Potassium tert-butoxide promoted annulation of 2-alkynylphenyl propargyl ethers: Selective synthesis of benzofuran and 12H-benzoannulene derivatives

Article abstract of DOI:10.1021/jo4020062

We present here our results on potassium tert-butoxide promoted annulation reactions of 2-alkynylphenyl propargyl ethers to give two different types of heterocycles: 3-benzyl-2-alkynylbenzofurans and 12H-benzoannulenbenzo[b]furans. A series of functionalized 2-alkynylphenyl propargyl ethers were efficiently cyclized by potassium tert-butoxide to the corresponding products. The optimized reaction conditions tolerated a large variety of functional groups, including electron-rich, electron-poor, and N-heterocyclic substrates. Selective product formation was obtained by controlling the solvent and temperature. When THF was used at room temperature, 3-benzyl-2-alkynylbenzofuran derivatives were exclusively obtained, while the use of DMF at 60 C gave selectively 12H-benzoannulen[b]benzofurans.

Full text of DOI:10.1021/jo4020062

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Article
Potassium tert-Butoxide Promoted Annulation of (2-
Alkynylphenyl) Propargyl Ethers: Selective Synthesis
of Benzofuran and 12H-Benzoannulene Derivatives
Tamiris B. Grimaldi, Davi Fernando Back, and Gilson Zeni
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Oct 2013
Downloaded from http://pubs.acs.org on October 1, 2013
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Potassium tert-Butoxide Promoted
Annulation of (2-Alkynylphenyl) Propargyl
Ethers: Selective Synthesis of Benzofuran
and 12H-Benzoannulene Derivatives
Tamiris B. Grimaldi,1 Davi F. Back2 and Gilson Zeni*,1
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1 Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica
de Organocalcogênios, UFSM, CCNE, Santa Maria, Rio Grande do Sul, Brazil,
97105-900.
2 Laboratório de Materiais Inorgânicos, CCNE, UFSM, Santa Maria, Rio Grande
do Sul, Brazil, 97105-900.
*gzeni@ufsm.br
Abstract:
We present here our results on potassium tert-butoxide promoted annulation
reaction of (2-alkynylphenyl) propargyl ethers to give two different types of
hetecocycles;
3-benzyl-2-alkynylbenzofurans
and
12H-
benzoannulenbenzo[b]furans. A series of functionalized (2-alkynylphenyl)
propargyl ethers were efficiently cyclized by potassium tert-butoxide to the
corresponding products. The optimized reaction condition tolerated a large
variety of functional groups, including electron-rich, electron-poor and N-
heterocyclic substrates. The selective product formation was obtained by
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controlling solvent and temperature. By choosing THF at room temperature, 3-
benzyl-2-alkynylbenzofuran derivatives were exclusively obtained, while the use
of DMF at 60 oC gave selectively 12H-benzoanulen[b]benzofurans.
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Keywords: cyclization, potassium tert-butoxide, heterocycle, benzoannulene,
benzofuran
Introduction
The annulation reaction, which involves a new carbon–carbon bond
formation, represents a powerful methodology in the synthesis of cyclic
compounds.1 Specifically, the intermolecular annulations have been widely
employed for the transformation of alkynes to the corresponding N-, O-
heterocycles.2 The most general and appropriate methodology includes the
transition-metal-catalyzed annulation of both terminal and internal alkynes via a
nucleophile attack to the activated triple bond.3 The other approach involves
the activation of carbon-carbon bond of alkynes with an electrophilic source
followed by an intramolecular carbon nucleophilic attack on the activated triple
bond to give both carbocycles and heterocycles.4 The synthesis of heterocyclic
compounds by using the base-promoted annulation of alkynes has attracted
considerable interest.5 This synthetic strategy has significant advantages over
other methodologies, particularly in the reduction of generation of chemical
wastes, reaction time, solvent and energy, demonstrating the clear economic
and environmental benefits. From the synthetic point of view, benzyl alkynyl
ethers are often chosen, in base-promoted annulation, as ideal substrates,
because they have an acid hydrogen between carbon-heteroatom bond,
adequately stabilized, making it more susceptible to carbanion formation.6 One
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of the interesting features of this process is the fact that the initial carbanion
formed could result in the intermediate allyl anion with two carbons having
nucleophilic character, which could undergo intramolecular cyclization via 5-
exo-dig or 6-endo-dig modes,7 determined by the steric, electronic effects and
by the Baldwin rules. Several authors have described intramolecular cyclization
of (2-alkynylphenyl) benzoylmethyl ethers as well as (2-alylphenyl)
benzoylmethyl ethers or (2-3-oxopropenyl) propargyl ethers but base-promoted
cyclization of (2-alkynylphenyl) propargyl ethers has not received much
attention.8 In addition, a tandem base-promoted annulation version of (2-
alkynylphenyl) propargyl ethers to prepare furan-fused tetracyclic has not been
thoroughly explored. In this way, our aim was to develop a condition to base-
promoted annulation of (2-alkynylphenyl) propargyl ethers 1 for the selective
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synthesis
of
3-benzyl-2-alkynylbenzofurans
2
or
12H-
benzoanulen[b]benzofurans 3 (Scheme 1). Tetracyclic furans bearing a fused
seven-membered ring are a class of natural or synthetic polycyclic that display a
range of different biological activities.9 Members of this family possess
antimicrobial,10 cytotoxic,11 antiulcer12 and anti-inflammatory activities.13
Although numerous studies for the chemistry and preparation of furan-fused
five- and six-membered tetracyclics have been reported, the preparation of
seven-membered derivatives is limited and it generally involves the multi-step
synthesis.14 Thus, a one-step synthesis of fused heterocycles containing a
seven-membered ring has been a great challenge.
