Facile synthesis of benzo[4,5]furo[3,2-c]pyridines via palladium-catalyzed intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2009.05.063

The heating of 4-chloropyridine with 2-bromophenol in either neat or DME as solvent gives rise to 2-bromophenoxy pyridines, which were treated with Pd(OAc)₂ and various ligands to afford functionalized benzo[4,5]furo[3,2-c]pyridines.

Full text of DOI:10.1016/j.tetlet.2009.05.063

Tetrahedron Letters 50 (2009) 4492–4494
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Tetrahedron Letters
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Facile synthesis of benzo[4,5]furo[3,2-c]pyridines via palladium-catalyzed
intramolecular Heck reaction
Woo Sub Yoon a, Su Jung Lee b, Seung Kyu Kang b, Deok-Chan Ha a, Jae Du Ha b,
*
a Department of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, Republic of Korea
b Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The heating of 4-chloropyridine with 2-bromophenol in either neat or DME as solvent gives rise to 2-
bromophenoxy pyridines, which were treated with Pd(OAc)2 and various ligands to afford functionalized
benzo[4,5]furo[3,2-c]pyridines.
Received 7 April 2009
Revised 15 May 2009
Accepted 19 May 2009
Available online 23 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Benzo[4,5]furo[3,2-c]pyridines are a common structural motif
in medicinal chemistry and often display important biological
activity.1 These heterocycles are also used as organic electrolumi-
nescent material.2 Pd-catalyzed intramolecular Heck reaction of
suitably tethered aryl halides has been utilized in the preparation
of dibenzofurans,3,5 benzo[4,5]furo heterocycles,4 and carbazoles,5
the corresponding application with halogenated phenoxy pyri-
dines has seen scant use in the synthesis of benzo[4,5]furo[3,2-
c]pyridines. There are only two reports6,7 on the Pd-catalyzed
intramolecular Heck reaction of halogenated phenoxy pyridines.
We now report a convenient synthesis of benzo[4,5]furo[3,2-c]pyr-
idines bearing several substituents on both rings by adaptation of
the Heck reaction.
Various catalysts, ligands, and bases were screened for the Heck
cyclization (Table 1). First, we examined reaction conditions re-
ported in the two literature precedents (Eqs. 1 and 2).6,7 When 2-
bromophenoxy pyridine was treated with 10 mol % Pd(OAc)2 in
refluxing DMA in the presence of Na2CO3 (Eq. 1), benzo[4,5]-
furo[3,2-c]pyridine 3a was obtained in 59% yield (entry 1). Cycliza-
tion of 2a under Janin’s conditions [5 mol % Pd(OAc)2, K2CO3, and
tetrabutylammonium bromide as promoter in refluxing DMF un-
der air, eq. 2] afforded 3a in significantly lower yield (31%, entry
2). When the reaction was conducted in sealed tube at 130 °C,
the yield improved to 65% (entry 3). A survey of different ligands
such as dppf (entry 4), palladacyclic precatalyst (entry 5), Josiphos
type ligand (entry 6), tricyclohexylphosphine (entry 7), and an
imidazole ligand (1,3-bis-(2,6-diisopropylphenyl)imidazolium
chloride, IPr–HCl) (entry 8), suggested that IPr–HCl was most effec-
tive for this cyclization in the presence of 5 mol % Pd(OAc)2,
10 mol % IPr–HCl, and K2CO3 in DME at 130 °C (sealed tube) to pro-
vide product 3a in 95% isolated yield (entry 7).
Br
Pd(OAc)2, Na2CO3
(1)
DMA, reflux
10%
N
O
O
N
By utilizing optimized conditions, we examined an intramolec-
ular Heck reaction of various 2-bromophenoxy pyridines as
summarized in Table 2. Under optimized conditions, both elec-
tron-deficient (entries 2, 3, and 4) and electron-donating (entry
5) substrates gave good yields of the desired products. Although
the scope is generally broad, several limitations have been noted.
O
O
O
Pd(OAc)2, TBAB
(2)
O
N
Br
DMF, air, reflux
21%
N
Rapid access to 2-bromophenoxy pyridines was found in coupling
of 4-chloropyridines with 2-bromophenols neat or in DME as sol-
vent at 160 °C (sealed tube) for 24 h (Scheme 1). The reaction pro-
ceeded satisfactorily in typical yields of 40–75%, but 2f was isolated
only in 13% yield.
