A convenient route to functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2- carboxamides

Article abstract of DOI:10.1016/j.tet.2011.05.035

The synthesis of novel functionalized 3-amino-N-methylfuro[3,2-b]pyridine- 2-carboxamides is described from cyanopyridine intermediates. Based on the difference in halogen reactivity, ethyl [(5-bromo-2-chloropyridin-3-yl)oxy] acetate was functionalized by a palladium-catalyzed reaction, before the cyclization to the desired furo[3,2-b]pyridines.

Full text of DOI:10.1016/j.tet.2011.05.035

Tetrahedron 67 (2011) 4767e4773
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A convenient route to functionalized 3-amino-N-methylfuro[3,2-b]pyridine-
2-carboxamides
a
a
b
ꢀ
ꢀ a
ꢀ
Anne Breteche , Pascal Marchand , Marie-Renee Nourrisson , Patrick Hautefaye ,
Guillaume De Nanteuil b, Muriel Duflos a
Universite de Nantes, Nantes Atlantique Universites, Laboratoire de Chimie Therapeutique, Cibles et Medicaments des Infections, de l’Immunite et du Cancer, IICiMed UPRES EA 1155,
,
*
a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Faculte de Pharmacie, 1 rue Gaston Veil, 44035 Nantes, France
b Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides is de-
scribed from cyanopyridine intermediates. Based on the difference in halogen reactivity, ethyl [(5-
bromo-2-chloropyridin-3-yl)oxy]acetate was functionalized by a palladium-catalyzed reaction, before
the cyclization to the desired furo[3,2-b]pyridines.
Received 23 March 2011
Received in revised form 29 April 2011
Accepted 9 May 2011
Available online 14 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Functionalized furo[3,2-b]pyridines
Ethyl 3-aminomethylfuro[3,2-b]pyridine-2-
carboxylates
3-Amino-N-methylfuro[3,2-b]pyridine-2-
carboxamides
[6-Chloro-5-(2-ethoxy-2-oxoethoxy)
pyridin-3-yl]benzoic acid
Heteroannulation
1. Introduction
3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides I, we decided
to apply the same strategy via the cyclization of an ethyl
As part of our continuing interest in aminofuro[3,2-b]pyridine
carboxamides as potent kinase inhibitors, we investigated the
synthesis of new functionalized 3-aminofuro[3,2-b]pyridine-2-
carboxamides of general structure I (Fig. 1). The fused aromatic
heterocycles like furopyridines seem to have especially attracted
much attention as pharmacophore units in medicinal chemistry,1
due to their isosterism with benzofurans, indoles or azaindoles,2
which are important moieties in many biological activities. Vari-
ous synthetic methodologies are described to obtain unsub-
stituted3 or substituted4 furo[3,2-b]pyridines and biological activity
of this heterocycle depends on the type and the position of the
substituents in the skeleton.2,5
[(2-cyanopyridin-3-yl)oxy]acetate with appropriate substituents
(route A in Fig. 1). To obtain the N-methylcarboxamide function, the
cyclization of
a 2-[(2-cyanopyridin-3-yl)oxy]-N-methylacetamide
could be envisaged, but this synthesis required the use of a toxic re-
agent (2-bromo-N-methylacetamide)7 to prepare the N-methyl
[(5-bromo-2-chloropyridin-3-yl)oxy] acetamide intermediate (route
B in Fig. 1). Then, we envisioned to synthesize the ethyl 3-aminofuro
[3,2-b]pyridine-2-carboxylates giving direct access to the corre-
sponding N-methylcarboxamide by aminolysis of the ester function.
Herein, we report our procedure for the access of 6-substituted
3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamide (route
A in
Fig. 1).
In previous works, we have developed an efficient access
of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamide derivatives
via a heteroannulation of 5-bromo-3-(cyanomethoxy)pyridine-2-
carbonitrile.6 In order to prepare the target 6-functionalized
2. Results and discussion
The synthetic route for the preparation of the key functionalized
pyridines 9 and 10 is outlined in Scheme 1. Heating at 180 ꢀC
3,5-dibromopyridine with benzyl alcohol in the presence of NaH
in DMF led to 3-benzyloxy-5-bromopyridine 2 in 63% yield, by
nucleophilic substitution of only one bromine.8
* Corresponding author. Tel.: þ33 240 411 100; fax: þ33 240 412 876; e-mail
address: muriel.duflos@univ-nantes.fr (M. Duflos).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.035

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
COOH
O
O
R
R
N
H
N
O
O
O
O
H
N
OEt
HN CH
2
N
3
N
O
route A
I
NH
NH
2
O
CN
OEt
route B
COOH
N
O
Br
Br
Br
O
OEt
CH
NH
3
O
Cl
N
N
CN
O
Fig. 1. Retro-synthetic plan of compounds I.
OH
Br
Br
NaH, DMF
Br
O
H2O2 35%, AcOH
Br
O
+
N
180°C, 2h
Reflux, 1h30
POCl3
N
_
N
1
3
63%
84%
O
2
CH2Cl2
Reflux
O
2h
Br
O
O
95%
Br
OH
Cl
NaH, DMF
HBr, AcOH
Br
O
Br
O
O
r.t., 2h
Reflux, 1h30
N
N
Cl
N
Cl
80%
91%
4
6
5
B(OH)2
3
HOOC
COOH
3
COOH
3
4
4
4
Zn(CN)2, S-Phos
Pd(OAc)2, DMF
Pd2(dba)3, DMF/H2O
Na2CO3, H2O
r.t., 48h
150°C, M.W.
O
O
N
COOEt
9, 10
N
COOEt
CN
Cl
7, 8
Position
Yield (%)
Position
Reaction time
Yield (%)
3
18 mn
5 mn
71
71
3
77
58
9
7
4
4
10
8
Scheme 1. Synthesis of functionalized pyridines 9 and 10.
Selective chlorination with POCl3 at position 2 of the pyridine
ring was performed on the N-oxide 3, prepared by oxidation of 2
with hydrogen peroxide in acetic acid at reflux.9 It can be noticed
that direct chlorination of 5-bromopyridin-3-ol provided a mixture
of 5-bromo-2-chloropyridin-3-ol with the C-6-chloro isomer and
the C-2,6-dichloro derivative.10 Then, the synthesis via the O-pro-
tected N-oxide 3 was more efficient.8 Benzyl group cleavage was
carried out using a mixture of bromhydric and acetic acids at reflux
for 1.5 h to afford 5 in good yield.8 For this last step, 2,5-
dibromopyridin-3-ol could be obtained in mixture with 5 when
a longer reaction time was used. After formation of the sodium salt
of the hydroxypyridine 5 using NaH in DMF, reaction with ethyl
bromoacetate provided ethyl [(5-bromo-2-chloropyridin-3-yl)oxy]
acetate 6 in 80% yield. Then, our strategy consisted in the in-
troduction of phenyl groups at C-5 position of the pyridine ring
before the cyanation, considering that the reaction of compound 6
with a cyanide source would give the brome displacement.
Therefore, based on this difference in halogen reactivity,
incorporation of a phenyl moiety was realized via a selective Suzuki
cross-coupling reaction of 3- or 4-phenylboronic acids with 6, using
palladium acetate as catalyst and sodium carbonate as base in DMF
at room temperature. Attempts to cyanate compounds 7 and 8 by
the Rosenmundevon Braun reaction were unsuccessful. Ultimately,
this conversion was carried out by a palladium-catalyzed cyanation
as reported for aryl or heteroaryl chlorides.11 Using Pd2(dba)3, ddpf
as ligand, Zn(CN)2 as the cyanide source, and addition of a catalytic
amount of Zn dust in DMF, the desired pyridine carbonitriles 9 and
10 were prepared but in low yields. Under microwave activation,
yields improved slightly. Finally, when the dppf ligand was replaced
with the S-Phos ligand, cyanation of 7 and 8 with Zn(CN)2, in the
presence of 4 mol % Pd2(dba)3, 10 mol % S-Phos in wet DMF led to
71% yield of 9 and 10 under microwave-assisted conditions.12
As depicted in Scheme 2, heteroannulation of nitriles 9 and 10
proceeded efficiently under basic conditions. The use of Cs2CO3 in
DMF for 20 h at 80 ꢀC was required to have a complete conversion
and to produce 3-[3-amino-2-(ethoxycarbonyl)furo[3,2-b]pyridin-

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
4769
R
COOH
NH
2
COOH
O
R
NH
4
3
, DMF
3
Cs CO
DEPBT
2
Et N, DMF
3
r.t., 24-48h
80°C, 20h
N
O
O
N
O
O
CN
O
N
O
H N
2
37 - 65% on 2 steps
OEt
OEt
H N
2
OEt
9, 10
11, 12
13-21
O
4
R
MeNH , EtOH
2
N
H
3
O
O
110-120°C, 24h
HN CH
N
3
22 - 80%
NH
2
22-30
Scheme 2. Synthesis of functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides 22e30.
