One-pot Synthesis of Dibenzofurans via SNAr and Subsequent Ligand-free Palladium-catalyzed Intramolecular Aryl-aryl Cross-coupling Reactions under Microwave Irradiation

Article abstract of DOI:10.1515/znb-2011-0808

An efficient one-pot synthesis of dibenzofurans, via SNAr reaction of aryl halides and ortho-bromophenols in the presence of anhydrous K₂CO ₃ and subsequent ligand-free palladium-catalyzed intramolecular aryl-aryl cross-coupling cyclization under microwave irradiation, is described.

Full text of DOI:10.1515/znb-2011-0808

One-pot Synthesis of Dibenzofurans via SNAr and Subsequent
Ligand-free Palladium-catalyzed Intramolecular Aryl-aryl
Cross-coupling Reactions under Microwave Irradiation
Zhiping Che and Hui Xu
Laboratory of Pharmaceutical Design & Synthesis, College of Science, Northwest A&F University,
Yangling 712100, Shaanxi Province, China
Reprint requests to Prof. Dr. Hui Xu. Fax: +86(0)29/87091952. E-mail: orgxuhui@nwsuaf.edu.cn
Z. Naturforsch. 2011, 66b, 833 – 836; received June 20, 2011
An efficient one-pot synthesis of dibenzofurans, via SNAr reaction of aryl halides and ortho-bromo-
phenols in the presence of anhydrous K2CO3 and subsequent ligand-free palladium-catalyzed in-
tramolecular aryl-aryl cross-coupling cyclization under microwave irradiation, is described.
Key words: Dibenzofurans, Ligand-free, Microwave, SNAr Reaction, Cross-coupling
Introduction
under conventional heating, but triphenylphosphane
was involved as a ligand, and especially for some
aryl halides, such as 4-fluorobenzonitrile and 2-fluoro-
benzonitrile, the results were often not satisfactory
even if the reaction time was prolonged [12]. In
the meantime, due to the efficiency of microwave
flash-heating, microwave-assisted organic synthesis
(MAOS) has been growing in different fields of or-
ganic and medicinal chemistry [13 – 16]. Based on the
above-mentioned reports, and in continuation of our
program aimed at the development of new methods
for the construction of heterocycles, consequently, in
the work presented in this paper we wanted to inves-
tigate the synthesis of dibenzofurans from 2-bromo-
phenols with aryl halides via an SNAr reaction and sub-
sequent ligand-free palladium-catalyzed intramolecu-
lar aryl-aryl coupling cyclization under microwave ir-
radiation.
Dibenzofuran derivatives, besides their uses for
molecular recognition [1 – 3], catalytic reactions [4, 5]
and metal-binding sites [6], also display interesting
biological activities, such as against the human im-
munodeficiency virus (HIV)-1 [7] and for protein ty-
rosine phosphatase 1B (PTP1B) inhibition [8]. There-
fore, much attention has been paid to the construc-
tion of dibenzofurans. Ames et al. reported the syn-
thesis of dibenzofurans, but step-wise procedures were
needed there, and the yields were usually low [9]. Al-
though dibenzofurans could also be prepared by the
reaction of ortho-iodophenols with silylaryl triflates
in the presence of CsF and palladium, expensive ex-
cess base and other not easily available starting ma-
terials were needed [10]. Another innovative route for
the synthesis of substituted dibenzofurans has been de-
scribed by Goel et al., however, special starting mate-
rials must be used for this tedious procedure [11]. In
our previous work, we have reported a one-pot syn-
thesis of dibenzofurans directly from 2-bromophenols
with aryl halides via an SNAr reaction and subsequent
palladium-catalyzed intramolecular aryl-aryl coupling
Results and Discussion
As outlined in Scheme 1, firstly, 2-bromophen-
ols 1a – c were reacted with aryl halides 2a – f
for 10– 60 min in the presence of anhydrous K2CO3
Scheme 1. The synthetic
route to dibenzofuran
derivatives 3a – j.
c
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834
Z. Che – H. Xu · One-pot Synthesis of Dibenzofurans
Table 1. One-pot synthesis of dibenzofurans 3a – j from 2-bromophenols and aryl halides under microwave irradiation.
