Synthesis of dibenzofurans directly from aryl halides and ortho-bromophenols via one-pot consecutive SNAr and intramolecular palladium-catalyzed aryl-aryl coupling reactions

Article abstract of DOI:10.1248/cpb.56.1496

A series of dibenzofurans were efficiently and conveniently synthesized via one-pot consecutive C(sp²)-O bond formation reaction (SNAr) in the presence of anhydrous K₂CO₃, followed by C(sp ²)-C(sp²) b

Full text of DOI:10.1248/cpb.56.1496

1496
Notes
Chem. Pharm. Bull. 56(10) 1496—1498 (2008)
Vol. 56, No. 10
Synthesis of Dibenzofurans Directly from Aryl Halides and ortho-
Bromophenols via One-Pot Consecutive SNAr and Intramolecular
Palladium-Catalyzed Aryl–Aryl Coupling Reactions
Hui XU* and Ling-Ling FAN
Laboratory of Pharmaceutical Synthesis, College of Sciences, Northwest A&F University; Yangling 712100, China.
Received June 27, 2008; accepted July 9, 2008; published online July 9, 2008
A series of dibenzofurans were efficiently and conveniently synthesized via one-pot consecutive C(sp2)–O
bond formation reaction (SNAr) in the presence of anhydrous K2CO3, followed by C(sp2)–C(sp2) bond formation
reaction (intramolecular palladium-catalyzed aryl–aryl coupling reaction) between aryl halides and ortho-bro-
mophenols. The desired dibenzofurans were obtained in 32—99% isolated yields.
Key words dibenzofuran; one-pot reaction; C(sp2)–O bond formation reaction; aryl–aryl coupling reaction
Tandem reactions involve a sequence of reactions per- 99% isolated yields. Take entry 1 (Table 1) for example, the
formed in the same reaction vessel.1) Nowadays, tandem re- mixture of 2-bromophenol (0.5 mmol), 4-fluoronitrobenzene
actions have emerged as powerful tools to meet the demands (0.5 mmol), and anhydrous K2CO3 (1.0 mmol) in DMF (3 ml)
of modern organic chemistry due to the synthetic efficiency, was stirred at 90 °C under an argon atmosphere. When the
molecular diversity, and low production costs, etc.2—5) Re- starting materials were nearly consumed after 0.75 h accord-
cently, we discovered tandem sequences for the efficient syn- ing to thin-layer chromatography (TLC) analysis, Pd(OAc)2
thesis of diaryl ethers from arylmethanesulfonates and aryl (0.025 mmol) and PPh3 (0.05 mmol) were added to the above
halides.6) Meanwhile, it is well-known that dibenzofurans are mixture, which was continued to be stirred at 90 °C for 0.5 h
good candidates for the study of molecular recognition,7—9) under an argon atmosphere to give 2-nitrodibenzofuran (3a)
catalytic reactions10—12) and the geometry of metal-binding in a 97% yield.
sites.13) Although Ames et al. had reported the synthesis of
It was found that the steric effects between 4-fluoroni-
dibenzofurans, step-wise procedures were needed and the trobenzene and 2-fluoronitrobenzene was obvious. For exam-
corresponding yields were also not good14); lately, Liu et al. ple, when 4-fluoro- or 2-fluoronitrobenzene was reacted with
discovered that the dibenzofurans could be prepared by the ortho-bromophenols, 2-nitrodibenzofuran (3a) and 4-ni-
reaction of ortho-iodophenols with silylaryl triflates in the trodibenzofuran (3b) were obtained in 97% for 1.25 h and
presence of CsF and palladium, but expensive and excess 85% for 3.5 h yields, respectively (entries 1 vs. 2); 7-fluoro-
base and not easily available starting material were used.15) 2-nitrodibenzofuran (3e) and 7-fluoro-4-nitrodibenzofuran
Thereby, the construction of dibenzofurans with simple, (3f) were obtained in 79% for 1 h and 64% for 6 h yields, re-
cheap and easily available organic molecules and base in a spectively (entries 5 vs. 6); 8-methoxy-2-nitrodibenzofuran
facile and efficient one-pot reaction is highly desirable. In the (3i) and 8-methoxy-4-nitrodibenzofuran (3j) were obtained
continuation of our program aimed at the discovery and de- in 99% for 1 h and 85% for 5.75 h yields, respectively (en-
velopment of new tandem reactions,6) herein we report the tries 9 vs. 10).