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Scheme 1
Results and Discussion
The starting (2-alkynylphenyl) propargyl ethers 1 were readily prepared
from commercial 2-halophenol derivatives by alkylation with propargyl
bromides15 followed by Sonogashira cross-coupling reaction with terminal
alkynes.16 After that, our efforts were concentrated to determine the reactional
parameters, which could affect the annulation reaction. We firstly began to
screen the action of bases, solvents and temperature in the cyclization of (2-
alkynylphenyl) propargyl ether 1a. The reaction carried out with t-BuOK (1.5
o
equiv) as base, in DMF (3 mL), at 90 C, for 1 h, under argon atmosphere,
unfortunately, failed to access the benzofuran 2a, giving the cyclized product 3a
in 74% yield (Table 1, entry 1). Although, the formation of 3a was encouraging,
the absence of 2a suggests that the combination of higher reaction temperature
(90 0C) and the solvent could induce the formation of 3a. Thus, by lowering the
0
reaction temperature to 0 C, the product 2a was obtained, after 8 h, in 56%
yield with 24% yield of 3a, while the reduction of amount of base afforded
exclusively 2a, although the yield was poor (Table 1, entries 2 and 3). Further
screening revealed that other bases such as K2CO3, NaH, KOH, Et3N, Cs2CO3,
K3PO4 and NaOAc, using tetrahydrofuran as solvent, were ineffective to provide
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the product 2a (Table 1, entries 4-10). The combination of t-BuOK (1.5 equiv)
and tetrahydrofuran, at room temperature, had a dramatic effect on the outcome
of this cyclization, leading to the desired benzofuran 2a in 92% yield, after 1h
(Table 1, entry 11). The results demonstrated that the loadings of t-BuOK also
had a fundamental influence on the cyclization reaction. With 1.0 and 1.2
equivalents of t-BuOK, for instance, no reaction was observed when
temperature and reaction time was changed (Table 1, entries 12-15). It is worth
noting that good yields were achieved using 2.0 and 2.5 equivalents of t-BuOK,
but no reaction took place in the presence of catalytic amount of t-BuOK (Table
1, entries 16-18). As can be seen from table 1, of the solvents screened,
dioxane gave similar result compared to that of THF. For the other solvents,
such as ethanol, water, dichloromethane and acetonitrile no trace of benzofuran
2a was obtained (Table 1, entries 19-24). However, when DMSO was used as
solvent, in the presence of t-BuOK (1.5 equiv), 12H-benzoanulen[b]benzofuran
3a, observed in table 1; entry 1, was obtained exclusively in 85% yield, after 1h
(Table 1, entry 25). This result supports our hypothesis that the temperature
and base play a crucial role in the rate and the product distribution of
benzofuran 2a and 12H-benzoanulen[b]benzofuran 3a. To test the effect of
dilution on the rate of reaction, 1 and 5 ml of THF were employed instead of 3
mL and a similar rate of reaction was obtained. On the basis of this
investigation, we concluded that the annulation reaction of (2-alkynylphenyl)
propargyl ether 1a (0.25 mmol) carried out in the presence of t-BuOK (1.5
equiv) in THF (3 mL), for 1h at room temperature, was the optimal condition to
provide the benzofuran 2a.
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Table 1. Effect of different reaction parameters on the preparation of
benzofuran 2aa
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entry base (equiv)
solvent
DMF
DMF
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
temp (oC)
yield (%)b
c
1
2
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (0.2)
K2CO3 (1.5)
NaH (1.5)
90
0
-
56d
3
0
39
-
4
25
25
25
25
25
25
25
25
25
75
0
5
-
6
KOH (1.5)
-
7
Et3N (1.5)
-
8
Cs2CO3 (1.5)
K3PO4 (1.5)
NaOAc (1.5)
t-BuOK (1.5)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.2)
t-BuOK (0.2)
t-BuOK (2.0)
t-BuOK (2.5)
t-BuOK (1.5)
-
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25
0
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0
86
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0
25
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t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (1.5)
H2O
25
25
25
25
25
25
-
-
CH2Cl2
dioxane
dioxane
CH3CN
DMSO
99
-
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-
e
-
a
The reaction was performed in the presence of 1a (0.25 mmol), t-BuOK (1.5
equiv) in THF (3 mL), under argon atmosphere for 1h at room temperature. b Yields
were determined by GC analysis. c The product 3a was obtained in 74% yield.
d
The product 3a was obtained in 24% yield. e The product 3a was obtained in 85%
yield.
