Phase-transfer-catalyzed intramolecular cyclization of ortho-alkynyl phenyl ether derivatives for synthesis of 2,3-disubstituted benzo[b]furans

Article abstract of DOI:10.1002/adsc.200900649

A variety of substituted benzo[b]furans are readily prepared in good to excellent yields under the mild reaction conditions from o-(1-alkyn-ylphenoxy)- 1-phenylethanone under phase-transfer catalysis (PTC). This methodology accommodates simple experimenta

Full text of DOI:10.1002/adsc.200900649

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DOI: 10.1002/adsc.200900649
Phase-Transfer-Catalyzed Intramolecular Cyclization of
ortho-Alkynyl Phenyl Ether Derivatives for Synthesis of
2,3-Disubstituted Benzo[b]furans
Jie Hu,a Lu-Yong Wu,a Xiang-Chuan Wang,a Yuan-Yuan Hu,a Yan-Ning Niu,a
Xue-Yuan Liu,a Shangdong Yang,a,* and Yong-Min Lianga,b,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-2582; phone: (+86)-931-891-2593; e-mail: yangshd@lzu.edu.cn or liangym@lzu.edu.cn
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science,
b
Lanzhou 730000, Peopleꢀs Republic of China
Received: September 20, 2009; Published online: February 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900649.
Abstract: A variety of substituted benzo[b]furans
are readily prepared in good to excellent yields
under the mild reaction conditions from o-(1-alkyn-
The benzo[b]furan moiety has attracted widespread
interest in view of its presence in natural products,
and their biological and pharmacological activities.[1–4]
As a result, a number of routes leading to differently
substituted benzo[b]furans have been described in the
literature.[5–26] Transition metal-catalyzed intramolecu-
lar cyclization of the corresponding ortho-alkynyl
phenyl ethers derivatives as a simple and efficient
protocol has attracted much attention in recent years
(Scheme 1, a).[27–31] However, the direct carbocycliza-
tion of ortho-alkynyl phenyl ethers under PTC
(phase-transfer catalyst) conditions for the synthesis
of 2,3-disubstituted benzo[b]furan under metal-free
conditions has not previously been reported
(Scheme 1, b). Compared with other methods phase-
transfer catalysis has long been recognized as a versa-
tile methodology for organic synthesis in both indus-
trial and academic laboratories, featuring its simple
reaction procedure, safe, inexpensive, environmentally
friendly reagents, absence of anhydrous solvents, ease
of scale-up, and metal-free conditions.[32–36] To the
ACHTUNGTRENNUNGylphenoxy)-1-phenylethanone under phase-transfer
catalysis (PTC). This methodology accommodates
simple experimental operations, inexpensive and
environmentally benign catalysts, metal catalyst-
free conditions, facile reagents and the possibility to
conduct large-scale preparations. The development
of carbon-carbon bond formation processes via an
overall structural isomerization represents the most
atom-economical approach.
À
Keywords: benzo[b]furans; C C bond formation;
cyclization; metal-free conditions; phase-transfer
catalysts
Scheme 1. Transition metal-catalyzed or phase-transfer-catalyzed intramolecular cyclization of the corresponding ortho-al-
kynyl phenyl ether derivatives.
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351

Jie Hu et al.
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best of our knowledge, this report is the first example
about the intramolecular cyclization of the corre-
sponding ortho-alkynyl phenyl ethers under phase-
transfer catalysis.
Initially, we investigated the reaction of 0.20 mmol
of 2-[4-methyl-2-(2-phenylethynyl)phenoxy]-1-phenyl-
ethanone (1a), 5 mol% of PTC-1 and 1.5 equivalents
of K2CO3 in DMSO at 608C in air. To our delight, the
desired product benzo[b]furan 2a was formed in 80%
yield after 2 h and the structure was unambiguously
secured by an X-ray crystal structure analysis
(Figure 1).[37] Encouraged by this result, we further
optimized the reaction conditions. Other solvents,
such as THF, 1,4-dioxane, and acetonitrile were also
tested; acetonitrile gave the best yield of 83%
(Table 1, entries 2–4). A subsequent screen of bases
revealed that the Cs2CO3 was superior to the others
(entries 5–12). In the absence of base or PTC condi-
Figure 1. X-ray crystal structure of 2a.
Table 1. Optimization of the phase-transfer-catalyzed intramolecular cycli-
zation
of
2-[4-methyl-2-(2-phenylethynyl)phenoxy]-1-phenylethanone
(1a).[a]
[a]
Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent in
air at 608C with 1.0 equiv. of 1a, 1.5 equiv. of base and 5 mol% equiv.
of PTC.
Isolated yield.
N.R. =no reaction.
[b]
[c]
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Adv. Synth. Catal. 2010, 352, 351 – 356

