Copper-promoted hydration and annulation of 2-fluorophenylacetylene derivatives: From alkynes to benzo[b]furans and benzo[b]thiophenes

Article abstract of DOI:10.3762/bjoc.10.305

An efficient copper-promoted hydration reaction and its application in the synthesis of benzo[b ] furan and benzo[ b ] thiophene derivatives is presented starting from readily available 2-fluorophenylacetylene derivatives. The key annulation step involves

Full text of DOI:10.3762/bjoc.10.305

Copper-promoted hydration and annulation of
2-fluorophenylacetylene derivatives: from alkynes to
benzo[b]furans and benzo[b]thiophenes
Yibiao Li*1, Liang Cheng1, Xiaohang Liu2, Bin Li1 and Ning Sun1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2886–2891.
1School of Chemical & Environmental Engineering, Wuyi University,
Jiangmen, Guangdong Province, 529090, China and 2BASF Catalyst,
23800 Mercantile Road, Beachwood, Ohio 44124, USA
doi:10.3762/bjoc.10.305
Received: 23 July 2014
Accepted: 20 November 2014
Published: 04 December 2014
Email:
Yibiao Li* - leeyib268@126.com
Associate Editor: D. O'Hagan
* Corresponding author
© 2014 Li et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
annulation; benzo[b]furan; C–F activation; copper-promoted;
heterocycle
Abstract
An efficient copper-promoted hydration reaction and its application in the synthesis of benzo[b]furan and benzo[b]thiophene
derivatives is presented starting from readily available 2-fluorophenylacetylene derivatives. The key annulation step involves the
hydration of the C–F bond of 2-fluorophenylacetylene derivatives followed by an intramolecular annulation to afford benzo[b]furan
and benzo[b]thiophene derivatives. Moreover, structurally important 2,2'-bisbenzofuran scaffolds are provided in good yields.
Introduction
The development of general and efficient methodologies for the Ackermann et al. utilized bromo- and iodo-substituted phenyl-
synthesis of complex heterocycle skeletons has received much acetylene in their TiCl4-catalyzed intramolecular nucleophilic
attention in the past decades. Among the most ubiquitous hete- annulation process (Scheme 1b) [24]. But this method involves
rocyclic moieties in natural and bioactive products are the a two-step process and the usage of two different metal salts
benzo[b]furan and benzo[b]thiophene units [1-8]. Despite may complicate further processing. The direct design of a Pd or
the existence of established methods for the synthesis of Cu-catalyzed one-pot synthesis of benzo[b]thiophenes from
benzo[b]furan and benzo[b]thiophene derivatives, the develop- 2-bromoalkynylbenzenes and a thiol derivative has eliminated
ment of more convenient methods is of significant importance these problems to a large extent [25-29]. Nevertheless, the
[9-14]. Commonly, the preparation of 2-substituted direct synthesis of benzo[b]furans from 2-haloalkynylbenzenes
benzo[b]furans involves the usage of 2-halophenols as reaction and the usage of 2-fluorophenylacetylene derivatives as
precursors (Scheme 1a) [15-18], which can be cumbersome due substrates continues to represent a challenge. Indeed, Tsuji and
to the precursors’ instability and the protecting and depro- co-workers have developed a transition metal-free process for
tecting steps necessary to synthesize the precursors [19-23]. the synthesis of benzo[b]furans from 2-fluorophenylacetylene
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Beilstein J. Org. Chem. 2014, 10, 2886–2891.
(Table 1, entry 5). To our delight, the use of 0.2 equiv of KI as
an additive afforded 2a in a satisfactory 95% yield (Table 1,
entry 6). The base loading had a strong influence on the yield
with 2 equiv KOH being the optimal amount (Table 1, entries 7
and 12). Further screening of bases did not lead to better yields
and confirmed that the reaction did not proceed in the presence
of CsCO3 (Table 1, entry 8). Other catalytic systems, such as
Cu(OAc)2, Cu(OTf)2 and Cu(acac)2, were less effective for this
annulation process (Table 1, entries 9–11). A decrease in the
temperature lowered the yield of the reaction (Table 1, entry
13). The importance of water was confirmed by a lower yield
under dry conditions (Table 1, entry 14). In the absence of CuI,
we found that the reaction of (2-(2-fluorophenyl)ethyn-
yl)benzene with KOH in DMSO at 80 °C for 4 h gave 55%
yield of the annulation product (Table 1, entry 15).