After the optimization of the reaction condition a range of (2-
alkynylphenyl) propargyl ethers 1 were evaluated for direct annulation and the
results are summarized in table 2. (2-Alkynylphenyl) propargyl ethers 1 of
diverse structural and electronic nature underwent the cyclization to form 3-
benzyl-2-alkynylbenzofurans 2 in good yields requiring a very short reaction
time. At the beginning we studied the effect of the substituent on aryl bonded to
the propargyl group. We found out that reaction proceeded very well when
either electron donor as well as electron acceptor group was on the aryl group
(Table 2, entries 1-7). In addition, it must be pointed out that it was possible to
perform the cylization with the (2-alkynylphenyl) propargyl ether 1h, which has a
hindered 1-naphthyl substituent at the terminal position of the alkyne (Table 2,
entry 8). Furthermore, the heteroaryl thiophene, directly bonded to the alkyne,
was also a suitable reactant in this cyclization conditions giving 3-benzyl-2-
alkynylbenzofuran 2i in 87% yield (Table 2, entry 9). The optimized condition
was also efficient for the terminal alkyne 2j, although, due to the acid-basic
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reaction with terminal hydrogen, t-BuOK (3.0 equiv) was required (Table 2,
entry 10). This result is significant particularly when one considers that there
are many ways to transform the resulting terminal alkynes into other
substituents.17 Besides, it is well described that acetylenic furan derivatives are
present in a wide range of compounds that show important biological and
pharmaceutical applications.18 Next, our attention was turned to the influence of
substituents directly bonded to the alkyne at the 2-position of the aromatic ring
(Table 2, entries 11-15). The yields of the reactions were not sensitive to
electronic effects on the aromatic ring. Indeed, electron-withdrawing reacted at
rates comparable to the electron-donating groups (Table 2, entries 11-15). On
the other hand, the presence of an alkyl group directly bonded to the triple bond
in the compound 1o led to a decrease in the cyclization efficiency, furnishing the
corresponding cyclized product 2i in 49% yield (Table 2, entry 15). In this case,
the absence of pi bonds in the alkyl chain could result in a decreased reactivity
for the nucleophilic attack on the carbon-carbon triple bond. Finally, we studied
the cyclization with (2-alkynylphenyl) propargyl ethers 1 having different
substitutions at the aromatic ring that contains the alkynes and propargyl
substituents. The p-methyl substituted 1p and 1q gave rise to cyclized 3-
benzyl-2-alkynylbenzofuran 2p and 2q in 75 and 73% yields, respectively
(Table 2, entries 16-17). A similar result was obtained when p-methoxyl
substituted 1r was utilized in the reaction (Table 2, entry 18). Further, we
carried out our study with pyridine derivatives to determine the influence N-
heterocycle in the curse of this cyclization. For instance, the cyclization reaction
of 2-alkynyl-3-propargyl pyridine with different substituted, such as hydrogen,
chlorine and 1-nahpthyl substituents gave the cyclized products in 61–81%
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yields (Table 2, entries 19-21). As expected, when the propargyl group was
replaced by benzyl group, the reaction gave the corresponding product in
moderate yield, even though t-BuOK (3.0 equiv) was necessary (Table 1, entry
22). It appears that smaller amount of the benzyl carbanion is formed when 1.5
equiv of t-BuOK was used.
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Table 2. Synthesis of 3-benzyl-2-alkynylbenzofurans 2a
R1
R1
t-BuOK (1.5 equiv), THF (3 mL)
R2
argon atmosphere, 25 oC
O
O
R2
1a v
-
2a v
-
entry
(2-alkynylphenyl) propargyl
ethers 1
products 2
yield (%)/time (min)
1
92/5
2a
1a
2
86/5
2b
1b
3
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90/5
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2d
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1d
5
84/5
2e
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7
8
75/5
87/10b
72/20
2f
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2g
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O
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1i
1j
10
11
67/5c
2j
81/20
2k
1k
12
82/5
2l
1l
13
90/5
2m
1m
14
85/3b
2n
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49/5d
2o
2p
1o
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75/5
1p
17
73/3b
2q
1q
18
76/5
2r
1r
19
67/5
2s
1s
20
61/5
2t
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2u
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1u
22
86/5c
2v
O
1v
a
The reaction was performed in the presence of (2-alkynylphenyl) propargyl ethers 1 (0.25
b
mmol), t-BuOK (1.5 equiv) in THF (3 mL), under argon atmosphere, at room temperature. The
reaction was performed at 0 °C. c t-BuOK (3.0 equiv) was used. d The reaction was performed in
the presence of (2-alkynylphenyl) propargyl ethers 1 (0.25 mmol), t-BuOK (1.0 equiv) in DMF (3
mL), under argon atmosphere, at 60 °C.
In the process of the reaction condition optimization for the formation of
benzofuran 2a, we observed that 12H-benzoanulen[b]benzofuran 3a could be
obtained, as the sole product, in 74% and 85% yields, depending on the
temperature and solvent (Table 1, entries 1 and 25). In light of this result, our
efforts were focused on optimizing the reaction conditions to obtain the 12H-
benzoanulen[b]benzofurans 3 directly from (2-alkynylphenyl) propargyl ethers 1,
via a one-pot cyclization. In the initial study, the cyclization was performed by
using (2-alkynylphenyl) propargyl ether 1a (0.25 mmol) in the presence of DMF
(3 mL). Thus, the influence of reaction parameters, such as different bases,
temperature and solvent was evaluated and the results are summarized in table
3. For comparison on the efficiency of t-BuOK, other bases were tested. When
t-BuOK, was replaced by KOH and NaOH, the yield decreased to 51% and 25%
respectively (Table 3, entries 2–3). When the reaction was carried out in the
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presence of K3PO4 no product was detected, just traces of the cyclized product
2a was obtained (Table 3, entry 4). Other bases, such as Et3N, Cs2CO3,
NaOAc and K2CO3 were also tested, however, no product was detected (Table
3, entries 5-8). The solvent remarkably affected the reaction, with EtOH, H2O,
CH2Cl2 and dioxane only the starting material 1a was recovered (Table 3,
entries 9-12). When DMSO was used as solvent, no further improvement in
yield was achieved. In the reaction, in which the solvent DMF was replaced by
DMSO, the product 3a was obtained in poor yield, while the use of CH3CN and
a mixture of THF/DMF afforded 2a as the sole product (Table 3, entries 13-15).