6-yl]benzoic acid 11 and 4-[3-amino-2-(ethoxycarbonyl)furo[3,2-b]
pyridin-6-yl]benzoic acid 12. These acids were used in the next step
without further purification. Amidation with several anilines was
then performed. Use of triethylamine or N-methylmorpholine in
combination with EDCI/HOBt, CMPI or DCP gave only low yields.
The amides 13e18 for the position 3 and 19e21 for the position 4
were obtained in 37e65% overall yield starting from 9 or 10 when
coupling was mediated by 1.2 equiv of recrystallized DEPBT13 in the
presence of triethylamine in DMF at room temperature (entries 1e9
in Table 1). The ethyl pyridine carboxylates 13e21 were finally
converted to the desired carboxamides 22e30 by aminolysis under
pressure with a solution of methylamine in ethanol (entries 10e18
in Table 1).
4. Experimental section
4.1. General
All reactions were carried out under argon. All reactions were
monitored by TLC analysis using Merck silica gel 60F-254 thin-layer
plates. Column chromatography was carried out on silica gel Merck
60 (70e230 mesh ASTM). Melting points were determined on an
Electrothermal IA 9000 melting point apparatus and are un-
corrected. Infrared spectra (IR) were recorded on a Paragon 1000 PC
PerkineElmer spectrometer. 1H and 13C NMR spectra were per-
formed in DMSO-d6 using a Bruker AC 250 MHz or an AVANCE
400 MHz spectrometer. Chemical shifts are reported as
d values
relative to tetramethylsilane as internal standard and coupling
constants (J) are given in hertz (Hz). The following abbreviations
are used to describe peak patterns when appropriate: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Mass
spectra were recorded on Waters ZQ 2000 spectrometer. Elemental
analyses were found within ꢁ0.4% of the theoretical values. Mi-
crowave experiments were carried out under pressure (0e20 bar,
tubes of 10 mL sealed with a septum), using a focused microwave
reaction (CEM DiscoverÔ). Reactions were performed in a glass
vessel. The target temperature was reached with a ramp of 1 min
(for compound 10) or 2 min (for compound 9) and the chosen
microwave power stayed constant to hold the mixture at this
temperature. The reaction time does not include the ramp period.
Table 1
Synthesis of ethyl 3-aminofuro[3,2-b]pyridine-2-carboxylates 13e21 and 3-amino-
N-methylfuro[3,2-b]pyridine-2-carboxamides 22e30
Entry
Compd
Position
R
Yielda (%)
1
2
3
4
5
6
7
8
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3
3
3
3
3
3
4
4
4
3
3
3
3
3
3
4
4
4
3-Cl
3-F
3-Ph
4-Cl
4-F
4-Ph
3-Cl
3-Ph
4-Ph
3-Cl
3-F
3-Ph
4-Cl
4-F
50b
43b
65b
52b
47b
63b
37b
43b
48b
71
54
77
30
22
52
80
65
73
9
10
11
12
13
14
15
16
17
18
4.1.1. 3-Benzyloxy-5-bromopyridine (2). Benzylalcohol (10 mL,
96 mmol) was dissolved in dry DMF (30 mL) and sodium hydride
(60% suspension in mineral oil) (2.5 g, 62.50 mmol) was slowly
added. When no more gas evolved, 3,5-dibromopyridine (10 g,
42.21 mmol) was added and the reaction mixture was stirred at
180 ꢀC for 2 h. After addition of water, the aqueous phase was
extracted with ethyl acetate. The organic layers were dried over
sodium sulfate, filtered, and evaporated to dryness. The resulting oil
was purified by column chromatography eluting with an 8/2 mix-
ture of petroleum ether and diethyl ether and then a second column
chromatography eluting with a 9/1 mixture of CH2Cl2 and ethyl ac-
etate to afford 2 (7.02 g, 63%) as a beige needle. Mp 67ꢂe168 ꢀC (lit.:14
4-Ph
3-Cl
3-Ph
4-Ph
a
Isolated yield.
Isolated yield in two steps.
b
3. Conclusion
64e65 ꢀC); IR (KBr): 1553, 1425, 1259, 990 cm
;
1H NMR
(400 MHz): 5.25 (s, 2H, eOCH2Ph), 7.37e7.51 (m, 5H, PheH), 7.84
(dd, J¼J0¼2.0 Hz,1H, pyridineeH), 8.33 (d, J¼2.0 Hz,1H, pyridineeH),
8.40 (d, J¼2.0 Hz, 1H, pyridineeH); 13C NMR (100 MHz): 70.2, 120.2,
124.3, 128.2, 128.4, 128.7, 136.2, 137.4, 142.5, 155.3; the data are in
Inthiswork, we havedescribed theaccessofnew 6-functionalized
3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides, based on
selective functionalizations of a dihalogenopyridine ring via palla-
dium cross-coupling reactions (Suzuki and cyanation).

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
4770
conformity with the literature.14 MS (ESI) m/z (%): 265.9 [(MþH)þ,
100], 267.9 [(MþH)þ2,100]. Anal. Calcd for C12H10BrNO: C, 54.57; H,
3.82; N, 5.30. Found: C, 54.63; H, 3.83; N, 5.31.
7.96 (d, J¼2.1 Hz,1H, pyridineeH), 8.21 (d, J¼2.1 Hz,1H, pyridineeH);
13C NMR (100 MHz): 14.1, 61.1, 65.7, 119.2, 124.7, 138.4, 141.6, 150.4,
167.8; MS (ESI) m/z (%): 293.8 [(MþH)þ, 75], 295.8 [(MþH)þ2, 100],
297.8 [(MþH)þ4, 25]. Anal. Calcd for C9H9BrClNO3: C, 36.70; H, 3.08;
N, 4.76. Found: C, 36.82; H, 3.09; N, 4.77.
4.1.2. 3-Benzyloxy-5-bromopyridine N-oxide (3). To a solution of 3-
(benzyloxy)-5-bromopyridine 2 (11 g, 41.65 mmol) in acetic acid
(124 mL) was added a 35% aqueous solution of hydrogen peroxide
(38 mL) and the reaction mixture was refluxed for 1 h 30 min. The
solution was cooled to room temperature and was slowly poured
into saturated aqueous solution of sodium carbonate (548 mL). The
solid was filtered off, washed with cold water, and dried to yield 3
(9.80 g, 84%) as a beige solid. Mp 117e118 ꢀC; IR (KBr): 1591, 1552,
1445, 1184, 991 cmꢂ1; 1H NMR (400 MHz): 5.24 (s, 2H, eOCH2Ph),
7.40e7.51 (m, 6H, PheH and pyridineeH), 8.21 (dd, J¼1.6, 2.0 Hz,
1H, pyridineeH), 8.25 (dd, J¼1.6, 2.0 Hz, 1H, pyridineeH); 13C NMR
(100 MHz): 70.9, 116.3, 119.8, 127.7, 128.3, 128.6, 128.7, 133.5, 135.6,
156.9; MS (ESI) m/z (%): 281.9 [(MþH)þ, 100], 283.9 [(MþH)þ2,
100]. Anal. Calcd for C12H10BrNO2: C, 51.45; H, 3.60; N, 5.0. Found: C,
51.53; H, 3.61; N, 5.01.
4.1.6. 3-[6-Chloro-5-(2-ethoxy-2-oxoethoxy)pyridin-3-yl]benzoic
acid (7). Ethyl [(5-bromo-2-chloropyridin-3-yl)oxy]acetate
6
(4.69 g, 15.94 mmol) was dissolved in dry DMF (47 mL). The solu-
tion was degassed during 30 min and Pd(OAc)2 (107.26 mg,
0.48 mmol) was added. The reaction mixture was degassed during
15 min and a solution of Na2CO3 2 M (24.2 mL, 48.4 mmol) was
added dropwise under vigorous stirring followed by 3-phenyl bo-
ronic acid (2.64 g, 15.94 mmol). The mixture was stirred at room
temperature for 48 h. After acidification with HCl 1 M, the solution
was extracted by ethyl acetate. The organic layers were washed
with brine, dried over sodium sulfate, filtered, and evaporated to
dryness. The resulting solid was purified by column chromatogra-
phy eluting with a 9/1 mixture of CH2Cl2 and ethanol to afford 7
(4.12 g, 77%) as a white solid. Mp 207e208 ꢀC; IR (KBr): 3442, 1747,
1692,1586,1397,1216,1105,1064 cmꢂ1; 1H NMR (400 MHz): 1.25 (t,
J¼7.3 Hz, 3H, eCOOCH2CH3), 4.23 (q, J¼7.3 Hz, 2H, eCOOCH2CH3),
5.21 (s, 2H, eOCH2COOCH2CH3), 7.69 (dd, J¼7.6, 8.0 Hz, 1H, PheH),
7.91 (d, J¼2.0 Hz, 1H, pyridineeH), 8.03e8.06 (m, 2H, PheH), 8.29
(br s, 1H, PheH), 8.40 (d, J¼2.0 Hz, 1H, pyridineeH), 13.25 (s, 1H,
eCOOH); 13C NMR (100 MHz): 14.2, 61.1, 65.5, 120.2, 128.1, 129.5,
129.6, 131.8, 131.9, 135.8, 136.4, 138.8, 139.2, 149.9, 167.2, 168.2; MS
(ESI) m/z (%): 335.9 [(MþH)þ, 100], 337.9 [(MþH)þ2, 33]. Anal.
