A convenient route to functionalized 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides

Article abstract of DOI:10.1016/j.tet.2010.04.071

An efficient synthesis of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides is described via the formation of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile. Functionalization of the amino group at position 3 of the heterocycle will be discussed.

Full text of DOI:10.1016/j.tet.2010.04.071

Tetrahedron 66 (2010) 4490e4494
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A convenient route to functionalized 3-amino-6-bromofuro[3,2-b]-
pyridine-2-carboxamides
,
a
b
a
Anne Bretéché a, Pascal Marchand a , Marie-Renée Nourrisson , Guillaume De Nanteuil , Muriel Duflos
*
a Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, Cibles et Médicaments des Infections, de l’Immunité et du Cancer,
IICiMed UPRES EA 1155, Faculté de Pharmacie, 1 rue Gaston Veil, 44035 Nantes, France
b Institut de Recherches Servier, 125 chemin de ronde, F-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:
An efficient synthesis of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamides is described via the for-
mation of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile. Functionalization of the amino group at
position 3 of the heterocycle will be discussed.
Received 21 March 2010
Received in revised form 12 April 2010
Accepted 16 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 21 April 2010
Keywords:
3-Amino-6-bromofuro[3,2-b]-
pyridine-2-carboxamides
3-Amino-6-bromofuro[3,2-b]-
pyridine-2-carbonitrile
Heteroannulation
1. Introduction
we envisioned to obtain the corresponding furo[3,2-b]pyridine-2-
carbonitrile, still not reported in the literature, and giving direct
We recently started a research program aimed at the synthesis
of a new class of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbox-
amide derivatives as potent kinase inhibitors. Furopyridines are
important scaffolds in medicinal chemistry. Unsubstituted pyridine
containing furo[3,2-b], [3,2-c], [2,3-c], [2,3-b]pyridine-2-carbox-
amides were described as FXa inhibitors,1 for treatment of adeno-
sine A2A receptor-related diseases2 or as inhibitors of leukotriene
biosynthesis.3 Furopyridines have also been used as bioisosteres of
the indole core.4
The preparation of furo[3,2-b]pyridines was recently described
using a one-pot Sonogashira coupling-heteroannulation sequence
followed by a regioselective functional approach at position 2.5 2-
Substituted furo[3,2-b]pyridines were previously obtained through
a coupling-cyclisation process starting from 2-ethynyl-3-pyri-
dinols.6 In 2007, the access to ethyl 3-aminofuropyridine-2-carbo-
xylates from 1-chloro-2-cyano or 1-hydroxy-2-cyano-substituted
pyridines was developed in a one-pot procedure.7
access to the target report an efficient amide by hydration of the
nitrile function. Herein, we report the procedure for the synthesis of
3-(benzylamino)-6-bromofuro[3,2-b]pyridine-2-carboxamides.
2. Results and discussion
The synthetic route used for the preparation of the 6-bromofuro
[3,2-b]pyridine-2-carbonitrile is outlined in Scheme 1. 3,5-Dibro-
mopyridine 1 reacted with sodium methoxide in DMF at 65 ꢀC to
give 3-bromo-5-methoxypyridine 2 in good yield by nucleophilic
substitution of one bromine atom only.8 Methoxy group cleavage
was performed using boron tribromide in CH2Cl2 at 0 ꢀC to afford
3-pyridinol 3 in 72% yield. Selective iodination at position 2 of the
pyridine ring was carried out by action of iodine in the presence of
Na2CO3 in H2O at room temperature.9 Subsequent alkylation of the
hydroxypyridine 4 was obtained by formation of the potassium salt
using potassium carbonate followed by its reaction with bromoa-
cetonitrile at room temperature as described for phenol analogs.10
The corresponding nitrile 6 was synthesized by heating the iodo
derivative 5 at 100 ꢀC with CuCN in pyridine via a Rosenmundevon
Braun reaction.11 Finally, heteroannulation of 6 under basic condi-
tions produced 3-amino-6-bromofuro[3,2-b]pyridine-2-carbon-
itrile 7 in good yield and its hydrolysis using concentrated H2SO4
led to the corresponding primary amide 8.