R2
R2
Cl
O
N
HO
Br
Br
R1
R1
neat or DME
N
sealed tube, 160 o
24 h
C
2
1
* Corresponding author. Tel.: +82 042 860 7072; fax: +82 042 860 7160.
E-mail address: jdha@krict.re.kr (J.D. Ha).
Scheme 1. Synthesis of 2-(2-bromophenoxy)pyridines.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.063

W. S. Yoon et al. / Tetrahedron Letters 50 (2009) 4492–4494
4493
Table 1
Table 2 (continued)
Optimization of cyclization conditions
Entry
3
Yielda (%)
29
Br
Br
N
[Pd], ligand
conditions
N
N
N
7
O
O
O
O
NO2
2g
NO2
3g
2a
3a
H
N
N
Entry
1a
Palladium/ligand
Pd(OAc)2
Conditions
Yields (%)
59
O
O
Na2CO3
DMA
Reflux
K2CO3, TBAB
DMF, air
Br
N
H
N
3h
H
N
8
50b
O
O
2b
3
Pd(OAc)2
31
65
72
80
82
85
95
O
N
2h
Reflux
O
Pd(OAc)2
K2CO3, TBAB
DMF, 130 °C
Sealed tube
Et3N
DMA, 130 °C
Sealed tube
NaOAc
DMA,130 °C
Sealed tube
K2CO3
DME,130 °C
Sealed tube
K2CO3
3h’
N
CO2Et
H
N
4
PdCl2 [dppf]
Br
CO2Et
N
O
O
3i
H
N
H
N
9
22c (1:1)
O
O
O
O
CO2Et
5
Pd2 (P(o-Tol)3)2 (u-OAc)2
Pd(OAc)2/Josiphos
N
2i
3i’
6
a
Isolated yields following purification by silica gel column chromatography.
The reaction was carried out with 10 mol % Josiphos type ligand and a trace
b
amount of 3h0 was observed in its crude 1NMR spectrum.
7
Pd(OAc)2/Cy3PꢀHBF4
Pd(OAc)2/IPr–HCl
c
DME,130 °C
Sealed tube
K2CO3
The reaction was carried out with 10 mol % Cy3PꢀHBF4 as a ligand.
8
DME,130 °C
Sealed tube
Substrates bearing strong electron-withdrawing groups on either
phenoxy (entry 6) or pyridine (entry 7) rings such as a nitro group
furnished 3f and 3g in <5% and 29% yields, respectively.
a
Following the condition described by Ames.
Following the condition described by Janin.
b
In addition, cyclization of 2-methylamide-substituted phenoxy-
pyridines (entries 8 and 9) proved to be problematic. Cyclization of
2h and 2i was very sluggish and gave only trace amounts of the de-
sired products. Poor yields obtained for substrates 2h and 2i were
presumably due to strong coordination of palladiumwith 2-pyridine
methylamide moietytoshutdowna catalyticcycle.8 However, useof
bidendate Josiphos ((S)-1-[(1R)-2-(dicyclohexylphosphino)ferroce-
nyl]ethyldicyclohexylphosphine) as the ligand was found to be
effective, and the product 3h (entry 8) was prepared in 50% yields
along with very small amounts of the regio-isomer 3h0 (determined
by crude 1H NMR). Cyclization of 2i bearing an electron-deficient
phenyl ring employing various bidendate ligands, such as Josiphos,
dppf, and BINAP, was unsuccessful. In conclusion, we have devel-
oped a convenient method for preparing functionalized benzo[4,5]-
furo[3,2-c]pyridines.9 The key intermediate, 2-bromophenoxy
pyridines9 was readily prepared from nucleophilic displacement of
chloropyridines with 2-bromophenols. Subsequent Pd-catalyzed
intramolecular Heck reaction afforded benzo[4,5]furo[3,2-c]pyri-
dine derivatives. This route should be applicable for the preparation
of many pharmacologically useful molecules.