Calcd for C16H14ClNO5: C, 57.24; H, 4.20; N, 4.17. Found: C, 57.32; H,
4.21; N, 4.18.
4.1.3. 3-Benzyloxy-5-bromo-2-chloropyridine (4). To a solution of
3-benzyloxy-5-bromopyridine N-oxide 3 (9 g, 32.13 mmol) in dry
CH2Cl2 wad added dropwise POCl3 (30 mL, 327.72 mmol) and the
reaction mixture was refluxed for 2 h. The solvent was evaporated
under vacuum and the residue was slowly poured into saturated
aqueous solution of sodium carbonate. The solid was filtered off,
washed with cold water, and dried to yield 4 (9.10 g, 95%) as a beige
solid. Mp 76e77 ꢀC; IR (KBr): 1547, 1415, 1266, 1071 cmꢂ1; 1H NMR
(400 MHz): 5.34 (s, 2H, eOCH2Ph), 7.41e7.52 (m, 5H, PheH), 8.03 (d,
J¼2.0 Hz, 1H, pyridineeH), 8.19 (d, J¼2.0 Hz, 1H, pyridineeH); 13C
NMR (100 MHz): 70.8, 119.2, 124.6, 127.7, 128.3, 128.6, 135.5, 138.4,
140.8,150.7; MS (ESI) m/z (%): 297.8 [(MþH)þ, 72], 299.8 [(MþH)þ2,
100], 301.8 [(MþH)þ4, 27]. Anal. Calcd for C12H9BrClNO: C, 48.27; H,
3.04; N, 4.69. Found: C, 48.37; H, 3.05; N, 4.71.
4.1.7. 4-[6-Chloro-5-(2-ethoxy-2-oxoethoxy)pyridin-3-yl]benzoic
acid (8). The title compound was prepared in 58% yield as a pale
yellow solid from 6 by a similar method to that described for 7
using 4-phenylboronic acid. Mp 230e231 ꢀC; IR (KBr): 3452, 1757,
4.1.4. 5-Bromo-2-chloropyridin-3-ol (5). A solution of 3-(benzy-
loxy)-5-bromo-2-chloropyridine 4 (4.8 g, 16.08 mmol) in a mixture
of AcOH (55 mL) and 40% HBr (14 mL) was refluxed for 1 h 30 min.
The reaction mixture was cooled to room temperature and was
slowly poured into saturated aqueous solution of sodium carbon-
ate. The resulting precipitate was collected by filtration and washed
with cold water. The solid was dissolved in ethyl acetate, dried over
sodium sulfate, and concentrated to dryness. The resulting oil was
purified by column chromatography eluting with an 8/2 mixture of
petroleum ether and diethyl ether to afford 5 (3.05 g, 91%)ꢂa1s
1681, 1609, 1578, 1393, 1301, 1214, 1104, 1057 cmꢂ1 1H NMR
;
(400 MHz): 1.25 (t, J¼7.3 Hz, 3H, eCOOCH2CH3), 4.22 (q, J¼7.3 Hz,
2H, eCOOCH2CH3), 5.19 (s, 2H, eOCH2COOCH2CH3), 7.93 (d,
J¼1.2 Hz, 1H, pyridineeH), 7.94 (d, J¼8.2 Hz, 2H, PheH), 8.09 (d,
J¼8.2 Hz, 2H, PheH), 8.44 (d, J¼1.2 Hz, 1H, pyridineeH), 13.16 (s, 1H,
eCOOH); 13C NMR (100 MHz): 14.2, 61.1, 65.5, 120.1, 127.6, 130.1,
130.9, 135.4, 139.1, 139.3, 140.0, 150.0, 167.1, 168.1; MS (ESI) m/z (%):
335.9 [(MþH)þ, 100], 337.9 [(MþH)þ2, 33]. Anal. Calcd for
C16H14ClNO5: C, 57.24; H, 4.20; N, 4.17. Found: C, 57.34; H, 4.21;
N, 4.19.
a white solid. Mp 182e183 ꢀC; IR (KBr): 3448,1558,1411,1173 cm
;
1H NMR (400 MHz): 7.53 (d, J¼2.1 Hz, 1H, pyridineeH), 8.04 (d,
J¼2.0 Hz, 1H, pyridineeH), 11.35 (s, 1H, eOH); 13C NMR (100 MHz):
118.8, 126.2, 137.5, 139.8, 150.7; the data are in conformity with the
literature.10,15 MS (ESI) m/z (%): 207.8 [(MþH)þ, 71], 209.8 [(MþH)þ
2, 100], 211.8 [(MþH)þ4, 28]. Anal. Calcd for C5H3BrClNO: C, 28.81;
H, 1.445; N, 6.72. Found: C, 28.75; H, 1.44; N, 6.71.
4.1.8. 3-[6-Cyano-5-(2-ethoxy-2-oxoethoxy)pyridin-3-yl]benzoic
acid (9). To a mixture of 3-[6-chloro-5-(2-ethoxy-2-oxoethoxy)
pyridin-3-yl]benzoic acid 7 (0.5 g, 1.49 mmol), Pd2(dba)3 (54 mg,
0.06 mmol), S-Phos (10%) (61 mg, 0.15 mmol), and Zn(CN)2 (199 mg,
1.69 mmol) in a sealed tube was added DMF/H2O 1% (6 mL). The
reaction mixture was degassed during 15 min and then stirred at
150 ꢀC under microwave irradiation (150 W) for 18 min. After
cooling at room temperature, the mixture was filtered over Celite
and solids were washed with acetone. The filtrate was evaporated
to dryness. The resulting oil was purified by column chromatog-
raphy eluting with CH2Cl2 and then 9/1 mixture of CH2Cl2 and
ethanol to afford 9 (345 mg, 71%) as a white solid. Mp 229e230 ꢀC;
4.1.5. Ethyl [(5-bromo-2-chloropyridin-3-yl)oxy]acetate (6). Sodium
hydride (60% suspension in mineral oil) (0.95 g, 23.75 mmol) was
slowly added to a solution of 5-bromo-2-chloropyridin-3-ol 5 (3.3 g,
15.83 mmol) in dry DMF (36 mL). When no more gas evolved, ethyl
bromoacetate (2.1 mL, 18.94 mmol) was added dropwise and the
reaction mixture was stirred at room temperature for 2 h. After
addition of water, the aqueous phase was extracted with CH2Cl2. The
organic layers were washed with brine, dried over sodium sulfate,
filtered, and evaporated to dryness. The resulting oil was purified by
column chromatographyeluting with CH2Cl2 to afford 6 (3.70g, 80%)
as a beige solid. Mp 53e54 ꢀC; IR (KBr): 1754, 1563, 1423, 1201,
1083 cmꢂ1; 1H NMR (250 MHz): 1.25 (t, J¼7.3 Hz, 3H, eCOOCH2CH3),
4.21(q, J¼7.3 Hz, 2H, eCOOCH2CH3), 5.10 (s, 2H, eOCH2COOCH2CH3),
IR (KBr): 3448, 2232, 1743, 1697, 1585, 1453, 1397, 1219, 1163 cmꢂ1
;
1H NMR (400 MHz): 1.26 (t, J¼7.1 Hz, 3H, eCOOCH2CH3), 4.23 (q,
J¼7.1 Hz, 2H, eCOOCH2CH3), 5.31 (s, 2H, eOCH2COOCH2CH3), 7.73
(dd, J¼J0¼7.6 Hz, 1H, PheH), 8.10 (d, J¼7.6 Hz, 1H, PheH), 8.12 (d,
J¼7.6 Hz, 1H, PheH), 8.15 (d, J¼1.6 Hz, 1H, pyridineeH), 8.36 (br, 1H,
PheH), 8.75 (d, J¼1.6 Hz, 1H, pyridineeH); 13C NMR (100 MHz):
14.2, 61.2, 65.6, 115.6, 120.1, 121.1, 128.6, 129.7, 130.4, 132.1, 135.8,
140.1, 142.2, 157.6, 167.2, 168.0, 197.8; MS (ESI) m/z (%): 327.0

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
4771
[(MþH)þ, 100]. Anal. Calcd for C17H14N2O5: C, 62.57; H, 4.32; N,
(ESI) m/z (%): 420.0 [(MþH)þ, 100]. Anal. Calcd for C23H18FN3O4: C,
8.59. Found: C, 62.69; H, 4.33; N, 8.61.
65.87; H, 4.33; N, 10.02. Found: C, 65.95; H, 4.34; N, 10.05.