In order to synthesizethe key intermediate 3-amino-6-bromofuro
[3,2-b]pyridine-2-carboxamide, we decided to apply such a strategy
via the cyclisation of the 5-(bromo-3-cyanomethoxy)pyridine-2-
carbonitrile. Instead of preparing carboxylic ester or acid precursors,
* Corresponding author. Tel.: þ33 240 412 874; fax: þ33 240 412 876; e-mail
address: pascal.marchand@univ-nantes.fr (P. Marchand).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.071

A. Bretéché et al. / Tetrahedron 66 (2010) 4490e4494
4491
Br
O
OH
Br
Br
Br
BBr3, CH2Cl2
MeONa, MeOH / DMF
70 °C, 24h, 88%
0 °C to r.t., 48h, 72%
N
N
N
1
2
3
I2, Na2CO3
Br
O
I
CN
Br
OH
I
K2CO3, Br-CH2-CN
H2O, r.t., 1h, 86%
CuCN, pyridine
100 °C, 1h
85%
propan-2-one, r.t., 18h, 90%
N
N
5
4
Br
O
Br
O
O
Br
O
CN
K2CO3, DMF
80 °C, 1h, 86%
H2SO4
r.t., 2h, 85%
CN
NH2
N
N
N
CN
NH2
NH2
6
7
8
Scheme 1. Synthesis of 3-amino-6-bromofuro[3,2-b]pyridine-2-carboxamide 8.
We then tried to introduce a benzyl moiety on the amino group
at position 3 of the furo[3,2-b]pyridine-2-carboxamide scaffold.
Heterocyclic amine 8 was reacted with 3-chlorobenzaldehyde in
the presence of NaBH3CN in methanolic acid acetic solution (2% v/v)
at room temperature and then at reflux. However, only starting
material was recovered using reductive amination conditions. From
the nitrile containing precursor 7, the same reaction conditions did
not provide the requested benzylamino derivative but 3-amino-6-
bromofuro[3,2-b]pyridine-2-carbonitrile 7 remained unchanged.
We planed to carry out the reaction in two steps by synthesizing the
Schiff base before subjecting it to reduction. According to the
methods previously described,12 (PTSA, toluene, reflux; piperidine,
EtOH, reflux or mixture of EtOH/toluene (5/1), catalytic amount of
glacial acetic acid, reflux), the condensation between the arylamine
7 and 3-chlorobenzaldehyde was unsuccessful.
Butoxycarbonylation was achieved by treating heterocyclic amine 7
with di-tert-butyl dicarbonate (Boc2O) in the presence of DMAP in
THF at reflux (Scheme 2). Excess of Boc2O (6 equiv) was employed
to obtain exclusively the N,N-di-Boc derivative instead of a mixture
of monoprotected and diprotected analogs.14
Subsequent removal of one of the Boc groups, involving a mild
procedure15 using montmorillonite K-10 in toluene at room tem-
perature, gave access to tert-butyl 6-bromo-2-cyanofuro[3,2-b]
pyridin-3-ylcarbamate 9 with 54% yield for two steps. Benzylation
of the carbamate intermediate 9 with 3-chloro or 2-nitrobenzyl
bromide, in the presence of K2CO3 as base in DMF at room tem-
perature, furnished compounds 10 and 11 in good yields (90% and
89%, respectively).
Carbonitrile derivative 7 was converted above to the corre-
sponding carboxamide 8 with 85% yield under usual harsh condi-
tions, using strong mineral acid (H2SO4). We decided to check the
possibility to perform this reaction under milder conditions using
the ureaehydrogen peroxide complex16, as previously described.