synthesis of dibenzofurans directly from aryl halides with
It was noteworthy that when the nitro group of 4-fluoro- or
ortho-bromophenols via one-pot C(sp2)–O bond formation 2-fluoronitrobenzene was substituted by cyano group to be
reaction (SNAr) in the presence of anhydrous K2CO3, fol- reacted with ortho-bromophenols, the yields of the corre-
lowed by C(sp2)–C(sp2) bond formation reaction (intramolec- sponding dibenzofurans decreased; in addition, the SNAr re-
ular aryl–aryl coupling reaction) catalyzed by Pd(OAc)2 action rates of 4-fluoro- or 2-fluorobenzonitrile reacted with
(Chart 1).
ortho-bromophenols slowed down sharply as compared with
4-fluoro- or 2-fluoronitrobenzene, such as entries 1 (97%,
0.75 h) vs. 3 (48%, 18 h), entries 2 (85%, 1 h) vs. 4 (71%,
Results and Discussion
Dibenzofurans were efficiently and conveniently prepared 24 h), entries 5 (79%, 0.5 h) vs. 7 (32%, 12 h), and entries 6
via one-pot C(sp2)–O bond formation reaction (SNAr), fol- (64%, 1 h) vs. 8 (39%, 12 h).
lowed by C(sp2)–C(sp2) bond formation reaction (intramolec-
Meanwhile, when the ortho-bromophenols having the
ular palladium-catalyzed aryl–aryl coupling reaction) be- electron-donating group (e.g., methoxy group) were reacted
tween aryl halides and ortho-bromophenols. As shown in with fluoronitrobenzene, the corresponding yields of diben-
Table 1, the dibenzofurans (3a—j) were obtained in 32— zofurans were higher than those having electron-withdrawing
Chart 1. The Synthetic Route of Dibenzofurans 3a—j
∗ To whom correspondence should be addressed. e-mail: orgxuhui@nwsuaf.edu.cn
© 2008 Pharmaceutical Society of Japan

October 2008
1497
Table 1. An Efficient One-Pot Synthesis of Dibenzofurans (3a—j) from Aryl Halides and 2-Bromophenols
2-Bromophenols
Aryl halides
Dibenzofurans
Time
(h)a)
Yield
(%)b)
Entry
1
(1)
(2)
(3)
3a
0.75ꢁ0.5
97
2
3
3b
3c
1ꢁ2.5
85
71
24ꢁ1.5
4
5
6
7
3d
3e
3f
18ꢁ24
0.5ꢁ0.5
1ꢁ5
48
79
64
32
3g
12ꢁ6
8
9
3h
3i
12ꢁ6
39
99
0.5ꢁ0.5
10
3j
0.75ꢁ5
4ꢁ3
85
83
68
11c)
12c)
3j
3i
7ꢁ0.5
a) “0.75ꢁ0.5” means 0.75 h for the SNAr reaction of compounds 1 and 2 in the presence of K2CO3, and 0.5 h for the sequent intramolecular palladium-catalyzed aryl–aryl
coupling reaction at 90 °C, respectively; b) isolated yields; c) under reflux conditions.
group (e.g., fluoro group) (entries 9 vs. 5; 10 vs. 6).
the yields.
Finally, other aryl halides, such as 2-chloronitrobenzene
and 4-bromonitrobenzene, reacted with 4-methoxy-ortho- Conclusion
bromophenol were also investigated. Based upon our previ-
In conclusion, we have reported an efficient and conven-
ous reports that the leaving ability of halogenes in SNAr reac- ient one-pot synthesis of dibenzofurans via SNAr reaction be-
tions decreases in order FꢀClꢀBr,6) therefore, 2-chloro- tween aryl halides and ortho-bromophenols in the presence
nitrobenzene or 4-bromonitrobenzene was reacted with 4- of anhydrous K2CO3, followed by aryl–aryl coupling reaction
methoxy-ortho-bromophenol under reflux conditions, and the catalyzed by Pd(OAc)2. Compared to the reported meth-
corresponding yields of 3j and 3i were 83% and 68%, re- ods,14,15) the main advantages of this method are as follows:
spectively (entries 11, 12). These results showed that fluoro 1) moderate to good yields; 2) use of very inexpensive base
derivatives might be replaced by the corresponding bromo or and easily available starting materials; 3) simple and practi-
chloro derivatives without causing a significant decrease in cal procedure.

