A facile synthesis of 2,3-disubstituted furo[2,3-b]pyridines

Article abstract of DOI:10.1016/j.tetlet.2008.11.125

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.

Full text of DOI:10.1016/j.tetlet.2008.11.125

Tetrahedron Letters 50 (2009) 781–784
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of 2,3-disubstituted furo[2,3-b]pyridines
*
Gregory L. Beutner , Jeffrey T. Kuethe, Nobuyoshi Yasuda
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted
furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide
and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-
position.
Received 3 November 2008
Revised 24 November 2008
Accepted 29 November 2008
Available online 6 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The frequent appearance of fused 5,6-ring systems in all classes
of biologically active compounds attests to the important position
these structures occupy in the development of new pharmaceutical
agents. While some ring systems, such as indoles and pyrrolopyri-
dines, are frequently employed as core scaffolds, others appear less
frequently. One such ring system, the furo[2,3-b]pyridines, has re-
ceived relatively little attention (Scheme 1). Furo[2,3-b]pyridines
are rarely found in naturally occurring alkaloids.1 However, this
core structure has shown activity against HIV,2 CNS disorders,3 skin
diseases4 and hyperglycemia.5 Furo[2,3-b]pyridines have also
demonstrated some in vitro activity as tubulin polymerization,6
Lck7 and Akt8 kinase inhibitors.
Despite the recent upsurge in interest regarding the medicinal
chemistry of these compounds, relatively few general methods
for their preparation have been reported.9 Two general classes of
disconnections have been reported in the literature (Scheme 1):
annulation of a pyridine ring onto an appropriately functionalized
furan (Route 1)2,10 and annulation of a furan ring onto a function-
alized pyridine (Routes 2–4).11–13 Most of these routes are limited
to the direct preparation of furo[2,3-b]pyridines with either
unfunctionalized furan rings2 or those bearing heteroatom substit-
uents at the 3-position. Only the palladium-catalyzed cyclization of
3-alkynyl-2-hydroxypyridines (Route 4) has been demonstrated to
provide access to 2,3-carbon disubstituted furo[2,3-b]pyri-
dines,13b,13c a substitution pattern which is prevalent in many re-
cent publications and patents describing the biological activity of
these heterocyclic systems.3,5,6 However, preparation of a target
furo[2,3-b]pyridine by Route 4 typically requires the use of multi-
ple palladium-catalyzed steps.
from readily accessible 2-fluoropyridines 2 and carboxylic acids 3
(Scheme 2). The method is based on Route 3 (Scheme 1) and begins
with the acylation of a 2-fluoropyridine 4 with a Weinreb amide 5,
followed by a one-pot, base-induced displacement and cyclization.
Following this method, compounds with an aryl or alkyl substitu-
ent at the 3-position and an ester, amide or ketone at the 2-posi-
tion can be accessed.
Initial studies focused on the preparation of the ethyl ester con-
taining furo[2,3-b]pyridine 12a (Scheme 3). Acylation of 2-fluoro-
pyridine 6 with the commercially available Weinreb amide 7a
was performed in THF at À78 °C with LDA. Using only 1 equiv of
LDA and 1 equiv of 2-fluoropyridine in THF at À78 °C led to poor
yields of the desired ketone 8a. The mass balance of the reaction
Route 12,10
Route 211
R
N
R
+
+
(1)
(2)
O
O
H2N
O
R'
N
R'
OH
R'
X
Br
CO2R
CO2R
N
OH
O
X = OH, NH2
R' = CO2R", CN
Route 312
Route 413
X
R'
+
Cl
(3)
(4)
HO
CO2R
CO2R
N
O
N
Considering this recent interest in 2,3-carbon disubstituted
furo[2,3-b]pyridines, the development of methods which allow ac-
cess to these biologically active compounds is an area of continuing
research. In this Letter, we describe a protocol for preparation of a
wide variety of 2,3-carbon disubstituted furo[2,3-b]pyridines 1
X = OH, NH2
E
R' = CO2R", CN
R
+
E
X
R
O
N
N
OH
E = H, I, Aryl
Scheme 1. Syntheses of furo[2,3-b]pyridines.
* Corresponding author. Tel.: +1 732 594 0494; fax: +1 732 594 5170.
E-mail address: gregory_beutner@merck.com (G.L. Beutner).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.125