Carboxamides 12 and 13 were obtained in good yields, without
observing any deprotection of the primary amino group, by treating
Benzylation reaction can be performed by nucleophilic sub-
stitution in the presence of a base and a benzyl halide. From the
primary amine, in order to avoid the formation of the dibenzylated
byproduct and to facilitate deprotonation, an electron-withdrawing
group was introduced on the primary amine in a first step.13 N-tert-
Br
O
1) Boc2O, DMAP cat
THF, reflux, 3h
Br
Br
O
O
Br , K2CO3,
R
CN
CN
CN
N
N
N
2) Montmorillonite K-10
toluene, r.t., 12h
DMF, r.t., 16h
NBoc
NH2
NHBoc
54% (2 steps)
10 R=3-Cl (90%)
11 R=2-NO2 (89%)
7
9
R
Br
Br
O
O
O
O
NH2
NH2
Zn / CH3COOH
N
N
urea-hydrogen peroxide
NBoc
NBoc
THF, r.t., 29h, 79%
(R=2-NO2)
K2CO3, propan-2-one / H2O (2 / 1)
r.t., 5h
H2N
R
12 R=3-Cl (87%)
14
13 R=2-NO2 (75%)
Br
O
O
Br
O
O
NH2
N
NH2
N
NH
TFA, CH2Cl2, r.t.
2h (from 12) and 7h (from 15)
CH3COCl, pyridine
r.t., 18h, 90%
NBoc
16 R=3-Cl (78%)
17 R=2-NHAc (86%)
R
AcHN
15
Scheme 2. Functionalization of 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile 7.

4492
A. Bretéché et al. / Tetrahedron 66 (2010) 4490e4494
the corresponding carbonitrile precursors 10 and 11 with ure-
aehydrogen peroxide (UHP) and K2CO3 in a mixture of propan-2-
one/water (2/1) at room temperature. Reduction of the nitro group
of compound 13, by action of zinc/acetic acid in THF afforded the
corresponding amino derivative 14, followed by its acetylation with
acetyl chloride in pyridine at room temperature. Finally, Boc
cleavage with trifluoroacetic acid provided target carboxamides 16
and 17 from 12 and 15, respectively.
added dropwise and the solvent was evaporated. MeOH (63 mL)
was added and the mixture was refluxed for 2 h. After cooling at
room temperature and evaporation to dryness, water was added
and pH was adjusted to 7e8 with solid Na2CO3 before extracting
with ethyl acetate. The organic layers were dried over Na2SO4, fil-
tered, and evaporated to dryness. The resulting oil was purified by
column chromatography eluting with a 7/3 mixture of petroleum
ether and ethyl acetate to yield 3 (4.00 g, 72%) as a white solid. Mp
165e166 ꢀC (lit.8: 162e164 ꢀC); IR (KBr): 2413, 1650, 1608,
1044 cmꢂ1; 1H NMR (250 MHz): 7.43 (m, 1H, pyridineeH), 8.16 (m,
2H, pyridineeH), 10.48 (s, 1H, -OH); 13C NMR (100 MHz): 117.5,
126.6, 137.3, 147.8, 155.9. The data are in conformity with the lit-
erature.8 MS (ESI) m/z (%): 174.1 [(MþH)þ, 100], 176.1 [(MþH)þ2,
100]. Anal. Calcd for C5H4BrNO: C, 34.51; H, 2.32; N, 8.05. Found: C,
34.47; H, 2.40; N, 8.09.
3. Conclusion
In conclusion, we have developed a method for synthesizing 3-
(benzylamino)-6-bromofuro[3,2-b]pyridine-2-carboxamide deri-
vatives via a ring closure reaction of 5-bromo-3-(cyanomethoxy)
pyridine-2-carbonitrile. We have obtained a promising scaffold
(compounds 7) for medicinal chemistry allowing the possibility of
a broad pharmacomodulation at the positions 2, 3 or 6 of the furo
[3,2-b]pyridine. Functionalization at the level of the bromine atom,
involving metal-catalyzed procedure, will be discussed in future
publications. Moreover, by functionalization of the amino group at
position 3 to give amides and ureas, we are currently looking for-
ward to obtaining new biological activities for these compounds.