4.1.9. 4-[6-Cyano-5-(2-ethoxy-2-oxoethoxy)pyridin-3-yl]benzoic
acid (10). The title compound was prepared in 71% yield as a white
solid from 8 by a similar method to that described for 9. Mp
246e247 ꢀC; IR (KBr): 3445, 2232, 1751, 1691, 1610, 1584, 1428, 1394,
4.1.12. Ethyl 3-amino-6-(3-{[(3-biphenyl)amino]carbonyl}phenyl)
furo[3,2-b]pyridine-2-carboxylate (15). The title compound was
prepared in 65% yield as a brown solid from 9 by a similar method
to that described for 13 using 3-phenylaniline. Mp 187e188 ꢀC; IR
(KBr): 3398, 3282, 1705, 1675, 1645, 1621, 1577, 1544, 1420, 1321,
1299, 1214, 1160 cmꢂ1
;
1H NMR (400 MHz): 1.26 (t, J¼7.0 Hz,
3H, eCOOCH2CH3), 4.23 (q, J¼7.0 Hz, 2H, eCOOCH2CH3), 5.29 (s,
2H, eOCH2COOCH2CH3), 8.02 (d, J¼7.8 Hz, 2H, PheH), 8.12 (d,
J¼7.8Hz, 2H, PheH), 8.17 (s,1H, pyridineeH), 8.79(s,1H, pyridineeH),
13.26 (s, 1H, eCOOH); 13C NMR (100 MHz): 14.2, 61.2, 65.6, 115.6,
120.2, 121.4, 128.1, 130.1, 131.7, 139.4, 139.6, 142.2, 157.5, 167.0, 168.0;
MS (ESI) m/z (%): 327.0 [(MþH)þ, 100]. Anal. Calcd for C17H14N2O5: C,
62.57; H, 4.32; N, 8.59. Found: C, 62.69; H, 4.34; N, 8.61.
1244, 1139 cmꢂ1
;
1H NMR (400 MHz): 1.38 (t, J¼7.0 Hz, 3H,
eCOOCH2CH3), 4.38 (q, J¼7.0 Hz, 2H, eCOOCH2CH3), 6.35 (s, 2H,
eNH2), 7.43e7.55 (m, 5H, 3PhePheH and 2PheHePh), 7.71 (d,
J¼6.8 Hz, 2H, PhePheH), 7.76 (dd, J¼8.0, 7.6 Hz, 1H, PheH), 7.89 (d,
J¼7.6 Hz, 1H, PheHePh), 8.08e8.10 (m, 2H, PheH), 8.16 (s, 1H,
PheHePh), 8.44 (s, 1H, PheH), 8.47 (s, 1H, furo[3,2-b]pyridineeH),
9.07 (s, 1H, furo[3,2-b]pyridineeH), 10.50 (s, 1H, eNH); 13C NMR
(100 MHz): 14.6, 60.1, 118.0, 118.9, 119.5, 122.3, 126.5, 126.7, 126.8,
127.8, 127.9, 129.2, 129.5, 129.6, 130.8, 135.4, 136.0, 137.2, 138.5,
139.5, 139.8, 140.3, 140.8, 144.7, 147.8, 160.6, 165.4; MS (ESI) m/z (%):
478.0 [(MþH)þ, 100]. Anal. Calcd for C29H23N3O4: C, 72.94; H, 4.85;
N, 8.80. Found: C, 73.13; H, 4.86; N, 8.82.
4.1.10. Ethyl 3-amino-6-(3-{[(3-chlorophenyl)amino]carbonyl}phe-
nyl)furo[3,2-b]pyridine-2-carboxylate (13). To a solution of 3-[6-
cyano-5-(2-ethoxy-2-oxoethoxy)pyridin-3-yl]benzoic acid 9 (0.6
g, 1.84 mmol) in dry DMF (4 mL) was added Cs2CO3 (0.6 g,
1.84 mmol). The reaction mixture was stirred at 80 ꢀC for 20 h.
After cooling at room temperature, ethyl acetate was added. The
solid was filtered off, washed with HCl 1 M and dried to yield 3-[3-
amino-2-(ethoxycarbonyl)furo[3,2-b]pyridin-6-yl]benzoic acid 11
as a light brown solid. To a solution of this crude solid in dry DMF
(24 mL) was added DEPBT (0.66 g, 2.21 mmol). The reaction
mixture was stirred at room temperature for 45 min and Et3N
(0.51 mL, 3.67 mmol) followed by 3-chloroaniline (0.24 mL,
2.27 mmol) were added. The mixture was stirred at room tem-
perature for 48 h and then diluted with ethyl acetate. The organic
layer was washed with NaOH 1 M, HCl 1 M, brine, dried over
sodium sulfate, filtered, and evaporated to dryness. The resulting
solid was washed with ethyl acetate and dried to afford 13
(402 mg, 50%) as a beige solid. Mp 144e145 ꢀC; IR (KBr): 3401,
3287, 1682, 1649, 1615, 1593, 1531, 1321, 1240, 1092 cmꢂ1; 1H NMR
(400 MHz): 1.38 (t, J¼7.1 Hz, 3H, eCOOCH2CH3), 4.38 (q, J¼7.1 Hz,
2H, eCOOCH2CH3), 6.35 (s, 2H, eNH2), 7.23 (dd, J¼1.8, 8.0 Hz, 1H,
PhCleH), 7.45 (dd, J¼J0¼8.0 Hz, 1H, PhCleH), 7.75 (dd, J¼J0¼8.0 Hz,
1H, PheH), 7.78 (dd, J¼1.8, 8.0 Hz, 1H, PhCleH), 8.03 (dd,
J¼J0¼1.8 Hz, 1H, PhCleH), 8.05 (d, J¼8.0 Hz, 1H, PheH), 8.10 (d,
J¼8.0 Hz, 1H, PheH), 8.40 (br, 1H, PheH), 8.45 (d, J¼1.7 Hz, 1H, furo
[3,2-b]pyridineeH), 9.05 (d, J¼1.7 Hz, 1H, furo[3,2-b]pyridineeH),
10.56 (s, 1H, eNH); 13C NMR (100 MHz): 14.6, 60.1, 118.0, 118.9,
120.0, 123.7, 126.5, 126.8, 128.0, 129.7, 130.6, 131.0, 133.2, 135.4,
135.7, 137.3, 138.5, 139.5, 140.7, 144.7, 147.8, 160.6, 165.7; MS (ESI)
m/z (%): 436.07 [(MþH)þ, 100], 438.07 [(MþH)þ2, 35]. Anal. Calcd
for C23H18ClN3O4: C, 63.38; H, 4.16; N, 9.64. Found: C, 63.28; H,
4.14; N, 9.62.
4.1.13. Ethyl 3-amino-6-(3-{[(4-chlorophenyl)amino]carbonyl}phe-
nyl)furo[3,2-b]pyridine-2-carboxylate (16). The title compound was
prepared in 52% yield as a beige solid from 9 by a similar method to
that described for 13 using 4-chloroaniline. Mp 272e273 ꢀC; IR
(KBr): 3390, 1699, 1661, 1625, 1527, 1139 cmꢂ1; 1H NMR (400 MHz):
1.38 (t, J¼7.0 Hz, 3H, eCOOCH2CH3), 4.38 (q, J¼7.0 Hz, 2H,
eCOOCH2CH3), 6.36 (s, 2H, eNH2), 7.47 (d, J¼8.8 Hz, 2H, PhCleH),
7.74 (dd, J¼J0¼7.8 Hz,1H, PheH), 7.91 (d, J¼8.8 Hz, 2H, PhCleH), 8.06
(d, J¼7.8 Hz, 1H, PheH), 8.09 (d, J¼7.8 Hz, 1H, PheH), 8.42 (br s, 1H,
PheH), 8.48 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 9.06 (d,
J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 10.63 (s, 1H, eNH); 13C NMR
(100 MHz): 14.6, 60.1, 118.0, 112.2, 126.5, 126.9, 127.5, 128.1, 128.6,
128.7, 129.6, 130.8, 135.4, 135.7, 137.2, 138.5, 139.5, 144.8, 147.8,
160.6, 165.5; MS (ESI) m/z (%): 436.2 [(MþH)þ, 100], 438.2 [(MþH)þ
2, 36]. Anal. Calcd for C23H18ClN3O4: C, 63.38; H, 4.16; N, 9.64.