Table 1: Optimization of the reaction conditions.a
Scheme 1: Synthetic approaches to benzo[b]furans from 2-alkynyl-
phenols, ketones and 2-fluorophenylacetylene derivatives.
derivatives. But the reaction requires conditions with a high
reaction temperature for satisfactory yields. Unfortunately, only
benzo[b]furans were obtained in this reaction [30].
Entry
Catalyst
Solvent
Additive
Yield [%]b
1
Pd(PPh3)4
CuCl
CuCl
CuCl
CuI
CH3CN
CH3CN
DMF
–
–
Typically, the aryl halides used in the annulation reactions are
iodides and bromides. It is rare to employ aryl fluorides because
of their low reactivity [31-33]. To extend the application of our
strategy of the copper-catalyzed synthesis of heterocycles,
we report herein a one-pot process for the synthesis of
benzo[b]furans and benzo[b]thiophenes with 2-fluorophenyl-
acetylene derivatives as precursors (Scheme 1c).
2
1,10-phen
35
71
75
88
95
68
<5
65
68
54
<5
25
38
55
3
1,10-phen
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,10-phen
5
1,10-phen
6
CuI
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
7c
8d
9
CuI
CuI
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
CuI
10
11
12e
13f
14g
15
Results and Discussion
We report an efficient synthesis of functionalized
benzo[b]furans from commercially available alkynes by a
copper-catalyzed, intramolecular annulation process. Initially,
our investigation commenced with the annulation of (2-(2-
fluorophenyl)ethynyl)benzene (1a) to give the corresponding
product 2-phenylbenzofuran (2a) by using 2 equiv KOH as a
base under various conditions. In the presence of the Pd(PPh3)4
catalyst the reaction of (2-(2-fluorophenyl)ethynyl)benzene in
CH3CN does not give any corresponding product (Table 1,
entry 1). The usage of CuCl and 1,10-phenanthroline (1,10-
phen) as a ligand in CH3CN at 80 °C showed that 2a could be
CuI
CuI
–
aReaction conditions: alkyne 1a (1.0 mmol), catalyst (10 mol %), base
(2.0 mmol), H2O (1.5 mmol) and additives (0.2 mmol) in 3 mL of
solvent at 80 °C for 4 h; byields are given for isolated products;
c1 equiv KOH was used; dCsCO3 instead of KOH; eomitting KOH and
starting material recovered; freaction was carried out at 30 °C.
gomitting H2O (dry conditions).
isolated in 35% yield (Table 1, entry 2). The screening of the Next, we explored the scope and generality of the process by
various solvents revealed that the solvent played an important using the conditions for Tabe 1, entry 6. As shown in Scheme 2,
role in this hydration and annulation process. Compared with substrates with either electron-donating or electron-with-
the other solvents, DMSO is more suitable for the annulation drawing substituents on the benzene ring can undergo the reac-
process (Table 1, entries 2–4). These investigations revealed tion smoothly, and the corresponding benzo[b]furan products
that the usage of CuI instead of CuCl as a catalyst resulted in were obtained in good to excellent yields. The reaction toler-
the isolation of 2a in a satisfactory 88% yield after 4 hour ated a variety of substituents including -Cl, -Br, -F, -OMe,
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Beilstein J. Org. Chem. 2014, 10, 2886–2891.
Scheme 2: Copper-promoted reaction of 2-fluorophenylacetylene derivatives to yield benzo[b]furans. Reaction conditions: Alkyne 1a (1.0 mmol),
catalyst (10 mol %), KOH (2.0 mmol), H2O (1.5 mmol) and KI (0.2 mmol) in 3 mL of DMSO at 80 °C for 4–8 h; yields are given for isolated products.
-NMe2 and thiophenyl groups. The use of 2-fluorophenyl- Unfortunately, when aliphatic alkynes were employed, the
acetylene derivatives with electron-withdrawing substituents as desired annulation products were formed in low yields.