10
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37
38
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Reactions at room temperature, gave comparable results to those at 90 C,
which was improved to 86% yields by running the reaction at 60 oC and 120 oC
(Table 3, entries 16-18). Further screening revealed that the change of the t-
BuOK amount from 1.1 to 2.5 equiv showed similar efficiency (Table 3, entries
20-23). However, the reaction using 20 mol % of t-BuOK gave a mixture of
products 3a and 2a in 27% and 55% yield, respectively (Table 3, entries 19).
Table 3. Effect of different reaction parameters on the preparation of 12H-
benzoanulen[b]benzofuran 3aa
entry
base (equiv)
t-BuOK (1.5)
KOH (1.0)
solvent temp (ºC) yield (%)b
1
2
3
4
DMF
DMF
DMF
DMF
90
90
90
90
74
51
25
NaOH (1.0)
K3PO4 (1.0)
c
-
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5
Et3N (1.0)
Cs2CO3 (1.0)
NaOAc (1.0)
K2CO3 (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (1.0)
t-BuOK (0.2)
t-BuOK (1.1)
t-BuOK (1.0)
t-BuOK (2.0)
t-BuOK (2.5)
DMF
DMF
90
90
90
90
75
90
40
90
90
90
25
25
60
120
90
60
90
90
90
-
-
6
7
DMF
-
8
DMF
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
EtOH
H2O
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
-
CH2Cl2
dioxane
DMSO
CH3CN
THF
-
-
27
c
-
d
-
DMF
77
86
86
27e
70
80
74
70
DMF
DMF
DMF
DMF
DMF
DMF
DMF
a
The reaction was performed in the presence of 1a (0.25 mmol), t-BuOK
(1.0 equiv) in DMF (3 mL), under Ar atmosphere for 1h at 60 °C. bYields
c
were determined by GC analysis.
The product 2a was obtained in 5%
yield. d The product 2a was obtained in 92% yield. e The product 2a was also
obtained in 55% yield.
As can be seen from table 3, the screened reaction parameters revealed
that the optimum conditions for the 12H-benzoanulen[b]benzofuran 3 formation
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involved stirring the corresponding (2-alkynylphenyl) propargyl ethers 1 in DMF
(3 mL) with 1.0 equiv of t-BuOK for 1h at 60 ºC. This optimized reaction
condition was then applied to other (2-alkynylphenyl) propargyl ethers 1a-y, and
the results are showed in table 4. The application of this condition to (2-
alkynylphenyl) propargyl ethers bearing hydrogen or electron-donating
substituents, at the aryl group directly bonded to the alkyne of the propargylic
function, gave the desired 12H-benzoanulen[b]benzofurans 3a-e in 61-91%
yields (Table 4, entries 1-6). Similar results were obtained when this aryl group
was substituted by electron-withdrawing substituents (Table 4, entries 6-7).
When the propargylic function is substituted by a 2-thyenyl group, the expected
product 3h was obtained in 78% yield (Table 4, entry 8). Thienyl azulene
derivatives offer a high degree of application in the semiconductor field and they
have been described as hole-injecting material in organic light-emitting
devices.19 The treatment of (2-alkynylphenyl) propargyl ether 1j, which has a
terminal alkyne, under the standard optimized condition, leaded to the
benzoanulen-7-benzofuran 3i in a yield of only 29% (Table 4, entry 9).
However, all the attempts to improve this reaction yield failed and resulted in
undesirable decomposition of starting material. The additional acidic hydrogen
on terminal alkynes most probably contributed to the limited success of this
cyclization, even though an excess of base was used. We also studied the
introduction of electron-rich and electron-donating groups in the aromatic ring
directly bonded to the alkyne at 2-postion. p-Methyl-, OMe and Cl were suitable
groups for the cyclization process in good yields (Table 4, entries 10-13).
However, the yield decreased when m-methyl substitute aryl group was used in
this alkyne (Table 4, entry 11). This result shows that the sterically hindered
10
11
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13
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18
19
20
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32
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37
38
39
40
41
42
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50
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60
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meta aryl position has a significant effect on the reaction yield, at least in the
second cyclization step. On the other hand, the electronic effect of the methyl
group highly influenced the regioselectivity obtained during the course of this
second cyclization. We also examined cyclizations of starting materials having
substituent on the central aromatic ring. The aromatic ring tolerated methyl and
methoxyl groups at the para-position. Although an additional reaction time was
required to the methyl substituent, the benzoanulen-7-benzofurans 3o-q were
obtained in moderate to good yields (Table 4, entries 15-17). We then turned
our attention to the cyclization of heteroaromatic substrates. The cyclization of
pyridine derivatives 1s-u, with different substitutions in the structure gave in all
cases the furo[3,2-b]pyridine derivatives 3r-t in moderate yields (Table 4,
entries 18-20). Particularly interestingly, with the substrate 1y, which has a
dimethylcarbinol instead of an aromatic group, the oxygen atom attacked the
carbon-carbon triple bond giving the mixture of hydrooxepine derivative 3u and
3-methyl-benzofuran 6 in 46% and 24% yields, respectively (Table 4, entry 21).