Found: C, 63.28; H, 4.15; N, 9.63.
4.1.14. Ethyl 3-amino-6-(3-{[(4-fluorophenyl)amino]carbonyl}phe-
nyl)furo[3,2-b]pyridine-2-carboxylate (17). The title compound was
prepared in 47% yield as a beige solid from 9 by a similar method to
that described for 13 using 4-fluoroaniline. Mp 281e282 ꢀC; IR
(KBr): 3388, 1696, 1662, 1623, 1580, 1538, 1509, 1324, 1262, 1227,
1138 cmꢂ1
;
1H NMR (400 MHz): 1.38 (t, J¼7.0 Hz,
3H, eCOOCH2CH3), 4.38 (q, J¼7.0 Hz, 2H, eCOOCH2CH3), 6.34 (s,
2H, eNH2), 7.25 (dd, J¼J0¼9.0 Hz, 2H, PhFeH), 7.73 (dd, J¼7.6, 8.0 Hz,
1H, PheH), 7.85 (dd, J¼9.0, 5.1 Hz, 2H, PhFeH), 8.04 (dd, J¼8.0,
1.6 Hz, 1H, PheH), 8.08 (dd, J¼7.6, 1.6 Hz, 1H, PheH), 8.39 (dd,
J¼J0¼1.6 Hz, 1H, PheH), 8.44 (d, J¼2.0 Hz, 1H, furo[3,2-b]
pyridineeH), 9.05 (d, J¼2.0 Hz, 1H, furo[3,2-b]pyridineeH), 10.46 (s,
1H, eNH); 13C NMR (100 MHz): 14.2, 59.6, 115.0 (d, JCeF¼22 Hz),
117.5, 122.0 (d, JCeF¼8 Hz), 126.1, 126.2, 127.5, 129.2, 130.3, 135.0,
135.1 (d, JCeF¼3 Hz), 135.5, 136.8, 138.1, 139.1, 144.3, 147.4, 159.0 (d,
JCeF¼220.0 Hz),160.2, 164.9; MS (ESI) m/z (%): 420.1 [(MþH)þ, 100].
Anal. Calcd for C23H18FN3O4: C, 65.87; H, 4.33; N, 10.02. Found: C,
66.07; H, 4.35; N, 10.05.
4.1.11. Ethyl 3-amino-6-(3-{[(3-fluorophenyl)amino]carbonyl}phe-
nyl)furo[3,2-b]pyridine-2-carboxylate (14). The title compound was
prepared in 43% yield as a beige solid from 9 by a similar method to
that described for 13 using 3-fluoroaniline. Mp 218e219 ꢀC; IR
(KBr): 3404, 3290, 1700, 1677, 1655, 1614, 1542, 1440, 1238,
1144 cmꢂ1
;
1H NMR (400 MHz): 1.38 (t, J¼7.1 Hz, 3H,
eCOOCH2CH3), 4.38 (q, J¼7.1 Hz, 2H, eCOOCH2CH3), 6.36 (s, 2H,
eNH2), 7.00 (ddd, J¼J0¼8.2 Hz, J¼2.0 Hz, 1H, PhFeH), 7.46 (ddd,
J¼J0¼J00¼8.2 Hz, 1H, PhFeH), 7.62 (d, J¼8.2 Hz, 1H, PhFeH), 7.75 (dd,
J¼J0¼7.6 Hz, 1H, PheH), 7.82 (ddd, J¼11.6 Hz, J¼J0¼2.0 Hz, 1H,
PhFeH), 8.05 (d, J¼7.6 Hz, 1H, PheH), 8.10 (d, J¼7.6 Hz, 1H, PheH),
8.39 (br s, 1H, PheH), 8.45 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH),
9.05 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 10.59 (s, 1H, NH); 13C
NMR (100 MHz): 14.6, 60.1, 107.2 (d, JCeF¼26 Hz), 110.5 (d,
JCeF¼21 Hz), 116.2 (d, JCeF¼2 Hz), 118.0, 126.5, 126.8, 128.0, 129.7,
130.5 (d, JCeF¼9 Hz), 130.9, 135.4, 135.8, 137.3, 138.5, 139.5, 141.0(d,
JCeF¼11 Hz), 144.7, 147.8, 160.6, 162.3 (d, JCeF¼240.0 Hz), 165.7; MS
4.1.15. Ethyl 3-amino-6-(3-{[(4-biphenyl)amino]carbonyl}phenyl)
furo[3,2-b]pyridine-2-carboxylate (18). The title compound was
prepared in 63% yield as an yellow-brown solid from 9 by a similar
method to that described for 13 using 4-phenylaniline. Mp
270e271 ꢀC; IR (KBr): 3400, 3286, 1677, 1644, 1616, 1529, 1484,
1374, 1320, 1239, 1139 cmꢂ1; 1H NMR (400 MHz): 1.39 (t, J¼7.1 Hz,
3H, eCOOCH2CH3), 4.38 (q, J¼7.1 Hz, 2H, eCOOCH2CH3), 6.36 (s, 2H,
eNH2), 7.39 (dd, J¼J0¼7.2 Hz, 1H, PhePheH), 7.50 (dd, J¼J0¼7.6 Hz,
2H, PhePheH), 7.73e7.78 (m, 5H, 2PhePheH, 2PheHePh, PheH),

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
4772
7.95 (d, J¼8.8 Hz, 2H, PheHePh), 8.07 (d, J¼8.4 Hz, 1H, PheH), 8.09
(d, J¼8.4 Hz, 1H, PheH), 8.42 (br s, 1H, PheH), 8.47 (d, J¼1.9 Hz, 1H,
furo[3,2-b]pyridineeH), 9.07 (d, J¼1.9 Hz, 1H, furo[3,2-b]
pyridineeH), 10.51 (s, 1H, eNH); 13C NMR (100 MHz): 14.6, 60.1,
118.0, 120.9, 126.5, 126.8, 127.0, 127.3, 128.0, 129.1, 129.6, 130.8,
135.5, 135.6, 136.0, 136.3, 137.2, 138.6, 138.8, 139.5, 139.8, 144.8,
147.8, 160.6, 165.4; MS (ESI) m/z (%): 478.1 [(MþH)þ, 100]. Anal.
Calcd for C29H23N3O4: C, 72.94; H, 4.85; N, 8.80. Found: C, 73.13; H,
4.86; N, 8.83.
MeNH2 in ethanol (8 M) (21.8 mL, 174.40 mmol) was added to the
ester 13 (378 mg, 0.86 mmol) in an Schlenk apparatus. The reaction
mixture was stirred at 110 ꢀC for 24 h. After cooling at room tem-
perature, the solution was evaporated. The resulting solid was
washed with CH2Cl2 and dried to afford 22 (260 mg, 71%) as a beige
solid. Mp 201e202 ꢀC; IR (KBr): 3620, 3290, 1656, 1594, 1534, 1481,
1371, 1326, 1255, 1161 cmꢂ1; 1H NMR (400 MHz): 2.83 (d, J¼4.5 Hz,
3H, eNHCH3), 5.95 (s, 2H, eNH2), 7.23 (dd, J¼8.0, 1.2 Hz, 1H,
PhCleH), 7.45 (dd, J¼8.0, 8.4 Hz,1H, PhCleH), 7.74 (dd, J¼8.0, 8.4 Hz,
1H, PheH), 7.78 (dd, J¼8.0, 1.2 Hz, 1H, PhCleH), 8.03 (br s, 1H,
PhCleH), 8.04 (d, J¼8.4 Hz, 1H, PheH), 8.10 (d, J¼8.0 Hz, 1H, PheH),
8.17 (q, J¼4.5 Hz, 1H, eNHCH3), 8.29 (d, J¼1.6 Hz, 1H, furo[3,2-b]
pyridineeH), 8.39 (br s, 1H, PheH), 9.01 (d, J¼1.6 Hz, 1H, furo[3,2-b]
pyridineeH), 10.57 (s, 1H, eNH); 13C NMR (100 MHz): 25.5, 117.3,
118.9, 119.9, 123.7, 126.8, 127.8, 129.6, 130.4, 130.6, 131.0, 133.2,
134.3, 134.7, 135.6, 137.5, 140.6, 140.8, 144.5, 146.4, 161.5, 165.7; MS
(ESI) m/z (%): 421.1 [(MþH)þ, 100], 423.1 (MþH)þ2, 33]. Anal. Calcd
for C22H17ClN4O3: C, 62.79; H, 4.07; N, 13.31. Found: C, 62.88; H,
4.09; N, 13.35.