Phase-Transfer-Catalyzed Intramolecular Cyclization of ortho-Alkynyl Phenyl Ether Derivatives
Table 2. Phase-transfer-catalyzed intramolecular cyclization of acetylenic ketones
and ester (1).[a]
[a]
All reactions were carried out under the optimal conditions reported in the
text for 2 h.
Isolated yields.
Reactions were carried out for 20 h.
[b]
[c]
tions, the reaction did not proceed (entries 6 and 7). yields (entry 19). Thus, we chose the following reac-
It should be pointed out that our work is limited to tion conditions as optimum for all subsequent cycliza-
substrates of sufficient acidity. When different PTCs tions: 0.20 mmol of 1a, 5 mol% PTC-1, and
were examined, the results showed that PTC-2 and 0.30 mmol Cs2CO3 in CH3CN at 608C in air.
PTC-3 could promote this cyclization, but the desired
With the optimized conditions in hand, the scope of
product 2a was only obtained with 40% and 76% this reaction was then investigated, and the results are
yields, respectively (entries 13 and 14). Tetraalkylam- summarized in Table 2. On employing arylacetylenes
monium salts, such as Et4NBr, Bu4NCl, Et4NI and bearing methoxy and bromide groups on the aromatic
Bu4NF have also been applied to this process, and the ring, cyclization products 2b and 2c were obtained in
yields were not better than with PTC-1 (entries 15– good yields, respectively (Table 2, entries 2 and 3).
18). Decreasing the loading of base will lead to lower The results indicated that the presence of an electron-
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Jie Hu et al.
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Table 3. Phase-transfer-catalyzed intramolecular cyclization
of acetylenic malonates (1).[a]
withdrawing group on the aromatic ring gave a higher
yield. When R2 was the TMS or H, the same product
was achieved almost quantitatively and the TMS
group happened to undergo desilylation at the same
time (entries 4 and 5). Surprisingly, when R2 was re-
placed by an alkyl group, the unexpected 5-methyl-2-
propylbenzo[b]furan (2f) was obtained in poor yield
(entry 6). On introducing the primary, secondary, ter-
tiary and THP-protected primary aryl alcohols on the
terminal alkynes, the desired products were generated
in moderate to good yields (entries 7–10). The elec-
tronic effect of the R groups on the aromatic ring is
not evident in the reaction (enties 11–13). Further-
more, the substituent R1 was also examined. On re-
placing the phenyl with methyl and ethoxy at the R1
position, the reaction proceeded smoothly to give the
corresponding cyclization/isomerization products in
good to excellent yields, although the substrate 1o re-
quired a longer reaction time (entries 14 and 15).
Probably the activity of the a-H the ester is lower
than that of a ketone. In light of the structure of prod-
ucts 2a–o, we believe that introducing a substituent in
the a-position of the carbonyl compounds should also
work. Hence, we prepared the substrate 1p and, as we
expected, 2p was obtained in 86% yield (entry 16).
To expand the scope of this reaction, we also inves-
tigated the substrates 1q–t. To our delight, the reac-
tion proceeded smoothly and gave the indane deriva-
tives 2q, 2r and 2s in good to excellent yield (Table 3,
entries 1–3), only 2t was obtained in a lower yield
(entry 4).
[a]
All reactions were carried out under the optimal condi-
tions reported in the text for 2 h.
Isolated yields.
The reaction was carried out for 5 h.
[b]
[c]
The proposed mechanism for the reaction is
showed in Scheme 2. Firstly, there is formation of an
ortho-alkynylphenylethanone ether ion by deprotona- to form the active intermediate a or b. Subsequently
tion with the corresponding base, and the cation ex- active intermediate a or b underwent an exo-dig
change possibly proceeds via phase-transfer catalyst model intramolecular cyclization, then aromatic iso-
Scheme 2. Proposed mechanism for the phase-transfer-catalyzed intramolecular cyclization.
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Phase-Transfer-Catalyzed Intramolecular Cyclization of ortho-Alkynyl Phenyl Ether Derivatives
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In conclusion, we have developed an efficient and
versatile route to 2,3-disubstituted benzo[b]furans via
phase-transfer-catalyed and base-mediated cyclization
of alkynyl compounds bearing various functional
groups under metal-free conditions. A wide range of
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Experimental Section
Representative Procedure
To a solution of 1a (65.2 mg, 0.20 mmol) in 2.0 mL of
CH3CN was added Cs2CO3 (97.7 mg, 0.30 mmol). The mix-
ture was allowed to stir at room temperature for 1 min and
PTC-1 (4.74 mg, 5 mol%) was added. The resulting mixture
was then heated under air at 608C. When the reaction was
considered complete as determined by TLC analysis, the re-
action mixture was allowed to cool to room temperature
and quenched with a saturated aqueous solution of ammoni-
um chloride, after which the mixture was extracted with
EtOAc. The combined organic extracts were washed with
water and saturated brine. The organic layers were dried
over Na2SO4 and filtered. Solvents were evaporated under
reduced pressure. The residue was purified by chromatogra-
phy on silica gel to afford 2,3-disubstituted benzo[b]furan
2a.
CCDC 734260 contains the supplementary crystallograph-
ic data for compound 2a of this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
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Acknowledgements
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We thank the NSF (NSF-20872052, NSF-20090443) for finan-
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