1498
Vol. 56, No. 10
Experimental
(1H, dt, Jꢃ8.8, 2.4 Hz), 7.32 (1H, dd, Jꢃ8.8, 2.4 Hz), 7.63 (1H, d,
Jꢃ8.4 Hz), 7.71 (1H, dd, Jꢃ8.4, 1.2 Hz), 7.90 (1H, dd, Jꢃ8.4, 1.2 Hz), 8.22
(1H, s); EI-MS m/z: 210.9 (Mꢁ, 100); HR-MS m/z: 211.0432 [M]ꢁ, Calcd
211.0428.
All the solvents were of analytical grade and the reagents were used as
purchased. TLC was performed with silica gel plates using silica gel 60
GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were deter-
1
1
mined on a digital melting-point apparatus and were uncorrected. H-NMR
3h: White solid, mp 177—177.5 °C; H-NMR (400 MHz, CDCl3) d: 7.15
spectra were recorded on a Bruker Avance DMX 400 MHz instrument using
TMS as internal standard and CDCl3 as solvent. HR-MS and EI-MS were
carried out with APEX II Bruker 4.7T AS and Thermo DSQ GC/MS instru-
ments, respectively.
(1H, dt, Jꢃ8.8, 2.0 Hz), 7.38 (2H, m), 7.70 (1H, d, Jꢃ8.0 Hz), 7.90 (1H, dd,
Jꢃ8.4, 5.6 Hz), 8.11 (1H, d, Jꢃ8.0 Hz); EI-MS m/z: 210.9 (Mꢁ, 100); HR-
MS m/z: 211.0426 [M]ꢁ, Calcd 211.0428.
1
3i: Yellow solid, mp 166—167 °C; H-NMR (400 MHz, CDCl3) d: 3.82
General Procedure for the Synthesis of Dibenzofurans 3a—j The
mixture of 2-bromophenols (1, 0.5 mmol), aryl halides (2, 0.5 mmol), and
anhydrous K2CO3 (1.0 mmol) in DMF (3 ml) in 25 ml rockered flask was
stirred at 90 °C (for 2-chloronitrobenzene or 4-bromonitrobenzene, under re-
flux conditions) under an argon atmosphere and the reaction process was
checked by TLC. When the starting materials was nearly consumed,
Pd(OAc)2 (0.025 mmol) and PPh3 (0.05 mmol) were added to the above mix-
ture, which was continued to be stirred at 90 °C (for 2-chloronitrobenzene or
4-bromonitrobenzene, under reflux conditions) under an argon atmosphere.
When the reaction was complete according to TLC analysis, the reaction
mixture was cooled to r.t., poured into ice water (30 ml), and extracted by
EtOAc (30 mlꢂ4). Subsequently, the combined organic phase was washed
by brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified
by silica gel column chromatography to give the pure dibenzofurans, which
were characterized by 1H-NMR (400 MHz), HR-MS, EI-MS and mp.
3a: White solid, mp 153—155 °C (lit.,14) 153—155 °C); 1H-NMR
(400 MHz, CDCl3) d: 7.43 (1H, t, Jꢃ7.6 Hz), 7.55 (1H, m), 7.63 (2H, m),
8.02 (1H, d, Jꢃ7.6 Hz), 8.38 (1H, dd, Jꢃ9.2, 2.4 Hz), 8.85 (1H, d,
Jꢃ2.4 Hz); EI-MS m/z: 213 (Mꢁ, 100).