4.1.3. 5-Bromo-2-iodo-3-hydroxypyridine (4). To a solution of 3
(1.00 g, 5.75 mmol) and Na2CO3 (1.28 g, 12.08 mmol) in H2O
(100 mL), iodine (1.46 g, 5.75 mmol) was added and the mixture
was stirred at 20 ꢀC for 2 h. Then HCl 1 M was added carefully until
approximate pH 4. The solid was filtered off, washed with cold H2O
and dried to yield 4 (1.48 g, 86%) as a beige solid. Mp 202e203 ꢀC;
IR (KBr): 3447, 1546, 1407, 1334, 1181, 1044 cmꢂ1
;
1H NMR
4. Experimental section
4.1. General
(400 MHz): 7.32 (d, J¼2.1 Hz, 1H, pyridineeH), 8.04 (d, J¼2.1 Hz, 1H,
pyridineeH), 11.44 (s, 1H, -OH); 13C NMR (100 MHz): 109.4, 119.8,
123.3, 141.9, 155.0; MS (ESI) m/z (%): 299.8 [(MþH)þ, 100], 301.8
[(MþH)þ2, 100]. Anal. Calcd for C5H3BrINO: C, 20.03; H, 1.01; N,
4.67. Found: C, 20.09; H, 1.07; N, 4.70.
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
a 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
4.1.4. [(5-Bromo-2-iodopyridin-3-yl)oxy]acetonitrile (5). A solution
of 4 (0.86 g, 2.87 mmol) in acetone (29 mL) was treated with K2CO3
(405 mg, 2.93 mmol), followed by bromoacetonitrile (0.21 mL,
3.01 mmol) and stirred at room temperature overnight. The mix-
ture was filtered and evaporated to dryness. The residue was
purified by column chromatography eluting with a 8/2 mixture of
petroleum ether and diethyl ether to afford 5 (0.87 g, 90%) as
a beige solid. Mp 112e113 ꢀC; IR (KBr): 3050, 2956, 2362, 1549,
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). Mass spectra were
recorded on Waters ZQ 2000 spectrometer. Elemental analyses
were found within ꢁ0.4% of the theoretical values.
1393, 1270, 1186, 1046 cmꢂ1 1H NMR (250 MHz): 5.40 (s, 2H,
;
eOCH2CN), 7.89 (d, J¼1.9 Hz, 1H, pyridineeH), 8.31 (d, J¼1.9 Hz, 1H,
pyridineeH); 13C NMR (100 MHz): 55.1, 110.5, 115.9, 120.1, 122.9,
145.1, 153.3; MS (ESI) m/z (%): 338.7 [(MþH)þ, 100], 340.7 [(MþH)þ
2, 100]. Anal. Calcd for C5H3BrINO: C, 24.81; H, 1.19; N, 8.27. Found:
C, 24.88; H, 1.24; N, 8.24.
4.1.1. 3-Bromo-5-methoxypyridine (2). A solution of 3,5-dibromo-
pyridine (15.00 g, 63.31 mmol) in dry DMF (60 mL) and sodium
methoxide (30% in MeOH) (20.50 mL) was stirred at 63e68 ꢀC for
4 h. Additional sodium methoxide (30% in MeOH) (10 mL) was then
added and the reaction mixture was allowed to stir at 63e68 ꢀC for
23 h. After cooling at room temperature, H2O (80 mL) was added
and the mixture was extracted with Et2O. The organic layers were
washed with brine, dried over Na2SO4, filtered, and evaporated to
dryness. The resulting oil was purified by column chromatography
eluting with a 8/2 mixture of petroleum ether and ethyl acetate to
afford 2 (10.48 g, 88%) as a light yellow solid. Mp 35e36 ꢀC (lit.8:
4.1.5. 5-Bromo-3-(cyanomethoxy)pyridine-2-carbonitrile (6). A so-
lution of 5 (0.25 g, 0.74 mmol), CuCN (86 mg, 0.96 mmol) and dry
pyridine (2 mL) was refluxed for 1 h at 100 ꢀC with magnetic stir-
ring under argon. The solution was cooled to room temperature and
was poured into 56 g/L aqueous potassium cyanide solution
(5.3 mL). The solution was extracted with CH2Cl2. The organic
layers were washed with brine, dried over Na2SO4, filtered, and
evaporated to dryness. The crude product was purified by column
chromatography eluting with a 7/3 mixture of petroleum ether and
ethyl acetate to give 6 (149 mg, 85%) as a beige solid. Mp
142e143 ꢀC; IR (KBr): 2927, 2360, 2216, 1560, 1406, 1236, 1155,
1015 cmꢂ1; 1H NMR (250 MHz): 5.49 (s, 2H, eOCH2CN), 8.39 (s, 1H,
pyridineeH), 8.65 (s, 1H, pyridineeH); 13C NMR (100 MHz): 55.3,
114.7, 115.6, 121.2, 125.4, 124.6, 145.7, 156.0; MS (ESI) m/z (%): 238.0
[(MþH)þ, 100], 240.0 [(MþH)þ2, 100]. Anal. Calcd for C8H4BrN3O:
C, 40.37; H, 1.69; N, 17.65. Found: C, 40.31; H, 1.64; N, 17.59.
