Synthesis of dibenzofurans by palladium-catalysed tandem denitrification/C-H activation

Article abstract of DOI:10.1055/s-0031-1289881

A palladium-catalysed method for intramolecular cyclisation of ortho-diazonium salts of diaryl ethers to give dibenzofurans is described. The protocol uses 3 mol% palladium acetate as the catalyst in refluxing ethanol in the absence of base. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289881

LETTER
3023
Synthesis of Dibenzofurans by Palladium-Catalysed Tandem Denitrification/
C–H Activation
Synthesis of
D
ib
h
enzofurans enting Du,* Jing Zhou, Changmei Si, Weili Ma
College of Science, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. of China
Fax +86(29)87092226; E-mail: duzt@nwsuaf.edu.cn
Received 30 August 2011
Our research group is searching for new heterocyclic
Abstract: A palladium-catalysed method for intramolecular cycli-
sation of ortho-diazonium salts of diaryl ethers to give dibenzo-
furans is described. The protocol uses 3 mol% palladium acetate as
the catalyst in refluxing ethanol in the absence of base.
structures that can serve as potential bioactive compounds
in agriculture.16 We are interested in developing an effi-
cient and convenient route to dibenzofurans catalysed by
a transition-metal catalyst. Gajera and co-workers have
reported a synthesis of dibenzofurans in which the in-
tramolecular Cu-catalysed coupling of diazonium salt was
a key step.11 To the best of our knowledge, there are few
reports on palladium catalysed synthesis of dibenzofuran
from diazonium salts.11,12c Herein, we wish to disclose the
details of an efficient synthesis of dibenzofurans from di-
azonium salts of diaryl ethers catalysed by palladium ace-
tate in 80–93% yield.
Key words: palladium acetate, dibenzofurans, diazonium salts
Dibenzofuran derivatives are important cyclic structures
in organic synthesis because they can be found in many
natural occurring products,1 pharmaceuticals,2 pesticides3
and optical materials.4 A literature survey reveals a num-
ber of classical methods that have been reported on the
synthesis of dibenzofurans. In general, there are mainly
two ways to construct dibenzofuran derivatives
(Scheme 1) and other miscellaneous methods.5 One in-
volves initial formation of diaryl ether compounds, fol-
lowed by a ring closure using light,6 iodine,7 triflate,8
palladium,9 decarboxylation/C–H activation,10 CuI,11 or
Pschorr-type ring closure (Scheme 1, path a).12 The sec-
ond approach involves initial preparation of biaryl deriv-
atives through the Suzuki reaction, and then formation of
an intramolecular ether bond using dehydration,13
Hartwig–Buchwald protocol,4b C–H activation/C–O
cyclisation14 or an intramolecular SNAr reaction
(Scheme 1, path b).15 However, these methods can suffer
some drawbacks such as harsh reaction conditions (high
temperature and basic or acidic conditions), low yields,
expensive metal or ligands, unpredictable products and
limited applicability. For this reason, an alternative, effi-
cient synthetic method to prepare dibenzofurans under
mild reaction conditions is highly desirable.
Initially, considering the radical cyclisation mecha-
nism,12c we were interested in using a variety of single-
electron donors such as Cu(I), Fe(acac)2, Ni(acac)2, SmI2,
to achieve a mild and general procedure for the synthesis
of dibenzofurans. However, the cyclisation of diazonium
salts of diaryl ethers did not occur, and these metal cata-
lysts proved to be inappropriate. Fortunately, when
Pd(OAc)2 (Table 1, entry 1) was used to catalyse the mod-
el reaction of 2-phenoxybenzenediazonium tetrafluorobo-
rate (1a) in N,N-dimethylformamide, a promising result
was obtained whereby dibenzofuran (2a) was obtained in
70% yield. Our studies subsequently showed that the na-
ture of the solvent was very important for this reaction. In
methanol (Table 1, entry 2) or ethanol (Table 1, entry 3),
a yield of 85% or higher could be obtained. In contrast, by
using dichloromethane (Table 1, entry 4) or acetonitrile
(Table 1, entry 5) as the solvent, the reaction was marked-
ly less effective. To our delight, ethanol was found to be
an excellent solvent in which the cyclisation reaction al-
ways gave appreciable yields in a shorter time; it is also
less harmful. Subsequently, the effect of catalyst loading
was investigated. For the model reaction, 3 mol% catalyst
was sufficient to transform the diazonium salt into diben-
zofuran within 30 minutes in 90% yield. Use of 1 mol%
catalyst required longer reaction time and gave lower
yield (Table 1, entry 6) and use of 5 mol% catalyst gave
only a slight increase in yield (Table 1, entry 7). We also
tried to add a base to the reaction. To our surprise, neither
inorganic base Na2CO3 (Table 1, entry 8) nor organic base
triethylamine (Table 1, entry 9) gave a positive effect. Fi-
nally, we established the optimised reaction conditions to
be ethanol as solvent and 3 mol% Pd(OAc)2 as catalyst,
and the reaction was conducted at reflux temperature
without the addition of any base (Table 1, entry 3).
transition-metal-
catalysed or
miscellaneous
X
Y
path a
– XY
O
O
X = Halo, H, OTs; Y = Halo, H, OTs
transition-metal-
catalysed or
miscellaneous
path b
– HX
O
OH X
X = Br, OH
Scheme 1
SYNLETT 2011, No. 20, pp 3023–3025
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289881; Art ID: W18911ST
© Georg Thieme Verlag Stuttgart · New York