Table 2
Preparation of Benzo[4,5]furo[3,2-c]pyridines
5 mol% Pd(OAc)2
R1
10 mol % IPr-HCl
K2CO3 ( 2 equiv)
DME, 130 oC
Br
R1
N
N
R2
R2
O
O
sealed tube
3
2
Entry
3
Yielda (%)
95
Br
N
N
1
2
3
4
O
O
3a
2a
Br
CO2Et
CO2Et
N
N
N
95
85
85
O
N
2b
O
3b
Cl
F
Br
Cl
F
Acknowledgment
O
N
N
2c
O
O
O
3c
We are grateful to the Korea Research Institute of Chemical
Technology for financial support.
Br
O
References and notes
2d
3d
OMe
Br
OMe
NO2
N
N
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5
6
80
<5
O
N
N
2e
2f
3e
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Br
NO2
3. a J.T. Link, Organic Reactions, John Wiley & Sons: Hoboken, NJ, United States,
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W. S. Yoon et al. / Tetrahedron Letters 50 (2009) 4492–4494
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2H),7.19 (d, J = 3.0 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.91 (dd, J = 9.0, 3.0 Hz, 1H),
6.85 (dd, J = 4.5, 1.5 Hz, 2H), 3.83 (s, 3H). 3e: 1H NMR (300 MHz, CDCl3) d 9.23 (s,
1H), 8.63 (d, J = 5.7 Hz, 1H), 7.53–7.48 (m, 3H), 7.12 (dd, J = 9.0, 1.8 Hz, 1H), 3.93
(s, 3H). Compound 2h: 1H NMR (300 MHz, CDCl3) d 8.41 (d, J = 5.6 Hz, 1H), 8.03
(br s, 1H), 7.69 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.40 (td, J = 7.8,
1.5 Hz, 1H), 7.22–7.15 (m, 2H), 6.96 (dd, J = 5.5, 2.5 Hz, 1H), 3.02 (d, J = 5.1 Hz,
3H). Compound 3h: 1H NMR (300 MHz, CDCl3) d 9.13 (s, 1H), 8.42 (s, 1H), 8.18
(br s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.58 (td, J = 7.3, 1.0 Hz,
1H), 7.45 (t, J = 7.3 Hz, 1H), 3.09 (d, J = 5.1 Hz, 3H). 2i: 1H NMR (300 MHz, CDCl3)
d 8.44 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 5.6, 2.0 Hz, 1H), 8.01
(br s, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 5.6, 2.5 Hz,
1H), 4.41 (q, J = 7.1 Hz, 2H), 3.01 (d, J = 5.1 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H).
Compound 3i: 1H NMR (300 MHz, CDCl3) d 9.22 (s, 1H), 8.80 (d, J = 1.5 Hz, 1H),
8.47 (s, 1H), 8.33 (dd, J = 8.6, 1.8 Hz, 1H), 8.15 (br s, 1H), 7.71 (d, J = 8.6 Hz, 1H),
4.48 (q, J = 7.1 Hz, 2H), 3.12(d, J = 5.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H). Compound
3i0: 1H NMR (300 MHz, CDCl3) d 9.99 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 5.4 Hz, 1H),
8.35 (dd, J = 8.6, 1.8 Hz, 1H), 8.33 (br s, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.67 (d,
J = 8.6 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.16 (d, J = 5.1 Hz, 3H), 1.47 (t, J = 7.1 Hz,
3H).
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9. Representative spectroscopic data. Compound 2b: 1H NMR (300 MHz, CDCl3) d
8.53 (dd, J = 4.8, 1.5 Hz, 2H), 8.37 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 8.4, 2.1 Hz, 1H),
7.17 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 4.8, 1.5 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.44
(t, J = 7.2 Hz, 3H). 3b: 1H NMR (300 MHz, CDCl3) d 9.33 (s, 1H), 8.76 (d, J = 1.8 Hz,
1H), 8.72 (d, J = 5.7 Hz, 1H), 8.29 (dd, J = 8.7, 1.8 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H),
7.58 (dd, J = 5.7, 0.8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz,
3H).Compound 2e: 1H NMR (300 MHz, CDCl3)
d 8.45 (dd, J = 4.5, 1.5 Hz,