37e39 ꢀC); IR (KBr): 2954, 1632, 1610, 1032 cmꢂ1
;
1H NMR
(250 MHz): 3.88 (s, 3H, eOCH3), 7.76 (d, J¼2.4 Hz, 1H, pyridineeH),
8.33 (m, 2H, pyridineeH); 13C NMR (100 MHz): 58.0, 120.3, 124.6,
135.8, 143.8, 155.9; The data are in conformity with the literature.8
MS (ESI) m/z (%): 188.0 [(MþH)þ, 100], 190.0 [(MþH)þ2, 100]. Anal.
Calcd for C6H6BrNO: C, 38.33; H, 3.22; N, 7.45. Found: C, 38.39; H,
3.28; N, 7.48.
4.1.6. 3-Amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile (7). A so-
lution of 6 (0.28 g, 1.18 mmol) in dry N,N-dimethylformamide
(3.7 mL) was treated with K2CO3 (0.15 g, 1.08 mmol) and the mix-
ture was stirred at 80 ꢀC for 1 h. After cooling at room temperature,
cold water was added and the resulting precipitate was collected by
4.1.2. 3-Bromo-5-hydroxypyridine (3). Boron tribromide (sol 1 M in
CH2Cl2) (96 mL, 96.00 mmol) was added dropwise to a cold (0 ꢀC)
solution of 2 (6.00 g, 31.91 mmol) in dry CH2Cl2. The mixture was
stirred at room temperature for 42.5 h, then MeOH (44 mL) was

A. Bretéché et al. / Tetrahedron 66 (2010) 4490e4494
4493
filtration and dried to yield 7 (241 mg, 86%) as a yellow-brown
solid. Mp 236e237 ꢀC; IR (KBr): 3424, 2367, 1647, 1458, 1382,
1244 cmꢂ1; 1H NMR (250 MHz): 6.85 (s, 2H, eNH2), 8.46 (s, 1H, furo
[3,2-b]pyridineeH), 8.75 (s, 1H, furo[3,2-b]pyridineeH); 13C NMR
(100 MHz): 117.0, 119.9, 121.9, 132.7, 135.1, 140.9, 144.3, 151.1; MS
(ESI) m/z (%): 237.9 [(MþH)þ, 100], 239.9 [(MþH)þ2, 100]. Anal.
Calcd for C8H4BrN3O: C, 40.37; H, 1.69; N, 17.65. Found: C, 40.30; H,
1.63; N, 17.60.
Anal. Calcd for C20H17BrClN3O3: C, 51.91; H, 3.70; N, 9.08. Found: C,
51.86; H, 3.64; N, 9.04.
4.1.10. tert-Butyl 6-bromo-2-cyanofuro[3,2-b]pyridin-3-yl(2-nitro-
benzyl)carbamate (11). The title compound was prepared in 89%
yield as a yellow solid from 9 by a similar method to that described
for 10 using 2-nitrobenzyl bromide. Mp 90e91 ꢀC; IR (KBr): 3062,
2945, 2241, 1712, 1542, 1420, 1346, 1244, 1132 cmꢂ1 1H NMR
;
(250 MHz):
d 1.41 (s, 9H, Boc), 5.59 (s, 2H, eCH2PhNO2), 7.59 (dd,
4.1.7. 3-Amino-6-bromofuro[3,2-b]pyridine-2-carboxamide (8). A
mixture of 7 (0.36 g, 1.51 mmol) in concentrated H2SO4 (3.1 mL)
was stirred at room temperature for 2 h. The mixture was poured
into ice-water and the solution was basified with aqueous NaOH.