782
G. L. Beutner et al. / Tetrahedron Letters 50 (2009) 781–784
alytic sodium iodide in DMAc did lead to formation of the interme-
O
F
R'
diate 11a at room temperature; however, after heating to 60 °C,
decomposition to unidentified products was observed. The use of
amine bases, such as diisopropylethylamine (DIPEA) or 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), also led to complex mixtures of
unidentified products.
R
N
4
+
F
R'
R
N
R"
R'
2
O
N
O
+
Using the optimal conditions, we examined the scope of the
method (Table 1). Weinreb amides 7b–d were easily prepared via
amidation of the corresponding carboxylic acids with N-methyl-
N-methoxyamine hydrochloride and carbonyl diimidazole (CDI)
in good yields. In all cases examined, the acylation of 2-fluoropyr-
idine 6 gave moderate yields, and the corresponding secondary
amide of type 9 was also observed. The cyclization of the ketones
to the furo[2,3-b]pyridines 12a–d proceeded smoothly in all cases.
With both electron-deficient and electron-rich aryl groups, the cor-
responding furo[2,3-b]pyridines could be obtained by direct crys-
1
N
OMe
R
R"O2C
OH
3
5
Scheme 2. Synthesis of 2,3-disubstituted furo[2,3-b]pyridines.
could be accounted for by the formation of amide 9a.14 Subsequent
studies revealed that maintaining an internal temperature below
À50 °C during the addition of the Weinreb amide and the use of
a slight excess of 2-fluoropyridine (1.3 equiv) and LDA (1.3 equiv)
gave a 51% yield of the desired ketone 8a (Scheme 3, Eq. 1). Despite
further attempts at optimization, the unproductive formation of 9a
could not be completely suppressed.
Table 1
Preparation of 3-substituted furo[2,3-b]pyridine esters
With ketone 8a in hand, the formation of the furo[2,3-b]pyri-
dine 12a was investigated (Scheme 3, Eq. 2). Rather than isolating
intermediate 11a and subjecting it to a second cyclization step, we
sought a one-pot synthesis of the furo[2,3-b]pyridine 12a. Depro-
tonation of ethyl glycolate 10 (2 equiv) with sodium hydride
(2 equiv) in THF followed by addition of the ketone 8a and heating
for 12 h at 60 °C gave the desired furo[2,3-b]pyridine 12a in 50%
yield after column chromatography. Under these conditions, the
formation of 11a was rapid, followed by slow cyclization to form
12a. The mass balance of the reaction could be accounted for by
the formation of the carboxylic acids 13 and 14. These two com-
pounds are derived from hydrolysis of 11a and 12a, respectively,
under the reaction conditions, presumably by hydroxide released
during the cyclization step. In an effort to increase the rate of the
cyclization and possibly minimize this unproductive hydrolysis,
examination of other solvents revealed that N,N’-dimethylacet-
amide (DMAc) was a far superior solvent when compared to THF.
In this case, reaction was complete in 1 h at 60 °C, and the product
could be isolated directly from the crude reaction mixture in 60%
yield by addition of water and filtration. The formation of carbox-
ylic acids 13 and 14 was still a competitive process, but these
impurities were easily removed during the crystallization. Addi-
tional experiments were conducted in an effort to replace sodium
hydride as the base for this transformation. Examination of a vari-
ety of inorganic bases, such as Cs2CO3 and NaOt-Bu, consistently
led to a complex mixture of products and very little of the desired
furo[2,3-b]pyridine 12a. The use of Cs2CO3 in conjunction with cat-
O
R
R
N
F
NaH
LDA
N
F
8a-d
+
6
CO2Et
+
X
DMAc
60oC
N
THF
O
-78oC
12a-e
N
OMe
R
HX
CO2Et
10,15
7a-d
Entry
R
Yield (%) Step 1
X
Yield (%) Step 2
1
2
3
4
5
Ph (7a)
51 (8a)
46 (8b)
54 (8c)
34 (8d)
51 (8a)
O (10)
O (10)
O (10)
O (10)
S (15)
60 (12a)
61 (12b)
55 (12c)
38 (12d)
59 (12e)
p-MeOC6H4 (7b)
p-F3CC6H4 (7c)
Me (7d)
Ph (7a)
tallization (entries 2 + 3). Introduction of a 3-alkyl group was also
possible, although lower yields of the desired furo[2,3-b]pyridine
were obtained, even under optimal conditions (entry 4). Thie-
no[2,3-b]pyridines are another interesting class of biologically ac-
tive compounds,15 typically prepared in a manner analogous to
O
O
O
LDA (1.3 equiv)
THF, -78oC
+
+
Ph
N
Ph
N
H
Ph
N
F
OMe
N
F
6
7a
8a
9a
51 % yield
O
O
NaH
Ph
Ph
8a
(2 equiv)
Ph
Ph
+
+
+
CO2Et
CO2H
N
O
N
O
60oC
O
O
N
N
HO
CO2Et
10
CO2Et
CO2H
11a
12a
13
14
(2 equiv)
50 % yield (from THF)
60 % yield (from DMAc)
Scheme 3. Synthesis of furo[2,3-b]pyridine 12a.