We reasoned that in this case, the acidic hydrogen in the hydroxyl group was
also effectively removed by t-BuOK generating the nucleophilic alkoxide anion
4, which attacks the carbon-carbon triple bond giving the product 3u. The
formation of 3-methyl-benzofuran derivative 6 can be explained by an
intramolecular nucleophilic attack of carbanion on the carbon-carbon triple bond
of terminal alkyne 5, which is formed in situ via a retro-Favorskii reaction20
(Scheme 2). This result is significant since a very simple substrate became a
versatile precursor for the preparation of an important family of polycyclic active
compounds,21 by a one-step cyclization.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Synthesis of 12H-benzoanulen[b]benzofurans 3a
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entry
(2-alkynylphenyl)
propargyl ether 1
product 3
yield (%)/time
(min)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
77/5
61/60
81/5
3a
1a
2
3
3b
1b
3c
1c
4
5
72/60
O
OMe
3d
3e
1d
91/5
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1e
4
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6
7
8
9
6
7
8
72/60
76/60
78/20
O
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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33
34
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50
51
52
53
54
55
56
57
58
59
60
3f
1f
3g
1g
3h
3i
1i
1j
9
29/5
10
70/30
3j
1k
11
62/5
3k
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7
8
9
1l
1m
1n
12
84/5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
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51
52
53
54
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57
58
59
60
3l
13
79/5
3m
14
15
16
82/5
70/60
50/5
3n
3o
1x
1p
1q
O
Cl
3p
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17
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74/5
58/5
3q
10
11
12
13
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15
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20
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59
60
1r
3r
1s
19
56/5
3s
3t
1t
20
21
58/5
1u
1y
46/5b
3u
a The reaction was performed in the presence of (2-alkynylphenyl) propargyl ether 1 (0.25 mmol),
t-BuOK (1.0 equiv) in DMF (3 mL), under argon atmosphere at 60 0C . t-BuOK (2.0 equiv) was
b
used.
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Scheme 2
The benzofurans 2 and 12H-benzoanulen[b]benzofurans 3 were
identified by their NMR data and the structures were confirmed by single
crystal X-ray diffraction (Figure 1, Supporting Information). In this context, our
cyclization methodology showed to be regioselective, providing the desired
benzofuran 2 via an intramolecular 5-exo-dig mode, as the unique regioisomers,
while 12H-benzoanulen[b]benzofuran 3 was formed exclusively via 7-endo-dig
mode. The formation of six-membered ring via intramolecular 6-endo-dig mode,
in the first cyclization or six-membered ring via a 6-exo-dig process, in the
second cyclization, was not observed in any case. Based on these results, we
propose the reaction mechanism for potassium tert-butoxide annulation of (2-
alkynylphenyl) propargyl ethers as illustrated in scheme 3. The formation of
benzofuran derivatives 2, could involve the abstraction of proton from 1 by t-
BuOK generating the carbanion a. The intramolecular nucleophilic attack of
carbanion a on the carbon-carbon triple bond gives intermediate b, via an
intramolecular 5-exo-dig mode. The isomerization of b gives the benzofuran
product 2 (Scheme 3). Regarding the possibility to form five versus six
membered ring, it is important to point out that the unique regioisomer obtained
during the course of this cyclization was the five-membered benzofuran
derivatives. This high regioselectivity can be explained by the stability of the
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new sigma-bond system formed, the formation of the more stable vinyl
carbanion from original alkyl anion and due to the carbon nucleophilic
cyclization normally goes on via 5-exo-dig over 6-endo closure in the substrate
9
with these interatomic distances.22
In addition, when (2-alkynylphenyl)
10
11
12
13
14
15
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23
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48
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50
51
52
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54
55
56
57
58
59
60
o
propargyl ethers 1 reacted with t-BuOK, in DMF at 60 C, the products 3 were
obtained as a single product. Besides, when isolated 2a was heated in DMF at
o
60 C, in the absence of t-BuOK, no cyclized 3a was obtained, while the
reaction of isolated 2a with t-BuOK (1 equiv), in DMF at 60 oC gave the product
3a in 80 % yield. These results suggested that products 3 could be formed
passing through a second cyclization of the benzofuran 2 via a carbo-
metallation of the triple bond with ortho-aryl-potassium intermediate c.23 Thus,
in this second cyclization the 7-endo-dig mode was preferred over 6-exo-dig,
albeit the both process are acceptable according to the Baldwin rule.24 It is
reasonable to assume that the influence of steric and electronic factors over the
competitive cyclization modes are involved.25
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2
3
R2
4
5
6
7
8
-
O
a
R1
R2
R2
9
10
11
12
13
14
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17
18
19
20
21
22
23
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57
58
59
60
first cyclization
R1
O
b
O
1
R1
R2
R1
O
2
R2 = Ar
second cyclization
K
R1
O
O
R1
3
c
Scheme 3
Conclusion
In conclusion, we have explored a base-promoted annulation of (2-
alkynylphenyl) propargyl ethers for the selective synthesis of 3-benzyl-2-
alkynylbenzofurans or 12H-benzoanulen[b]benzofurans. The essential role of
solvent and temperature to the selectivity in the cyclization was described. In
this regard, THF at room temperature gave 3-benzyl-2-alkynylbenzofurans,
o
while the use of DMF at 60 C gave 12H-benzoanulen[b]benzofurans. The
method tolerated the presence of neutral, electron-donating, electron-
withdrawing groups and N-heterocycles in any part of the substrates. More
importantly, this methodology required only one synthetic step to prepare
conjugated polycyclic compounds. The 3-benzyl-2-alkynylbenzofurans and
12H-benzoanulen[b]benzofurans were identified by their NMR data and the
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structures were confirmed by single crystal X-ray diffraction. In this context, our
cyclization methodology showed to be regioselective, providing the desired
benzofurans via an intramolecular 5-exo-dig mode, as the unique regioisomers,
while 12H-benzoanulen[b]benzofurans were formed exclusively via 7-endo-dig
mode.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
Experimental Section
General Procedure for the Synthesis of (2-alkynylphenyl) propargyl ethers
(1).26, 27 To a solution of bis-(triphenylphosphine)palladium(II) dichloride (0.5
mmol) and copper(I) iodide (1 mmol) in dry toluene (50 mL) was added 2-
iodophenol (10 mmol), ethynylbenzene (15 mmol) corresponding, and
diisopropylamine (10 mmol). The resulting solution was stirred at room
temperature under argon atmosphere for 2 h. The residue was dissolved in
ethyl acetate and the solution was washed with sat. NH4Cl, dried (MgSO4), and
concentrated in vacuo. The residue was purified by column chromatography
over silica gel (hexane/ethyl acetate-98:2) to provide 2-(phenylethynyl)phenols.