The solid was filtered off, washed with cold water and dried to give
8 (271 mg, 70%) as a yellow solid. Mp 240e241 ꢀC; IR (KBr): 3404,
3297, 3140, 1663, 1564, 1440, 1383, 1147 cmꢂ1; 1H NMR (400 MHz):
5.95 (s, 2H, eNH2), 7.53 (m, 2H, eCONH2), 8.31 (d, J¼1.7 Hz, 1H, furo
[3,2-b]pyridineeH), 8.69 (d, J¼1.7 Hz, 1H, furo[3,2-b]pyridineeH);
13C NMR (100 MHz): 118.0, 122.3, 130.1, 135.0, 134.0, 146.0, 146.1,
162.8; MS (ESI) m/z (%): 255.9 [(MþH)þ, 100], 257.9 [(MþH)þ2,
100]. Anal. Calcd for C8H6BrN3O2: C, 37.53; H, 2.36; N, 16.41. Found:
C, 37.61; H, 2.39; N, 16.46.
J¼7.1, 8.0 Hz, 1H, PhNO2eH), 7.63 (d, J¼8.0 Hz, 1H, PhNO2-H), 7.79
(dd, J¼7.1, 8.0 Hz, 1H, PhNO2-H), 8.06 (d, J¼8.0 Hz, 1H, PhNO2eH),
8.76 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 8.92 (d, J¼1.8 Hz, 1H,
furo[3,2-b]pyridineeH). 13C NMR (100 MHz): 27.8, 49.6, 81.6, 117.3,
119.9, 122.6, 123.3, 128.0, 129.8, 129.9, 131.4, 134.3, 140.6, 147.2,
148.0, 148.9, 152.9, 159.8; MS (ESI) m/z (%): 473.0 [(MþH)þ, 100],
475.0 [(MþH)þ2, 100]. Anal. Calcd for C20H17BrN4O5: C, 50.76; H,
3.62; N, 11.84. Found: C, 50.86; H, 3.66; N, 11.80.
4.1.11. tert-Butyl 2-(aminocarbonyl)-6-bromofuro[3,2-b]pyridin-3-yl
(3-chlorobenzyl)carbamate (12). A solution of 10 (0.50 g,
1.08 mmol), ureaehydrogen peroxide (1.03 g, 10.94 mmol), and
K2CO3 (15 mg, 0.11 mmol) in acetoneewater (v/v, 2/1, 16.5 mL) was
stirred at room temperature for 5 h. It was then diluted with ethyl
acetate and washed with saturated aqueous NH4Cl solution and
brine. The organic layer was concentrated, and the residue was
purified by column chromatography eluting with a 99/1 then 98/2
mixture of CH2Cl2 and EtOH to afford 12 (452 mg, 87%) as a white
solid. Mp 159e160 ꢀC; IR (KBr): 3409, 3245, 3181, 3071, 2976, 1678,
1603, 1433, 1368, 1303, 1164 cmꢂ1; 1H NMR (400 MHz): 1.34 (s, 9H,
Boc), 5.18 (s, 2H, eCH2PhCl), 7.25 (m, 2H, PhCleH), 7.33 (m, 1H,
PhCleH), 7.55 (s, 1H, PhCleH), 8.02 (s, 1H, eCONH2), 8.22 (s, 1H,
eCONH2), 8.48 (s, 1H, furo[3,2-b]pyridineeH), 8.82 (s, 1H, furo[3,2-
b]pyridineeH); 13C NMR (100 MHz): 27.9, 51.0, 80.9, 117.7, 123.1,
126.1, 127.1, 127.4, 130.1, 133.2, 140.2, 142.2, 144.7, 145.5, 148.2, 153.7,
159.3, 159.5; MS (ESI) m/z (%): 479.9 [(MþH)þ, 73], 481.9 [(MþH)þ
2, 100], 483.9 [(MþH)þ4, 29]. Anal. Calcd for C20H19BrClN3O4: C,
49.97; H, 3.98; N, 8.74. Found: C, 49.89; H, 3.94; N, 8.70.
