the solvents employed:
DMSO: 0.768, DMF: 0.686, THF: 0.515, CH3CN: 0.363, see ref. 8.
Normalized solvent polarity values (ENT) of the solvents employed:
DMSO: 0.444, DMF: 0.404, THF: 0.207, CH3CN: 0.460, see ref. 9.
y Mass spectroscopic analysis of crude mixtures obtained from the
reaction of 1k exhibited molecular ion peaks at nearly, but not exactly,
twice as much as the molecular mass of 2k, although we have not
determined yet the structures of these dimeric side-products.
9 For normalized solvent polarity values (ENT ), see: (a) C. Reichardt
and E. Harbusch-Gornert, Liebigs Ann. Chem., 1983, 721;
¨
(b) C. Laurence, P. Nicolet and C. Reichardt, Bull. Soc. Chim.
Fr., 1987, 125.
10 T. Imahori, C. Hori and Y. Kondo, Adv. Synth. Catal., 2004, 346,
1090.
11 A protic additive, H2O or EtOH, was employed as an efficient
proton source for quenching a reactive carbanion (B). Also see:
(a) C. Kanazawa and M. Terada, Tetrahedron Lett., 2007, 48, 933;
(b) M. Terada, C. Kanazawa and M. Yamanaka, Heterocycles,
2007, 74, 819.
1 For reviews on benzofuran syntheses, see: (a) Methoden Der
Organischen Chemie (Houben-Weyl), ed. R. P. Kreher, Georg
Thieme Verlag, Stuttgart, 1994, vol. E6b, p. 33; (b) Science
ꢀc
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5250 | Chem. Commun., 2009, 5248–5250