To a solution of 2-(phenylethynyl)phenols (7 mmol) in dry acetonitrile (20 mL)
was added propargyl bromides (8.75 mmol) followed by anhydrous K2CO3 (35
mmol). The reaction was refluxed under argon atmosphere for 4 h. The mixture
was cooled to room temperature, dissolved in ethyl acetate and the solution
was washed with sat. NH4Cl, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography over silica gel (hexane/ethyl
acetate-99:1) to provide (2-alkynylphenyl) propargyl ethers 1.
General Procedure for the Synthesis of benzofurans (2). To a solution of (2-
alkynylphenyl) propargyl ethers 1 (0.25 mmol) in dry THF (3 mL), t-BuOK (0.375
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2
mmol) was added. The resulting solution was stirred at room temperature under
argon atmosphere until complete consumption of the starting material. The
progress of the reaction was monitored by TLC. The residue was dissolved in
ethyl acetate and the solution was washed with sat. NH4Cl, dried (MgSO4), and
concentrated in vacuo. The residue was purified by column chromatography
over silica gel to provide benzofurans 2. The column chromatography was
carried out using hexane as eluent except for 2d, 2e and 2m, which was used
hexane/ethyl acetate (99:1) and 2s, 2t and 2u which was used hexane/ethyl
acetate (97:3) as eluent. 3-benzyl-2-(phenylethynyl)benzofuran (2a).
3
4
5
6
7
8
9
10
11
12
13
14
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16
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20
21
22
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60
0
1
Obtained as a white solid. Yield: 0.071 g (92%); m.p. 129.5-132.0 C. H NMR
(CDCl3, 400 MHz): δ 7.54-7.51 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.32-7.30 (m,
6H), 7.25 (t, J = 7.7 Hz, 3H), 7.16 (t, J = 7.2 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H),
4.16 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ 154.8, 139.1, 136.5, 131.6, 129.0,
128.6, 128.6, 128.5, 128.0, 126.5, 125.7, 124.3, 123.0, 122.1, 120.2, 111.3,
97.7, 79.2, 30.7. MS (EI, 70 eV) m/z (relative intensity): 309 [M+1, (24)], 308
(100), 307 (54), 292 (6), 276 (11), 231 (58), 202 (23), 153 (4), 138 (11), 91 (6).
Anal. (%) Calcd for C23H16O: C 89.58; H 5.23. Found: C 89.66; H 5.30.
3-benzyl-2-(p-tolylethynyl)benzofuran (2b). Obtained as a white solid. Yield:
0
1
0.069 g (86%); m.p. 126.0-128.2 C. H NMR (CDCl3, 400 MHz): δ 7.43 (t, J =
8.1 Hz, 3H), 7.31 (d, J = 7.7 Hz, 3H), 7.29-7.24 (m, 3H), 7.20-7.11 (m, 4H), 4.16
(s, 2H), 2.35 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 154.7, 139.3, 139.1, 136.7,
131.5, 129.2, 128.6, 128.5, 128.0, 126.4, 125.5, 123.9, 122.9, 120.1, 119.1,
111.2, 97.9, 78.6, 30.7, 21.5. MS (EI, 70 eV) m/z (relative intensity): 323 [M+1,
(25)], 322 (100), 321 (40), 307 (23), 305 (18), 245 (24), 231 (30), 202 (23), 153
(27), 139 (15), 138 (20), 91 (12). Anal. (%) Calcd for C24H18O: C 89.41; H 5.63.
Found: C 89.63; H 5.72.
3-benzyl-2-(m-tolylethynyl)benzofuran (2c). Obtained as a pallid yellow solid.
0
1
Yield: 0.063 g (78%); m.p. 119.6-121.0 C. H NMR (CDCl3, 400 MHz): δ 7.42
(d, J = 8.3 Hz, 1H), 7.36-7.31 (m, 5H), 7.28-7.11 (m, 7H), 4.16 (s, 2H), 2.33 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 154.8, 139.1, 138.2, 136.6, 132.2, 130.0,
128.7, 128.6, 128.6, 128.4, 128.0, 126.4, 125.6, 124.2, 122.9, 121.9, 120.2,
111.3, 97.9, 78.9, 30.7, 21.2. MS (EI, 70 eV) m/z (relative intensity): 323 [M+1,
(27)], 322 (100), 321 (43), 307 (24), 245 (18), 231 (31), 202 (18), 153 (14), 138
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(13), 91 (14). Anal. (%) Calcd for C24H18O: C 89.41; H 5.63. Found: C 89.60; H
5.69.