4.1.16. Ethyl 3-amino-6-(4-{[(3-chlorophenyl)amino]carbonyl}phe-
nyl)furo[3,2-b]pyridine-2-carboxylate (19). The title compound was
prepared in 37% yield as a beige solid from 10 by a similar method
to that described for 13 using 3-chloroaniline. Mp 246e247 ꢀC; IR
(KBr): 3499, 3394, 1690, 1624, 1594, 1535, 1484, 1378, 1310, 1261,
1140 cmꢂ1
;
1H NMR (400 MHz): 1.38 (t, J¼7.1 Hz,
3H, eCOOCH2CH3), 4.38 (q, J¼7.1 Hz, 2H, eCOOCH2CH3), 6.35 (s,
2H, eNH2), 7.22 (ddd, J¼8.0, 2.0, 0.8 Hz, 1H, PhCleH), 7.45 (dd,
J¼8.4, 8.0 Hz, 1H, PhCleH), 7.79 (ddd, J¼8.4, 2.0, 0.8 Hz, 1H,
PhCleH), 8.04e8.05 (m, 1H, PhCleH), 8.06 (d, J¼8.4 Hz, 2H, PheH),
8.16 (d, J¼8.4 Hz, 2H, PheH), 8.46 (d, J¼2.0 Hz, 1H, furo[3,2-b]
pyridineeH), 9.04 (d, J¼2.0 Hz, 1H, furo[3,2-b]pyridineeH), 10.54 (s,
1H, eNH); 13C NMR (100 MHz): 14.6, 60.1, 118.0, 118.8, 119.9, 123.6,
126.2, 127.6, 128.7, 130.5, 132.4, 133.1, 134.3, 134.9, 139.7, 140.3,
140.8, 144.7, 147.8, 160.6, 165.4; MS (ESI) m/z (%): 435.9 [(MþH)þ,
100], 437.9 [(MþH)þ2, 33]. Anal. Calcd for C23H18ClN3O4: C, 63.38;
H, 4.16; N, 9.64. Found: C, 63.53; H, 4.17; N, 9.67.
4.1.20. 3-Amino-6-(3-{[(3-fluorophenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (23). The title compound
was prepared in 54% yield as a beige solid from 14 by a similar
method to that described for 22. Mp 218e219 ꢀC; IR (KBr): 3359,
3303, 1656, 1610, 1540, 1490, 1370, 1328, 1254, 1146 cmꢂ1; 1H NMR
(400 MHz): 2.83 (d, J¼4.6 Hz, 3H, eNHCH3), 5.95 (s, 2H, eNH2), 7.00
(ddd, J¼J0¼8.2, 2.0 Hz, 1H, PhFeH), 7.46 (ddd, J¼J0¼J00¼8.2 Hz, 1H,
PhFeH), 7.62 (dd, J¼8.2, 1.2 Hz, 1H, PhFeH), 7.74 (dd, J¼J0¼8.0 Hz,
1H, PheH), 7.82 (dt, J¼11.6, 2.0 Hz, 1H, PhFeH), 8.04 (d, J¼8.0 Hz,
1H, PheH), 8.10 (d, J¼8.0 Hz, 1H, PheH), 8.18 (q, J¼4.6 Hz, 1H,
eNHCH3), 8.29 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 8.38 (br s,
1H, PheH), 9.01 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 10.59 (s,
1H, eNH); 13C NMR (100 MHz): 25.5, 107.1 (d, JCeF¼26 Hz), 110.4 (d,
JCeF¼21 Hz), 116.2 (d, JCeF¼2 Hz), 117.3, 126.8, 127.8, 129.6, 130.3,
130.5 (d, JCeF¼9 Hz), 131.0, 134.3, 134.6, 135.7, 137.4, 140.6, 141.0 (d,
JCeF¼11 Hz), 144.5, 146.3, 161.5, 162.3 (d, JCeF¼240 Hz), 165.7; MS
(ESI) m/z (%): 405.1 [(MþH)þ, 100]. Anal. Calcd for C22H17FN4O3: C,
65.34; H, 4.24; N, 13.85. Found: C, 65.50; H, 4.26; N, 13.88.
4.1.17. Ethyl 3-amino-6-(4-{[(3-biphenyl)amino]carbonyl}phenyl)
furo[3,2-b]pyridine-2-carboxylate (20). The title compound was
prepared in 43% yield as a beige solid from 10 by a similar method
to that described for 13 using 3-phenylaniline. Mp 213e214 ꢀC; IR
(KBr): 3493, 3396, 1673, 1623, 1542, 1479, 1374, 1314, 1256,
1137 cmꢂ1
;
1H NMR (400 MHz): 1.39 (t, J¼7.1 Hz, 3H,
eCOOCH2CH3), 4.38 (q, J¼7.1 Hz, 2H, eCOOCH2CH3), 6.36 (s, 2H,
eNH2), 7.47e7.56 (m, 5H, 3PhePheH, 2PheHePh), 7.71 (dd, J¼8.4,
1.0 Hz, 2H, PhePheH), 7.89 (dt, J¼8.0,1.0 Hz,1H, PheHePh), 8.07 (d,
J¼8.4 Hz, 2H, PheH), 8.20 (d, J¼8.4 Hz, 2H, PheH), 8.19e8.20 (m,
1H, PheHePh), 8.47 (d, J¼2.0 Hz, 1H, furo[3,2-b]pyridineeH), 9.05
(d, J¼2.0 Hz, 1H, furo[3,2-b]pyridineeH), 10.48 (s, 1H, eNH); 13C
NMR (100 MHz): 14.6, 60.1, 117.9, 118.8, 119.5, 122.2, 126.5, 126.8,
127.5,127.7,128.7,129.1,129.4,134.6,134.8,134.9,139.7,139.8,140.0,
140.3, 140.8, 144.6, 147.8, 160.6, 165.2; MS (ESI) m/z (%): 478.0
[(MþH)þ, 100]. Anal. Calcd for C29H23N3O4: C, 72.94; H, 4.85; N,
8.80. Found: C, 73.13; H, 4.87; N, 8.81.
4.1.21. 3-Amino-6-(3-{[(3-biphenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (24). The title compound
was prepared in 77% yield as a beige solid from 15 by a similar
method to that described for 22. Mp 247e248 ꢀC; IR (KBr): 3357,
3308, 1648, 1615, 1544, 1500, 1479, 1420, 1370, 1327, 1255,
1160 cmꢂ1
;
1H NMR (400 MHz): 2.83 (d, J¼4.5 Hz, 3H, eNHCH3),
5.96 (s, 2H, eNH2), 7.41e7.56 (m, 5H, 3PhePheH and 2PheHePh),
7.71 (d, J¼7.2 Hz, 2H, PhePheH), 7.75 (dd, J¼J0¼8.0 Hz, 1H, PheH),
7.89 (d, J¼8.0 Hz, 1H, PheHePh), 8.08 (d, J¼8.0 Hz, 1H, PheH), 8.10
(d, J¼8.0 Hz, 1H, PheH), 8.16 (br s, 1H, PheHePh), 8.17 (q, J¼4.5 Hz,
1H, eNHCH3), 8.31 (d, J¼1.6 Hz, 1H, furo[3,2-b]pyridineeH), 8.43
(br s,1H, PheH), 9.03 (d, J¼1.6 Hz,1H, furo[3,2-b]pyridineeH), 10.51
(s, 1H, eNH); 13C NMR (100 MHz): 25.4, 117.3, 118.9, 119.5, 122.3,
126.7, 126.8, 127.8, 129.2, 129.5, 129.6, 130.3, 130.8, 134.4, 134.6,
135.9, 137.4, 139.8, 140.3, 140.6, 140.9, 145.0, 146.4, 161.5, 165.5; MS
(ESI) m/z (%): 463.2 [(MþH)þ, 100]. Anal. Calcd for C28H22N4O3: C,
72.71; H, 4.79; N, 12.11. Found: C, 72.93; H, 4.80; N, 12.14.