3024
Z. Du et al.
LETTER
Table 1 Screening of Reaction Conditions for the Cyclisation of
2-Phenoxybenzenediazonium Tetrafluoroborate (1a)
Table 2 Pd(OAc)2-Catalysed Cyclisation 2-Phenoxybenzenediazo-
nium Tetrafluoroborate
O
O
R3
Pd(OAc)2
solvent
R3
Pd(OAc)2 (5 mol%)
EtOH, reflux
O
O
+
N2
1a
2a
R1
N2
R2
+
0.5–1 h
R1
R2
Temp (°C) Yield (%)a
–
1
2
Entry Catalyst
Base
none
none
none
none
none
none
none
Na2CO3
Et3N
Solvent
DMF
BF4
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
100
70
Entry 1, 2
R1
R2
R3
H
H
H
H
H
H
H
H
Isolated yield (%)
MeOH
EtOH
CH2Cl2
MeCN
EtOH
EtOH
EtOH
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
85
1
2
a
b
c
d
e
f
H
H
89
88
90
90
85
90
92
92
90
75
88
89
90
93
85
89
H
Me
n.r.
10
3
H
OMe
F
4
H
60b
91c
N/Ad
N/Ad
5
H
Br
6
Cl
Cl
Cl
Cl
Cl
H
H
7
g
h
i
Br
8
OMe
H
a Isolated yield.
9
OMe
H
b 1 mol% ratio Pd(OAc)2 was used.
c 5 mol% ratio Pd(OAc)2 was used.
d Complex mixture of products.
10
11
12
13
14
15
j
t-Bu
t-Bu
H
k
l
H
H
OMe
Me
With the optimised reaction conditions established, we
next examined the scope of the Pd(OAc)2 catalysed cycli-
sation for the synthesis of substituted dibenzofurans; the
results are summarised in Table 2. A wide range of struc-
turally diverse 2-phenoxybenzenediazonium tetrafluoro-
borates (Table 2), including chloro (Table 2, entries 6–
10), bromo (entry 5), fluoro (entry 4), and methoxy groups
(entry 3) were reacted under this protocol to provide the
corresponding dibenzofurans in high yields. Neither the
electronic nature nor the steric bulk of the substituent on
the aromatic rings had any clear influence upon the reac-
tivity. When R2 was varied, it was found that electron-
neutral (Table 2, entries 1, 9, 12, and 13), electron-rich
(Table 2, entries 2, 3, 10, and 11) and electron-deficient
(Table 2, entries 4, 5, 7, 14, and15) substituents were all
good substrates for this reaction. Electron-donating R3
groups were of benefit to this protocol (Table 2, entries 9,
11, and 12). To the best of our knowledge, these condi-
tions gave the best results for the preparation of halod-
ibenzofurans reported to date (Table 2, entries 5–10). The
bromo- and chlorodibenzofuran derivatives could be eas-
ily functionalised to the boric acid or stannane derivatives,
which makes it possible to obtain more complex substitut-
ed dibenzofurans by subsequent coupling reactions (Su-
zuki and Stille reaction). All the products in the reactions
listed in Table 2 were characterised on the basis of physi-
cal and spectral data and also by comparison with authen-
tic samples. The structure of compound 2i was determined
by X-ray crystallography, and the ORTEP diagram is
shown in Figure 1.17
m
n
o
H
H
H
OMe
OMe
COOEt
COOPh
H
Figure 1 ORTEP drawing of 2i
A proposed mechanism of this intramolecular cyclisation
is shown in Scheme 2.18 Firstly, Pd(II) was reduced to
Pd(0) by reducing reagents,19 followed by oxidative addi-
tion of the diazonium salt to form intermediate I and re-
lease nitrogen. Subsequent insertion of an ortho aromatic
C–H bond to the metal gives intermediate II. Finally, re-
ductive elimination of intermediate II leads to formation
of the dibenzofuran and regeneration of the Pd(0) catalyst.
In conclusion, an efficient and convenient method has
been developed for the formation of dibenzofurans from
common ortho-diazonium salts of diaryl ethers by the
Synlett 2011, No. 20, 3023–3025 © Thieme Stuttgart · New York