3
4
5
6
7
8
9
3-benzyl-2-((4-methoxyphenyl)ethynyl)benzofuran (2d). Obtained as a white
1
solid. Yield: 0.076 g (90%); m.p. 116.2-118.6 0C. H NMR (CDCl3, 400 MHz): δ
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7.48 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.3 Hz, 3H), 7.26
(t, J = 7.3 Hz, 3H), 7.20-7.15 (m, 1H), 7.13 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.9
Hz, 2H), 4.16 (s, 2H), 3.79 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 160.3, 154.7,
139.2, 136.8, 133.2, 128.6, 128.5, 128.1, 126.4, 125.4, 123.5, 122.8, 120.1,
114.2, 114.2, 111.2, 97.7, 78.0, 55.3, 30.7. MS (EI, 70 eV) m/z (relative
intensity): 339 [M+1, (26)], 338 (100), 337 (26), 323 (18), 293 (15), 261 (14),
231 (16), 189 (23), 176 (14), 132 (18). HRMS Calcd for C24H18O2 (M + Na+):
361.1199. Found: 361.1211.
3-benzyl-2-((3-methoxyphenyl)ethynyl)benzofuran (2e). Obtained as a pallid
0
1
yellow solid. Yield: 0.071 g (84%); m.p. 61.9-63.0 C. H NMR (CDCl3, 400
MHz): δ 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 3H), 7.29-7.22 (m, 4H),
7.18 (d, J = 7.1 Hz, 1H), 7.15-7.11 (m, 2H), 7.06 (s, 1H), 6.91 (dd, J = 8.3 Hz, J
= 2.5 Hz, 1H), 4.17 (s, 2H), 3.78 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 159.5,
154.8, 139.0, 136.4, 129.6, 128.6, 128.6, 128.0, 126.5, 125.7, 124.4, 124.2,
123.1, 123.0, 120.2, 116.3, 115.8, 111.3, 97.6, 79.0, 55.3, 30.7. MS (EI, 70 eV)
m/z (relative intensity): 339 [M+1, (25)], 338 (100), 337 (28), 305 (15), 261 (16),
231 (28), 189 (18), 138 (13), 91 (13). Anal. (%) Calcd for C24H18O2: C 85.18; H
5.36. Found: C 85.25; H 5.42.
3-benzyl-2-((4-fluorophenyl)ethynyl)benzofuran (2f). Obtained as a white
0
1
solid. Yield: 0.061 g (75%); m.p. 92.6-94.9 C. H NMR (CDCl3, 400 MHz): δ
7.58-7.54 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.39-7.30 (m, 6H), 7.26-7.24 (m,
1H), 7.19 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 8.7 Hz, 2H), 4.21 (s, 2H). 13C NMR
(CDCl3, 100 MHz): δ 162.9 (d, 1J = 251.1 Hz), 154.8, 139.0, 136.6, 133.6 (d, 3J
= 8.6 Hz), 128.6, 128.5, 127.9, 126.4, 125.7, 124.3, 123.0, 120.2, 118.2 (d, 4J =
2
3.6 Hz), 115.8 (d, J = 22.4 Hz), 111.3, 96.5, 78.9, 30.6. MS (EI, 70 eV) m/z
(relative intensity): 327 [M+1, (25)], 326 (100), 325 (57), 249 (29), 231 (41), 220
(24), 147 (23), 138 (14), 91 (20). HRMS Calcd for C23H15FO (M + Na+):
349.0999. Found: 349.1009.
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3-benzyl-2-((4-chlorophenyl)ethynyl)benzofuran (2g). Obtained as a pallid
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0
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yellow solid. Yield: 0.074 g (87%); m.p. 112.2-114.3 C. H NMR (CDCl3, 400
MHz): δ 7.44-7.40 (m, 3H), 7.31-7.26 (m, 8H), 7.20-7.12 (m, 2H), 4.15 (s, 2H).
13C NMR (CDCl3, 100 MHz): δ 154.8, 138.9, 136.2, 135.2, 132.8, 128.9, 128.6,
128.6, 127.9, 126.5, 125.8, 124.7, 123.0, 120.6, 120.3, 111.3, 96.5, 80.2, 30.7.
MS (EI, 70 eV) m/z (relative intensity): 334 [M+1, (36)], 343 (39), 342 (100), 341
(45), 307 (32), 305 (36), 276 (22), 265 (23), 231 (51), 202 (27), 153 (31), 138
(36). HRMS Calcd for C23H15ClO (M + Na+): 365.0704. Found: 365.0725.
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3-benzyl-2-(naphthalen-1-ylethynyl)benzofuran (2h). Obtained as a pallid
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brown solid. Yield: 0.064 g (72%); m.p. 84.9-86.2 C. H NMR (CDCl3, 400
MHz): δ 8.37 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 7.1 Hz,
1H), 7.57-7.41 (m, 4H), 7.38 (d, J = 7.2 Hz, 3H), 7.32-7.25 (m, 3H), 7.21-7.14
(m, 2H), 4.26 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ 154.9, 139.1, 136.7, 133.2,
133.0, 130.8, 129.6, 128.6, 128.4, 128.1, 127.2, 126.7, 126.5, 126.1, 125.8,
125.3, 124.5, 123.0, 120.3, 119.7, 111.4, 96.1, 84.0, 30.8. MS (EI, 70 eV) m/z
(relative intensity): 359 [M+1, (38)], 358 (100), 357 (50), 342 (15), 281 (22), 252
(21), 231 (18), 207 (19), 178 (17), 163 (20), 150 (17). Anal. (%) Calcd for
C27H18O: C 90.47; H 5.06. Found: C 90.59; H 5.10.