4.1.18. Ethyl 3-amino-6-(4-{[(4-biphenyl)amino]carbonyl}phenyl)
furo[3,2-b]pyridine-2-carboxylate (21). The title compound was
prepared in 48% yield as a yellow-brown solid from 10 by a similar
method to that described for 13 using 4-phenylaniline. Mp
311e312 ꢀC; IR (KBr): 3402, 3270, 1679, 1644, 1619, 1566, 1532,
1488, 1375, 1312, 1258, 1167 cmꢂ1 1H NMR (400 MHz): 1.39 (t,
;
J¼7.1 Hz, 3H, eCOOCH2CH3), 4.38 (q, J¼7.1 Hz, 2H, eCOOCH2CH3),
6.35 (s, 2H, eNH2), 7.38 (dd, J¼J0¼7.2 Hz, 1H, PhePheH), 7.50 (dd,
J¼8.2, 7.2 Hz, 2H, PhePheH), 7.72e7.75 (m, 2H, PhePheH), 7.74 (d,
J¼8.8 Hz, 2H, PheHePh), 7.97 (d, J¼8.8 Hz, 2H, PheHePh), 8.07 (d,
J¼8.4 Hz, 2H, PheH), 8.19 (d, J¼8.4 Hz, 2H, PheH), 8.46 (d, J¼1.8 Hz,
1H, furo[3,2-b]pyridineeH), 9.05 (d, J¼1.8 Hz, 1H, furo[3,2-b]
pyridineeH), 10.50 (s, 1H, eNH); 13C NMR (100 MHz): 14.6, 60.1,
118.0,120.9,126.5,126.6,127.0,127.6,128.7,129.1,131.5,134.6,134.9,
135.5, 138.8, 139.7, 139.9, 140.0, 144.6, 147.8, 160.6, 165.1; MS (ESI)
m/z (%): 478.1 [(MþH)þ, 100]. Anal. Calcd for C29H23N3O4: C, 72.94;
H, 4.85; N, 8.80. Found: C, 72.85; H, 4.84; N, 8.78.
4.1.22. 3-Amino-6-(3-{[(4-chlorophenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (25). The title compound
was prepared in 30% yield as a beige solid from 16 by a similar
method to that described for 22. Mp 274e275 ꢀC; IR (KBr): 3276,
1647, 1529, 1325, 1252, 1163, 1093 cmꢂ1 1H NMR (400 MHz): 2.83
;
(d, J¼4.6 Hz, 3H, eNHCH3), 5.94 (s, 2H, eNH2), 7.48 (d, J¼8.8 Hz, 2H,
PhCleH), 7.74 (dd, J¼7.6, 8.0 Hz, 1H, PheH), 7.88 (d, J¼8.8 Hz, 2H,
PhCleH), 8.03 (dt, J¼8.0, 1.2 Hz, 1H, PheH), 8.09 (dt, J¼7.6, 1.2 Hz,
1H, PheH), 8.16 (q, J¼4.6 Hz, 1H, eNHCH3), 8.28 (d, J¼1.7 Hz, 1H,
4.1.19. 3-Amino-6-(3-{[(3-chlorophenyl)amino]carbonyl}phenyl)-
N-methylfuro[3,2-b]pyridine-2-carboxamide (22). A solution of

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A. Breteche et al. / Tetrahedron 67 (2011) 4767e4773
4773
furo[3,2-b]pyridineeH), 8.38 (dd, J¼J0¼1.2 Hz, 1H, PheH), 9.01 (d,
J¼1.7 Hz, 1H, furo[3,2-b]pyridineeH), 10.53 (s, 1H, eNH); 13C NMR
(100 MHz): 25.4, 117.3, 122.1, 126.7, 127.6, 127.8, 128.8, 129.6, 130.3,
130.8, 134.3, 134.6, 135.8, 137.4, 138.2, 140.6, 144.5, 146.3, 161.5,
165.5; MS (ESI) m/z (%): 421.2 [(MþH)þ, 100], 423.2 (MþH)þ2, 35].
Anal. Calcd for C22H17ClN4O3: C, 62.79; H, 4.07; N, 13.31. Found: C,
62.90; H, 4.09; N, 13.33.
eNH2), 7.42e7.56 (m, 5H, 3PhePheH, 2PheHePh), 7.71 (dd, J¼8.8,
1.6 Hz, 2H, PhePheH), 7.89 (d, J¼8.0 Hz, 1H, PheHePh), 8.07 (d,
J¼8.6 Hz, 2H, PheH), 8.19 (d, J¼8.6 Hz, 2H, PheH), 8.18e8.20 (m, 2H,
PheHePh, eNHCH3), 8.28 (d, J¼1.9 Hz, 1H, furo[3,2-b]pyridineeH),
9.01 (d, J¼1.9 Hz, 1H, furo[3,2-b]pyridineeH), 10.48 (s, 1H, eNH);
13C NMR (100 MHz): 25.4, 117.3, 118.9, 119.5, 122.3, 126.8, 127.6,
127.8, 128.7, 129.2, 129.4, 130.4, 133.9, 134.4, 134.6, 139.9, 140.3,
140.8, 144.4, 146.3, 161.5, 165.2; MS (ESI) m/z (%): 463.2 [(MþH)þ,
100]. Anal. Calcd for C28H22N4O3: C, 72.71; H, 4.79; N, 12.11. Found:
C, 72.86; H, 4.80; N, 12.15.
4.1.23. 3-Amino-6-(3-{[(4-fluorophenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (26). The title compound
was prepared in 22% yield as a beige solid from 17 by a similar
method to that described for 22. Mp 269e270 ꢀC; IR (KBr): 3263,
1644, 1567, 1514, 1408, 1325, 1237, 1162 cmꢂ1; 1H NMR (400 MHz):
2.83 (d, J¼4.6 Hz, 3H, eNHCH3), 5.94 (s, 2H, eNH2), 7.26 (dd,
J¼J0¼9.0 Hz, 2H, PhFeH), 7.73 (dd, J¼7.6, 8.0 Hz,1H, PheH), 7.85 (dd,
J¼9.0, 5.1 Hz, 2H, PhFeH), 8.04 (d, J¼7.6 Hz, 1H, PheH), 8.08 (d,
J¼8.0 Hz, 1H, PheH), 8.15 (q, J¼4.6 Hz, 1H, eNHCH3), 8.28 (d,
J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 8.38 (s, 1H, PheH), 9.01 (d,
J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 10.46 (s, 1H, eNH); 13C NMR
(100 MHz): 26.4, 116.4 (JCeF¼22 Hz), 118.3, 123.5 (JCeF¼8 Hz), 127.7,
128. 8, 130.6, 131.4, 131.8, 135.4, 135.6, 136.6 (JCeF¼2 Hz), 136.9,
138.4, 141.6, 145.5, 147.4, 159.6 (JCeF¼239 Hz), 162.5, 166.3; MS (ESI)
m/z (%): 405.6[(MþH)þ, 100]. Anal. Calcd for C22H17FN4O3: C, 65.34;
H, 4.24; N, 13.85. Found: C, 65.48; H, 4.26; N, 13.89.
4.1.27. 3-Amino-6-(4-{[(4-biphenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (30). The title compound
was prepared in 73% yield as a yellow solid from 21 by a similar
method to that described for 22. Mp 324e325 ꢀC; IR (KBr): 3390,
3274, 1642, 1568, 1533, 1482, 1401, 1371, 1318, 1257, 1162 cmꢂ1 1H
;
NMR (400 MHz): 2.84 (d, J¼4.8 Hz, 3H, eNHCH3), 5.95 (s, 2H,
eNH2), 7.38 (dd, J¼J0¼7.3 Hz, 1H, PhePheH), 7.50 (dd, J¼7.3, 7.0 Hz,
2H, PhePheH), 7.73 (d, J¼7.0 Hz, 2H, PhePheH), 7.74 (d, J¼8.8 Hz,
2H, PheHePh), 7.97 (d, J¼8.8 Hz, 2H, PheHePh), 8.06 (d, J¼8.2 Hz,
2H, PheH), 8.18 (d, J¼8.2 Hz, 2H, PheH), 8.17 (br, 1H, eNHCH3), 8.27
(d, J¼1.6 Hz, 1H, furo[3,2-b]pyridineeH), 9.01 (d, J¼1.6 Hz, 1H, furo
[3,2-b]pyridineeH), 10.49 (s, 1H, eNH); 13C NMR (100 MHz): 25.5,
117.3, 120.9, 126.5, 127.0, 127.3, 127.6, 128.7, 129.1,130.4, 133.9, 134.5,
134.6, 135.5, 138.8, 139.9, 140.3, 140.8, 144.4, 146.3, 161.5, 165.2; MS
(ESI) m/z (%): 463.2 [(MþH)þ, 100]. Anal. Calcd for C28H22N4O3: C,
72.71; H, 4.79; N, 12.11. Found: C, 72.91; H, 4.81; N, 12.15.