4.1.8. tert-Butyl 6-bromo-2-cyanofuro[3,2-b]pyridin-3-ylcarbamate
(9). Compound 7 (2.30 g, 9.66 mmol) was dissolved in dry THF
(92 mL), Boc2O (12.66 g, 58.01 mmol) and a catalytic amount of
DMAP was added. The solution was heated at reflux for 3 h. After
cooling and evaporated to dryness, the crude product was puri-
fied by column chromatography eluting with a 9/1 mixture of
petroleum ether and ethyl acetate to yield di-tert-butyl(6-bromo-
2-cyanofuro[3,2-b]pyridin-3-yl) imidodicarbonate. Commercially
available montmorillonite K-10 (4.60 g) was added to a stirred
solution of this intermediate (4.20 g, 9.58 mmol) in dry toluene
(42 mL). The mixture was stirred at room temperature for 12 h.
The reaction mixture was filtered, and the solid was washed with
ethyl acetate. The solution was concentrated and a column
chromatography purification eluting with a 9/1 then 8/2 mixture
of petroleum ether and ethyl acetate yielded 9 (1.76 g, 54%) as
a beige solid. Mp 156e157 ꢀC; IR (KBr): 3316, 3075, 2972, 2229,
4.1.12. tert-Butyl 2-(aminocarbonyl)-6-bromofuro[3,2-b]pyridin-3-yl
(2-nitrobenzyl)carbamate (13). The title compound was prepared in
75% yield as a yellow solid from 11 by a similar method to that
described for 12. Mp 164e165 ꢀC; IR (KBr): 3412, 3232, 3165, 3057,
2967, 1663, 1613, 1423, 1354, 1313, 1132 cmꢂ1; 1H NMR (250 MHz):
1.33 (s, 9H, Boc), 5.29 (s, 2H, eCH2PhNO2), 7.49 (m, 1H, PhNO2eH),
7.69 (m, 1H, PhNO2eH), 7.97 (s, 1H, eCONH2), 8.00 (s, 1H, eCONH2),
8.22 (m, 1H, PhNO2eH), 8.27 (m, 1H, PhNO2eH), 8.50 (s, 1H,
furo[3,2-b]pyridineeH), 8.83 (s, 1H, furo[3,2-b]pyridineeH); 13C
NMR (100 MHz): 28.0, 52.2, 82.0, 119.5, 124.3, 127.6, 128.4, 129.6,
132.6, 135.7, 142.5, 143.2, 145.5, 147.3, 149.8, 154.9, 159.4, 160.8; MS
(ESI) m/z (%): 491.1 [(MþH)þ, 100], 493.1 [(MþH)þ2, 100]. Anal.
Calcd for C20H19BrN4O6: C, 48.89; H, 3.90; N, 11.40. Found: C, 48.96;
H, 3.93; N, 11.43.
1712, 1564, 1523, 1455, 1372, 1253, 1152 cmꢂ1
;
1H NMR
(250 MHz): 1.53 (s, 9H, Boc), 8.66 (d, J¼1.8 Hz, 1H, furo[3,2-b]
pyridineeH), 8.87 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 10.48
(s, 1H, eNHBoc); 13C NMR (100 MHz): 27.9, 81.4, 112.0, 119.8,
120.0, 123.2, 129.7, 138.1, 147.5, 148.6, 152.4; MS (ESI) m/z (%):
281.9 [(MþH)þ, 100], 283.8 [(MþH)þ2, 100]. Anal. Calcd for
C13H12BrN3O3: C, 46.17; H, 3.58; N, 12.43. Found: C, 46.24; H,
3.63; N, 12.47.