Entry 2-Bromophenols
Aryl halides
(2)
Dibenzofurans
(3)
Time
Yield
(%)b
(1)
(min)a
1
1a
2a
3a
10 (100 ◦C) + 20×6 (100 ◦C)
93
2
3
1a
1a
2a
2b
3a
3b
10 (100 ◦C) + 10 (150 ◦C)
10 (100 ◦C) + 30 (150 ◦C)
96
88
4
5
1b
1b
2a
2b
3c
10 (100 ◦C) + 10 (150 ◦C)
10 (100 ◦C) + 30 (150 ◦C)
82
89
3d
6
7
1c
1c
2a
2b
3e
3f
10 (100 ◦C) + 10 (150 ◦C)
10 (100 ◦C) + 30 (150 ◦C)
95
89
8
9
1b
1b
2c
3g
3h
30×2 (150 ◦C) + 30 (150 ◦C)
30×2 (150 ◦C) + 30 (150 ◦C)
72
75
2d
30 × 2 (150 ◦C)
+
30 × 2
10
11
1c
1c
2c
3i
3j
88
86
(150 ◦C)
2d
30×2 (150 ◦C) + 30 (150 ◦C)
12
1a
2e
3a
30 (150 ◦C) + 10 (150 ◦C)
72
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Z. Che – H. Xu · One-pot Synthesis of Dibenzofurans
835
Table 1 (continued).
Entry 2-Bromophenols
Aryl halides
(2)
Dibenzofurans
(3)
Time
Yield
(%)b
(1)
(min)a
13
1a
2f
3b
30 (150 ◦C) + 30 (150 ◦C)
81
14
15
16
17
18c
1b
1b
1c
1c
1c
◦
2e
2f
2e
2f
2c
3c
3d
3e
3f
3i
30 (150 ◦C) + 10 (150 ◦C)
30 (150 ◦C) + 30 (150 ◦C)
30 (150 ◦C) + 10 (150 ◦C)
30 (150 ◦C) + 30 (150 ◦C)
370 (150 ◦C) + 30 (150 ◦C)
75
78
77
85
75
a
◦
◦
“10 (100 C) + 20 × 6 (10 C)” means 10 min at 100 C for the SNAr reaction of compounds 1 and 2 in the presence of K2CO3, and
◦
20 × 6 min at 10 C for the subsequent ligand-free palladium-catalyzed intramolecular arylaryl coupling reaction, reaction temperature is
given in parentheses; b isolated yields; c under conventional heating.
◦
(1.0 mmol) under microwave irradiation to afford the As expected, even at 150 C the reaction time needs
intermediates 4 via an SNAr reaction, which were then also to be prolonged to 1 h to improve the yields of the
used directly for the subsequent ligand-free palladium- SNAr reaction. The results of 1c reacting with 2c un-
catalyzed intramolecular aryl-aryl coupling cycliza- der microwave irradiation were compared with those
tion. With microwave irradiation for 10 – 60 min, under conventional heating (entry 10 vs. entry 18), and
dibenzofurans 3a – j were smoothly obtained in 72 – it was obvious that under microwave irradiation the re-
96 % yields.
action time could be sharply reduced from 670 min
to 120 min.
As shown in Table 1, the reaction temperature
for the subsequent ligand-free palladium-catalyzed in-
Finally, 1a, 1b or 1c reacted with 4-bromonitro-
tramolecular aryl-aryl coupling cyclization was im- benzene (2e) or 2-chloronitrobenzene(2f), respectively
(entries 12 – 17). As described in Table 1, due to the
nature of the leaving ability of the halogens of the
der microwave irradiation for 10 min at 100 C to aryl halides, the main difference in this tandem re-
portant. For example, 4-methoxy-2-bromophenol (1a)
completely reacted with 4-fluoronitrobenzene (2a) un-
◦
action between 4-fluoronitrobenzene or 2-fluoronitro-
benzene and 4-bromonitrobenzene or 2-chloronitro-
give the intermediate◦4a, which was further catalyzed
by Pd(OAc)2 at 100 C for 20 × 6 min to produce 8-
methoxy-2-nitrodibenzofuran (3a) in 93 % yield; how- benzene lies in the SNAr reaction. Compared with the
◦
ever, when 4a was exposed to Pd(OAc)2 at 150 C fluoro derivatives, although the SNAr reaction took
a relatively long time at a higher reaction tempera-
only for 10 min, 3a was obtained in 96 % yield (en-
try 1 vs. entry 2). A steric effect was also observed
ture for 2e or 2f, these results have demonstrated that
in the palladium-catalyzed intramolecular cyclization the fluoro derivatives might be replaced by the corre-
sponding bromo or chloro compounds without caus-
ing a significant decrease in the yields (entry 1 vs. en-
of 4-fluoronitrobenzene (2a) and 2-fluoronitrobenze◦ne
(2b). For the 2a series, it only took 10 min at 150 C
to finish the subsequent cyclization, while on the con- try 12; entry 3 vs. entry 13; entry 4 vs. entry 14; en-
trary, it usually took 30 min for the 2b series at the try 5 vs. entry 15; entry 6 vs. entry 16; entry 7 vs.