R2 afforded benzo[b]furan products in higher yields. It is note-
The above studies dealt only with 1,2-diphenylethyne deriva-
tives as a reactive group in the substrates. Inspired by the
results of the nucleophilic annulation process, we wondered
whether we could further explore the annulation of 1,3-
diynes, which have great synthetic potential in medicine and
materials sciences [38-40]. For extensions, we used 1,4-bis(2-
fluorophenyl)buta-1,3-diyne as a substrate to investigate
the possibility of this transformation. Similar to (2-(2-fluoro-
phenyl)ethynyl)benzene, 1,4-bis(2-fluorophenyl)buta-1,3-diyne
was able to offer the corresponding annulation products 2s in
78% yield (Scheme 3).
worthy that the 2-(2-(2-fluorophenyl)ethynyl)thiophene was
also successfully converted to 2-(thiophen-2-yl)benzofuran (2j)
in good yields. Subsequently, the R1 substituent of the 2-fluoro-
phenylacetylene derivatives was varied from hydrogen to other
functional groups. Substituents at the ortho position of the
benzyl group did not have an impact on the reaction yield. The
presence of an additional electron-donating substituent margin-
ally decreased the conversion of 2-fluorophenylacetylene
derivatives resulting in products in moderate yields (Scheme 2,
2k and 2o). Interestingly, the p-fluoro atom was kept intact
during the reaction and fluoro-substituted benzofuran was
obtained (Scheme 2, 2q) [34-37]. This shows the good selec-
tivity of the current reaction system. It should be emphasized
that the 1,3-bis(2-(2-fluorophenyl)ethynyl)benzene was also
successfully converted to benzo[b]furan 2r in good yield.
To gain a deeper mechanistic understanding of the present
catalytic process, the direct intramolecular annulation of
1-bromo-2-(2-(2-fluorophenyl)ethynyl)benzene and 1-chloro-2-
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Beilstein J. Org. Chem. 2014, 10, 2886–2891.
Scheme 3: Copper-promoted synthesis of 2,2'-bisbenzofuran derivatives.
(2-(2-fluorophenyl)ethynyl)benzene were performed, as
shown in Scheme 4. In F/Br-substituted 1-bromo-2-(2-(2-
fluorophenyl)ethynyl)benzene, the fluoro moiety served as
leaving group and gave 2-(2-bromophenyl)benzofuran (2t) as a
major product. In F/Cl-substituted 1-chloro-2-(2-(2-fluoro-
phenyl)ethynyl)benzene was able to offer the chloro-substi-
tuted product 2v as the only product. A reactivity order of
F > Br > Cl can be derived from these data.
Scheme 5: Copper-promoted synthesis of benzo[b]thiophenes.
Reactions with Na2S·9H2O as a nucleophile were successful,
and the corresponding benzo[b]thiophene products were
obtained in high yields (Scheme 5). We obtained the best results
with DMSO as the solvent and a reaction temperature of 60 °C.
Using the optimized reaction conditions, 3-chloro and 4-chloro
substituted 2-fluoroalkynylbenzenes were reacted with
Na2S·9H2O to yield benzo[b]thiophenes in good yields.
The postulated reaction mechanism is depicted in Scheme 6
[25-29]. The catalytic cycle is initiated by the nucleophilic
substitution of 2-fluorophenylacetylene derivative 1 with OH−.
This might provide unstable 2-alkynylphenol A, which could
then form the corresponding potassium phenolate intermediate
B. The coordination of CuI with B may provide intermediate C,
and the subsequent addition to the C–C triple bond gives the
Scheme 6: Proposed mechanism for the annulation reaction.
copper complex D. Protonolysis of intermediate D generates starting from 2-fluorophenylacetylene derivatives. The hydra-
benzo[b]furan 2 and regenerates the active catalyst species.
tion and annulation is catalyzed by CuI with KOH or
Na2S·9H2O as a base at 60–80 °C to give the corresponding
products in moderate to good yields. Various functional groups
Conclusion
In summary, we have developed a new protocol for the syn- are accepted resulting in a wide range of substituted
thesis of benzo[b]furan and benzo[b]thiophene derivatives benzo[b]furans and benzo[b]thiophenes. Further studies, which
Scheme 4: Intramolecular competition experiments.
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17.Cano, R.; Yus, M.; Ramón, D. J. Tetrahedron 2012, 68, 1393–1400.
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Supporting Information
Supporting Information File 1
21.Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292–10296.
doi:10.1021/jo051299c
Full experimental details and copies of NMR spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-305-S1.pdf]
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Acknowledgements
We thank the National Natural Science Foundation of China
(21302146), the Guangdong Natural Science Foundation
(S2013040012354), the Foundation for Distinguished Young
Talents in Higher Education of Guangdong (2013LYM_0094),
and the Science Foundation for Young Teachers of Wuyi
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