(3H, s), 7.12 (1H, dd, Jꢃ9.2, 2.4 Hz), 7.45 (1H, d, Jꢃ2.0 Hz), 7.51 (1H, d,
Jꢃ8.8 Hz), 7.59 (1H, d, Jꢃ9.2 Hz), 8.35 (1H, dd, Jꢃ9.2, 2.0 Hz), 8.82 (1H,
d, Jꢃ1.6 Hz); EI-MS m/z: 243 (Mꢁ, 50).
3j: Yellow solid, mp 198—198.5 °C; 1H-NMR (400 MHz, CDCl3) d: 3.91
(3H, s), 7.13 (1H, dd, Jꢃ8.8, 2.4 Hz), 7.40 (2H, m), 7.62 (1H, d, Jꢃ9.2 Hz),
8.18 (1H, dd, Jꢃ7.6, 1.2 Hz), 8.25 (1H, dd, Jꢃ8.4, 1.2 Hz); EI-MS m/z: 243
(Mꢁ, 100); HR-MS m/z: 243.0522 [M]ꢁ, Calcd 243.0526.
Acknowledgments This work has been supported by the program for
New Century Excellent University Talents, State Education Ministry of
China (NCET-06-0868).
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3b: Yellow solid, mp 137—138 °C (lit.,14) 137—138 °C); 1H-NMR
(400 MHz, CDCl3) d: 7.43 (2H, m), 7.56 (1H, dt, Jꢃ8.4, 1.2 Hz), 7.74 (1H,
d, Jꢃ8.0 Hz), 7.99 (1H, d, Jꢃ8.0 Hz), 8.24 (1H, dd, Jꢃ7.6, 1.2 Hz), 8.27
(1H, dd, Jꢃ8.4, 1.2 Hz); EI-MS m/z: 213 (Mꢁ, 92).
1
3c: White solid, mp 135—136 °C; H-NMR (400 MHz, CDCl3) d: 7.40
(2H, t, Jꢃ7.6 Hz), 7.53 (1H, t, Jꢃ8.0 Hz), 7.62 (1H, d, Jꢃ8.0 Hz), 7.71 (1H,
d, Jꢃ7.6 Hz), 7.96 (1H, d, Jꢃ7.6 Hz), 8.15 (1H, d, Jꢃ7.6 Hz); EI-MS m/z:
192.9 (Mꢁ, 100); HR-MS m/z: 193.0520 [M]ꢁ, Calcd 193.0522.
3d: White solid, mp 145—146 °C (lit.,14) 141—143 °C); 1H-NMR
(400 MHz, CDCl3) d: 7.40 (1H, m), 7.53 (1H, m), 7.61 (2H, m), 7.73 (1H,
dd, Jꢃ8.4, 1.6 Hz), 7.97 (1H, d, Jꢃ8.0 Hz), 8.27 (1H, d, Jꢃ0.8 Hz); EI-MS
m/z: 192.9 (Mꢁ, 100).
1
3e: White solid, mp 187—188 °C; H-NMR (400 MHz, CDCl3) d: 7.16
(1H, dt, Jꢃ8.8, 2.0 Hz), 7.33 (1H, dt, Jꢃ8.8, 2.0 Hz), 7.63 (1H, d,
Jꢃ9.2 Hz), 7.94 (1H, dd, Jꢃ8.8, 2.4 Hz), 8.35 (1H, dd, Jꢃ8.8, 2.0 Hz), 8.81
(1H, d, Jꢃ2.4 Hz); EI-MS m/z: 231 (Mꢁ, 100); HR-MS m/z: 231.0330 [M]ꢁ,
Calcd 231.0326.
1
3f: White solid, mp 166—167 °C; H-NMR (400 MHz, CDCl3) d: 7.17
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(1H, dt, Jꢃ8.8, 2.0 Hz), 7.45 (2H, m), 7.92 (1H, m), 8.19 (1H, d, Jꢃ7.2 Hz),
8.25 (1H, d, Jꢃ8.0 Hz); EI-MS m/z: 231 (Mꢁ, 92); HR-MS m/z: 231.0322
[M]ꢁ, Calcd 231.0326.
1
3g: White solid, mp 175—176 °C; H-NMR (400 MHz, CDCl3) d: 7.15