3-benzyl-2-(thiophen-3-ylethynyl)benzofuran (2i). Obtained as a pallid yellow
1
solid. Yield: 0.068 g (87%); m.p. 133.0-135.5 0C. H NMR (CDCl3, 400 MHz): δ
7.55 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33-7.24 (m, 7H), 7.20-7.16
(m, 2H), 7.13 (t, J = 7.3 Hz, 1H), 4.15 (s, 2H). 13C NMR (CDCl3, 100 MHz): δ
154.8, 139.0, 136.5, 129.8, 129.7, 128.6, 128.5, 128.0, 126.4, 125.7, 125.6,
124.1, 122.9, 121.2, 120.2, 111.2, 92.8, 78.7, 30.6. MS (EI, 70 eV) m/z (relative
intensity): 314 (64), 281 (41), 253 (20), 237 (20), 207 (100), 191 (21), 133 (23),
96 (19), 73 (43). HRMS Calcd for C21H14OS (M + H+): 315.0838. Found:
315.0856.
3-benzyl-2-ethynylbenzofuran (2j). Obtained as a pallid yellow solid. Yield:
0.034 g (59%); m.p. 82.0-83.3 0C. 1H NMR (CDCl3, 400 MHz): δ 7.40 (d, J = 8.2
Hz, 1H), 7.32-7.23 (m, 6H), 7.21-7.16 (m, 1H), 7.13 (t, J = 7.4 Hz, 1H), 4.12 (s,
2H), 3.61 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 154.6, 138.8, 135.4, 128.5,
127.5, 126.4, 125.9, 125.5, 123.0, 120.4, 111.4, 85.7, 73.7, 30.4. MS (EI, 70
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eV) m/z (relative intensity): 233 [M+1, (16)], 232 (94), 231 (100), 202 (48), 176
(10), 155 (41), 126 (10), 101 (20), 88 (9). HRMS Calcd for C17H12O (M + Na+):
255.0780. Found: 255.0791.
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3-(4-methylbenzyl)-2-(phenylethynyl)benzofuran (2k). Obtained as a white
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solid. Yield: 0.065 g (81%); m.p. 85.9-88.8 C. H NMR (CDCl3, 400 MHz): δ
7.54-7.52 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.34-7.33 (m, 4H), 7.27 (t, J = 7.4
Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.7 Hz,
2H), 4.13 (s, 2H), 2.27 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 154.8, 136.4,
136.0, 135.9, 131.6, 129.2, 129.0, 128.5, 128.5, 128.0, 125.6, 124.6, 122.9,
122.2, 120.3, 111.3, 97.6, 79.3, 30.3, 21.0. MS (EI, 70 eV) m/z (relative
intensity): 323 [M+1, (25)], 322 (100), 321 (38), 307 (46), 305 (23), 245 (40),
231 (19), 202 (23), 153 (15), 138 (17), 77 (12). HRMS Calcd for C24H18O (M +
H+): 323.1430. Found: 323.1444.
3-(3-methylbenzyl)-2-(phenylethynyl)benzofuran (2l). Obtained as a pallid
0
1
yellow solid. Yield: 0.066 g (82%); m.p. 119.3-120.6 C. H NMR (CDCl3, 400
MHz): δ 7.55-7.53 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.35-7.31 (m, 4H), 7.26 (t, J
= 8.3 Hz, 1H), 7.15-7.11 (m, 4H), 6.98 (d, J = 7.0 Hz, 1H) 4.13 (s, 2H), 2.27 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 154.8, 139.0, 138.1, 136.5, 131.6, 129.4,
129.0, 128.5, 128.5, 128.1, 127.2, 125.7, 125.7, 124.5, 123.0, 122.2, 120.3,
111.3, 97.7, 79.3, 30.6, 21.5. MS (EI, 70 eV) m/z (relative intensity): 323 [M+1,
(29)], 322 (100), 321 (38), 307 (36), 305 (21), 245 (32), 231 (30), 202 (25), 153
(16), 138 (16). Anal. (%) Calcd for C24H18O: C 89.41; H 5.63. Found: C 89.55; H
5.67.
3-(4-methoxybenzyl)-2-(phenylethynyl)benzofuran (2m). Obtained as a
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1
pallid yellow solid. Yield: 0.076 g (90%); m.p. 51.3-52.5 C. H NMR (CDCl3,
400 MHz): δ 7.55-7.53 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.34-7.32 (m, 4H), 7.29
(d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 6.80 (d, J =
8.7 Hz, 2H) 4.11 (s, 2H), 3.71 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 158.3,
154.8, 136.3, 131.6, 131.1, 129.6, 129.0, 128.5, 128.0, 125.7, 124.8, 122.9,
122.1, 120.3, 114.0, 111.3, 97.6, 79.3, 55.2, 29.8. MS (EI, 70 eV) m/z (relative
intensity): 339 [M+1, (25)], 338 (100), 323 (23), 307 (21), 293 (10), 261 (18),
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