4.1.24. 3-Amino-6-(3-{[(4-biphenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (27). The title compound
was prepared in 52% yield as a beige solid from 18 by a similar
method to that described for 22. Mp 300e301 ꢀC; IR (KBr): 3359,
3271, 1640, 1570, 1524, 1446, 1372, 1323, 1286, 1239, 1163 cmꢂ1; 1H
NMR (400 MHz): 2.84 (d, J¼4.5 Hz, 3H, eNHCH3), 5.95 (s, 2H,
eNH2), 7.38 (dd, J¼7.2, 7.6 Hz,1H, PhePheH), 7.50 (dd, J¼7.6, 8.0 Hz,
2H, PhePheH), 7.72e7.78 (m, 5H, 2PhePheH, 2PheHePh, PheH),
7.96 (d, J¼8.8 Hz, 2H, PheHePh), 8.07 (d, J¼8.0 Hz, 1H, PheH), 8.10
(d, J¼8.0 Hz, 1H, PheH), 8.18 (q, J¼4.5 Hz, 1H, eNHCH3), 8.30 (d,
J¼1.6 Hz, 1H, furo[3,2-b]pyridineeH), 8.41 (br s, 1H, PheH), 9.03 (d,
J¼1.6 Hz, 1H, furo[3,2-b]pyridineeH), 10.52 (s, 1H, eNH); 13C NMR
(100 MHz): 25.4, 117.3, 120.9, 126.5, 126.8, 127.0, 127.3, 127.8, 129.1,
129.6, 130.3, 130.8, 134.4, 134.6, 135.6, 136.0, 137.4, 138.8, 139.8,
140.6, 144.5, 146.4, 161.5, 165.4; MS (ESI) m/z (%): 463.2 [(MþH)þ,
100]. Anal. Calcd for C28H22N4O3: C, 72.71; H, 4.79; N, 12.11. Found:
C, 72.86; H, 4.81; N, 12.14.
References and notes
1. (a) Pracitto, R.; Kadow, J. F.; Bender, J. A.; Beno, B. R.; Grant-Young, K. A.; Han, Y.;
Hewawasam, P.; Nickel, A.; Parcella, K. E.; Yeung, K. S.; Chupak, L. U.S. Patent
0184800A1, 2010; (b) Miyazaki, Y.; Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart,
J. D.; Narten, E. N.; Hightower, K. E.; Kane-Carson, L. Bioorg. Med. Chem. Lett.
2007, 17, 250e254; (c) Debenham, J. S.; Madsen-Duggan, C. B.; Toupence, R. B.;
Walsh, T. F.; Wang, J.; Tong, X.; Kumar, S.; Lao, J.; Fong, T. M.; Xiao, J. C.; Huang,
C. R. R. C.; Shen, C. P.; Feng, Y.; Marsh, D. J.; Stribling, D. S.; Shearman, P.; Strack,
A. M.; Goulet, M. T. Bioorg. Med. Chem. Lett. 2010, 20, 1448e1452.
2. (a) Mathes, B. M.; Filla, S. A. Tetrahedron Lett. 2003, 44, 725e728; (b) Mathes, B.
M.; Hudziak, K. J.; Schaus, J. M.; Xu, Y.-C.; Nelson, D. L.; Wainscott, D. B.; Nutter,
S. E.; Gough, W. H.; Branchek, T. A.; Zgombick, J. M.; Filla, S. A. Bioorg. Med.
Chem. Lett. 2004, 14, 167e170.
3. Chartoire, A.; Comoy, C.; Fort, Y. Tetrahedron 2008, 64, 10867e10873.
4. (a) Cailly, T.; Lemaître, S.; Fabis, F.; Rault, S. Synthesis 2007, 20, 3247e3251; (b)
Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 14,
2409e2412; (c) Campos, P. J.; Anon, E.; Malo, M. C.; Rodriguez, M. A. Tetrahe-
dron 1999, 55, 14079e14088.
5. Elliott, R. L.; Ryther, K. B.; Anderson, D. J.; Piattoni-Kaplan, M.; Kuntzweiler, T.
A.; Donnelly-Roberts, D.; Arneric, S. P.; Holladay, M. W. Bioorg. Med. Chem. Lett.
1997, 21, 2703e2708.
6. Breteche, A.; Marchand, P.; Nourrisson, M. R.; De Nanteuil, G.; Duflos, M.
Tetrahedron 2010, 66, 4490e4494.
4.1.25. 3-Amino-6-(4-{[(3-chlorophenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (28). The title compound
was prepared in 80% yield as a light yellow solid from 19 by
a similar method to that described for 22. Mp 258e259 ꢀC; IR (KBr):
3452, 3363, 1666, 1641, 1594, 1527, 1481, 1418, 1292, 1256,
ꢀ
ꢀ
7. Bazzicalupi, C.; Bianchi, A.; Berni, E.; Calabi, L.; Giorgi, C.; Mariani, P.; Losi, P.;
Valtancoli, B. Inorg. Chim. Acta 2002, 329, 93e99.
1160 cmꢂ1
;
1H NMR (400 MHz): 2.83 (d, J¼4.7 Hz, 3H, eNHCH3),
8. Zhu, G.-D.; Gong, J.; Claiborne, A.; Woods, K. W.; Gandhi, V. B.; Thomas, S.; Luo,
Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S. R.; Klinghofer, V.; Johnson, E. F.; Bouska,
J.; Shoemaker, A.; Oleksijew, A.; Stoll, V. S.; De Jong, R.; Oltersdorf, T.; Li, Q.;
Rosenberg, S. H.; Giranda, V. L. Bioorg. Med. Chem. Lett. 2006, 16, 3150e3155.
9. (a) Sasaki, K.; Tsurumori, A.; Hirota, T. J. Chem. Soc., Perkin Trans. 1 1998,
3851e3856; (b) Bjorsvik, H. R.; Gambarotti, C.; Jensen, V. R.; Gonzalez, R. R.
J. Org. Chem. 2005, 70, 3218e3224.
5.95 (s, 2H, eNH2), 7.22 (ddd, J¼8.0, 2.0, 0.8 Hz, 1H, PhCleH), 7.44
(dd, J¼J0¼8.0 Hz, 1H, PhCleH), 7.79 (ddd, J¼8.0, 2.0, 0.8 Hz, 1H,
PhCleH), 8.05e8.06 (m, 1H, PhCleH), 8.06 (d, J¼8.4 Hz, 2H, PheH),
8.15 (d, J¼8.4 Hz, 2H, PheH), 8.18 (q, J¼4.7 Hz,1H, eNHCH3), 8.26 (d,
J¼1.9 Hz,1H, furo[3,2-b]pyridineeH), 8.99 (d, J¼1.9 Hz,1H, furo[3,2-
b]pyridineeH), 10.54 (s, 1H, eNH); 13C NMR (100 MHz): 25.4, 117.3,
118.8, 119.9, 123.6, 127.6, 128.7, 130.4, 130.5, 133.1, 133.8, 134.1, 134.6,
140.5, 140.8, 144.4, 146.3, 161.5, 165.4; MS (ESI) m/z (%): 421.1
[(MþH)þ, 100], 123.1 (MþH)þ2, 33]. Anal. Calcd for C22H17ClN4O3:
C, 62.79; H, 4.07; N, 13.31. Found: C, 62.63; H, 4.05; N, 13.28.
ꢀ
ꢀ
10. Morgentin, R.; Jung, F.; Lamorlette, M.; Maudet, M.; Menard, M.; Ple, P.; Pasquet,
G.; Renaud, F. Tetrahedron 2009, 65, 757e764.
11. (a) Littke, A.; Soumeillant, M.; Kaltenbach, R. F.; Cherney, R. J.; Tarby, C. M.; Kiau,
S. Org. Lett. 2007, 9, 1711e1714; (b) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J.
Tetrahedron Lett. 2001, 42, 6707e6710; (c) Jin, F.; Confalone, P. N. Tetrahedron
Lett. 2000, 41, 3271e3273.
12. Chobonian, H. R.; Fors, B. P.; Lin, L. S. Tetrahedron Lett. 2006, 47, 3303e3305.
13. (a) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett. 1999, 1,
91e93; (b) Hanessian, S.; Del Valle, J. R.; Xue, Y.; Blomberg, N. J. Am. Chem. Soc.
2006, 128, 10491e10495.
4.1.26. 3-Amino-6-(4-{[(3-biphenyl)amino]carbonyl}phenyl)-N-
methylfuro[3,2-b]pyridine-2-carboxamide (29). The title compound
was prepared in 65% yield as a beige solid from 20 by a similar
method to that described for 22. Mp 249e250 ꢀC; IR (KBr): 3383,
3296, 1671, 1639, 1610, 1547, 1478, 1375, 1314, 1259, 1160 cmꢂ1; 1H
NMR (400 MHz): 2.84 (d, J¼4.6 Hz, 3H, eNHCH3), 5.95 (s, 2H,
14. Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron 2001,
57, 4447e4454.
15. Bunnelle, W. H.; Daanen, J. F.; Ryther, K. B.; Schrimpf, M. R.; Dart, M. J.; Gelain,
A.; Meyer, M. D.; Frost, J. M.; Anderson, D. J.; Buckley, M.; Curzon, P.; Cao, Y. J.;
Puttfarcken, P.; Searle, X.; Ji, J.; Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D.
J. Med. Chem. 2007, 20, 3627e3644.