LETTER
Synthesis of Dibenzofurans
3025
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C–H activation
O
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Crystallographic Data Center.
O
Pd
H
L
2a
II
Scheme 2 Proposed mechanism of palladium-catalysed formation
of dibenzofuran
action of Pd(OAc)2.20,21 This method is bestowed with
several unique merits, such as high conversions and
yields, simplicity in operation, cost-effectiveness and
functional-group tolerance. Thus, we believe that this
novel methodology will be a practical alternative to the
existing procedures and cater to the needs of academia as
well as industry. Further exploration of the mechanism,
scope, and synthetic application of the reaction are under-
way.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial supports from the Fundamental Research Funds for the
Central Universities in NWSUAF (No. QN2009048) and the Natio-
nal Natural Science Foundation of China (20802058) are greatly ap-
preciated.
(18) Jiro, T. Palladium Reagents and Catalysts: New
Perspectives for the 21st Century; Wiley: New York, 2004.
(19) Zeng, M.; Du, Y.; Shao, L.; Qi, C.; Zhang, X.-M. J. Org.
Chem. 2010, 75, 2556.
References and notes
(20) General procedure for the preparation of dibenzofurans from
ortho-diazonium salts of diaryl ethers using Pd(OAc)2: To a
stirred suspension of the ortho-diazonium salt of the
appropriate diaryl ether (5 mmol) in EtOH (20 mL), a
catalytic amount Pd(OAc)2 (33 mg, 0.15 mmol) was added,
and the resulting mixture was heated at reflux for 30–60 min.
The precipitate of metal was filtered, the filtrate was
evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel eluting
with a mixture of petroleum ether and EtOAc to give
dibenzofurans.
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(21) Spectral data of compound 2i: 1H NMR (500 MHz, CDCl3):
d = 7.88 (s, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.48 (d, J =
7.6 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.28 (t, J = 7.8 Hz,
1 H), 7.01 (d, J = 7.6 Hz, 1 H), 4.07 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 154.4, 145.9, 145.6, 128.3, 127.2, 125.8,
124.8, 123.8, 120.6, 112.9, 112.8, 109.9, 56.2. IR: 1443,
1296, 1258, 1199, 1105 cm–1.
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