G. L. Beutner et al. / Tetrahedron Letters 50 (2009) 781–784
783
Applying this protocol to the synthesis of 2-keto furo[2,3-b]pyr-
idines proved more challenging. Under the conditions described
above (NaH, DMAc, 60 °C for 1 h), none of the desired ketone
O
Br
Br
LDA (1.3 equiv)
+
7b
THF
N
F
N
F
(22) could be obtained in the addition of
to 8a. A high throughput screen of bases and solvents was under-
taken at 50 mol scale in a 96-well plate in an attempt to rapidly
a-hydroxy acetophenone
OMe
-78oC
16
17
53 % yield
l
OMe
improve the reaction using only minimal amounts of material. It
was found that the use of KOAc, K3PO4, NaHCO3, Cs2CO3, K2CO3,
KF, Na2CO3 and CsF in either THF or DMAc led to either no conver-
sion or decomposition. On the other hand, the use of NaOH, KOH,
NaOt-Bu and NaOt-Bu in DMAc did lead to partial conversion to
the ketone 22. However, upon scaling up these conditions, complex
reaction mixtures were obtained and the desired furo[2,3-b]pyri-
dine ketone 22 could only be isolated after column chromatogra-
phy in low yields (<20% yield). Careful examination of the crude
NaH (2 equiv)
HOCH2CO2Et
(2 equiv)
O
F
Br
Br
CO2Et
DMAc, 60oC
N
O
N
OMe
17
18
61 % yield
Scheme 4. Preparation of furo[2,3-b]pyridine 18.
reaction mixture revealed that
a-hydroxy acetophenone was not
stable under the strongly basic conditions required for the dis-
placement and cyclization. Therefore, an alternative approach to
2-keto furo[2,3-b]pyridines was envisioned. The displacement of
heteroaromatic morpholine amides with lithium reagents has been
demonstrated in the literature18, and it was thought that this strat-
egy could be extended to the preparation of 2-keto furo[2,3-b]pyr-
idines. The high yielding preparation of 2-amido furo[2,3-
b]pyridine 21b could serve as an access point to a wide variety of
2-keto furo[2,3-b]pyridines. In the case of 21b, reaction with either
PhLi or MeLi at À78 °C gave excellent yields of the desired ketones
22 and 23 without the formation of any observable impurities
(Scheme 5). A similarly high yield of 23 could be obtained by treat-
ing 21b with MeMgBr at 0 °C followed by warming to room
temperature.
Routes 1–3 shown in Scheme 1.16 Under the conditions described
above for the synthesis of the furo[2,3-b]pyridines, the related thi-
eno[2,3-b]pyridine 12e could be easily prepared in comparable
yield after recrystallization from ethanol (entry 5). As in previous
examples, the mass balance of the reaction could be accounted
for by the formation of carboxylic acid by-products.
With the scope of the reaction with respect to the 3-position
substituent defined, the possibility of installing additional substit-
uents on the pyridine ring was briefly investigated. Starting with 5-
bromo-2-fluoropyridine 16, the trisubstituted furo[2,3-b]pyridine
18 could be prepared in a two-step sequence using the conditions
described above (Scheme 4). The possibility of subsequent cross-
coupling with the 5-bromo substituent offers many options for fur-
ther elaboration of this heterocyclic core.
In conclusion, we have developed a straightforward and versa-
tile method for the preparation of 2,3-disubstituted furo[2,3-b]pyr-
idines. Starting from readily available and inexpensive materials,
the ester, amide and ketone containing furo[2,3-b]pyridines could
all be prepared rapidly using robust chemistry that did not require
complex transition metal catalysts or chromatographic purifica-
tion. This class of compound is known to possess interesting bio-
logical activities, and we feel that this method will further
Having demonstrated the ability to access 2-carboxy furo[2,3-
b]pyridines, we sought to extend the method to furo[2,3-b]pyri-
dines containing amide and ketone substituents at the 2-position.
In the case of furo[2,3-b]pyridine amides, the required
a-hydroxy
amides were easily prepared via opening of the 2,2-dimethyl-1,3-
dioxolan-4-one 19 with the desired amine (Table 2).17 Reaction
of the resulting a-hydroxy amides 20a-c with the ketone 8a under
the conditions described above led to the desired furo[2,3-b]pyri-
dines 21a–c in good yields. The products could easily be isolated
directly from the crude reaction mixture by addition of water
and filtration. In contrast to the formation of the furo[2,3-b]pyri-
dine esters (Table 1), none of the corresponding carboxylic acids
related to 13 and 14 were formed in these reactions, presumably
since the amides 21a–c are resistant to hydrolysis under the reac-
tion conditions.
facilitate
exploration
of
this
increasingly
important
pharmacophore.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.125.
Table 2
Preparation of 3-substituted furo[2,3-b]pyridine amides
Ph
O
HNR2
NaH
O
O
O
+
8a
Ph
Ph
OH
O
CONR2
R2N
RLi (1.1 equiv)
THF, -78oC
R
O
DMAc
60oC
N
O
O
N
(1)
19
20a-c
21a-c
O
O
N
N
21b
90 % yield 22 (R=Ph)
98 % yield 23 (R=Me)
O
Entry
NR2
Yield (%) Step 1
Yield (%) Step 2
Ph
Ph
1
NEt2
— (20a)17
75 (21a)
MeMgBr (1.1 equiv)
THF, 0oC-RT
Me
N
(2)
O
O
O
N
N
O
N
N
2
88 (20b)
89 (20c)
70 (21b)
86 (21c)
O
21b
23
98 % yield
3
NBoc
Scheme 5. Preparation of 3-substituted furo[2,3-b]pyridine ketones.

784
G. L. Beutner et al. / Tetrahedron Letters 50 (2009) 781–784
9. Shiotani, S. Heterocycles 1997, 45, 975–1011.
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