entry 17).
same reaction temperature to transform the interme-
diates into the final products (entry 1 vs. entry 3; en-
try 4 vs. entry 5; entry 6 vs. entry 7). Based on the re-
sults of our previous research that the SNAr reaction of
5-fluoro-2-bromophenol (1b) or 2-bromophenol (1c)
Conclusion
We have reported an efficient one-pot synthesis of
with 4-fluorobenzonitrile (2c) or 2-fluorobenzonitrile dibenzofuran derivatives in 72 – 96 % yields in short
(2d) is more difficult as compared with 2a and 2b [12], reaction times via the SNAr reaction of aryl halides and
the corresponding reaction temperature was then di- 2-bromophenols in the presence of anhydrous K2CO3
rectly raised to 150 ◦C for the first-step SNAr reaction. and subsequent ligand-free palladium-catalyzed in-
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836
Z. Che – H. Xu · One-pot Synthesis of Dibenzofurans
◦
◦
tramolecular aryl-aryl cross-coupling cyclization un- tion of 50 W for 100 C and 100 W for 150 C was used,
der microwave irradiation.
the temperature being raised from r. t. to 100 or 150 ◦C.
Once the given temperature was reached, the reaction mix-
Experimental Section
ture was held at this temperature for 10 – 30 min. The reac-
tion progress was checked by TLC at the end of each irra-
diation period. When the starting materials were nearly con-
sumed, Pd(OAc)2 (0.025 mmol) was added to the mixture,
the reaction being continued under microwave irradiation
for 10 – 60 min. When the reaction was completed according
to TLC analysis, the vessel was allowed to cool to r. t., and
the mixture was poured into ice water (20 mL) and extracted
with EtOAc (3 × 40 mL). Then the organic phases were
combined and dried over anhydrous Na2SO4, concentrated
in vacuo, and purified by silica gel column chromatogra-
phy to give the pure dibenzofurans 3a – j in 72 – 96 % yields.
Compounds 3a – j were all known compounds and identified
by comparison of the data as described in our previous pa-
per [12].
All reagents and solvents were of reagent grade. Analyt-
ical thin-layer chromatography (TLC) was performed with
silica gel plates using silica gel 60 GF254 (Qingdao Haiyang
Chemical Co., Ltd.). Melting points were determined on a
digital melting point apparatus and are uncorrected. Pro-
ton nuclear magnetic resonance spectra (1H NMR) were
recorded on a Bruker Avance DMX 400 MHz instrument,
using TMS as the internal standard and CDCl3 as the sol-
vent. Electron ionization mass spectrometry (EI-MS) was
carried out with a Thermo DSQ GC/MS instrument. High-
resolution mass spectra (HR-MS) were carried out with an
APEX II Bruker 4.7T AS instrument. Microwave irradiation
was performed in a CEM Discover Synthesis Unit (CEM
Corp., Matthews, NC, made in USA).
Acknowledgement
General procedure for the synthesis of dibenzofuran deriva-
This work was financially in part supported by the Pro-
gram for New Century Excellent University Talents, State
Education Ministry of China (NCET-06-0868), the National
Natural Science Foundation of China (No. 31071737), and
the Special Funds of Central Colleges Basic Scientific Re-
search Operating Expenses (QN2009045).
tives 3a – j
A mixture of 1a – c (0.5 mmol), 2a – f (0.5 mmol), an-
hydrous K2CO3 (1.0 mmol), and DMF (2 mL) was placed
in a 10-mL glass tube, which was sealed with a septum
and placed into the microwave cavity. Microwave irradia-
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