4.1.9. tert-Butyl 6-bromo-2-cyanofuro[3,2-b]pyridin-3-yl(3-chloro-
benzyl)carbamate (10). K2CO3 (368 mg, 2.66 mmol) followed by
3-chlorobenzyl bromide (0.39 mL, 2.96 mmol) were added to a
solution of 9 (0.90 g, 2.66 mmol) in dry DMF (27 mL). The reaction
mixture was stirred at room temperature for 16 h. H2O was added
and the solution was extracted with diethyl ether. The organic
layers were washed with a saturated NaHCO3 solution, brine, dried
over Na2SO4, filtered, and evaporated to dryness. The crude product
was purified by column chromatography eluting with a 95/5 then
9/1 mixture of petroleum ether and ethyl acetate to afford 10
(1.11 g, 90%) as a white solid. Mp 80e81 ꢀC; IR (KBr): 3080, 2983,
4.1.13. tert-Butyl 2-aminobenzyl[2-(aminocarbonyl)-6-bromofuro[3,2-b]-
pyridin-3-yl]carbamate (14). Acetic acid (0.69 mL, 12.04 mmol) fol-
lowed by zinc (1.60 g, 24.48 mmol) were added to a solution of 13
(0.30 g, 0.61 mmol) in dry THF (30 mL). The reaction mixture was
stirred at room temperature for 29 h. Ethyl acetate was added and
the mixture was filtered. The filtrate was washed with a saturated
aqueous NaHCO3 solution, dried over Na2SO4, filtered, and evapo-
rated to dryness. The residue was purified by column chromatog-
raphy eluting with a 99/1 then 98/2 mixture of CH2Cl2 and EtOH to
yield 14 (223 mg, 79%) as a beige solid. Mp 105e106 ꢀC; IR (KBr):
3362, 3253, 3190, 2977, 1689, 1606, 1432, 1371, 1312, 1159 cmꢂ1; 1H
NMR (400 MHz): 1.34 (s, 9H, Boc), 5.01 (s, 2H, eCH2PhNH2), 5.06 (s,
2H, eNH2), 6.31 (dd, J¼7.2, 6.8 Hz, 1H, PhNH2eH), 6.58 (d, J¼7.2 Hz,
2230, 1720, 1598, 1413, 1369, 1322, 1251, 1149 cmꢂ1 1H NMR
;
(250 MHz): 1.45 (s, 9H, Boc), 5.18 (s, 2H, eCH2PhCl), 7.25 (m, 1H,
PhCleH), 7.39 (m, 3H, PhCleH), 8.77 (m, 1H, furo[3,2-b]
pyridineeH), 8.95 (m, 1H, furo[3,2-b]pyridineeH); 13C NMR
(100 MHz): 27.8, 48.0, 80.9, 115.1, 116.0, 117.4, 120.1, 122.9, 125.0,
128.4, 129.6, 142.2, 145.3, 146.7, 148.0, 153.8, 159.1; MS (ESI) m/z (%):
462.0 [(MþH)þ, 78], 464.0 [(MþH)þ2, 100], 466.0 [(MþH)þ4, 27].

4494
A. Bretéché et al. / Tetrahedron 66 (2010) 4490e4494
1H, PhNH2eH), 6.87 (m, 2H, PhNH2eH), 7.99 (s,1H, eCONH2), 8.05 (s,
1H, eCONH2), 8.47 (d, J¼1.6 Hz, 1H, furo[3,2-b]pyridineeH), 8.78 (d,
J¼1.6 Hz,1H, furo[3,2-b]pyridineeH); 13C NMR (100 MHz): 27.8, 47.9,
80.9, 115.1, 116.1, 117.4, 120.1, 121.7, 122.9, 125.0, 128.4, 129.6, 133.5,
135.6, 145.3, 148.0, 159.1, 163.1; MS (ESI) m/z (%): 460.9 [(MþH)þ,
100], 462.9 [(MþH)þ2, 100]. Anal. Calcd for C20H21BrN4O4: C, 52.07;
H, 4.59; N, 12.15. Found: C, 52.18; H, 4.63; N, 12.19.
yield as a beige solid from 15 by a similar method to that described
for 16. Mp 191e192 ꢀC; IR (KBr): 3452, 3373, 3273, 1654, 1602, 1530,
1452, 1375, 1180, 1153 cmꢂ1 1H NMR (400 MHz): 2.07 (s, 3H,
;
eNHCOCH3), 5.06 (s, 2H, eCH2PhNHAc), 6.83 (s, 1H, eNH), 7.10 (dd,
J¼7.8, 6.6 Hz, 1H, PhNHAceH), 7.22 (dd, J¼7.8, 6.6 Hz, 1H,
PhNHAceH), 7.36 (d, J¼7.8 Hz,1H, PhNHAceH), 7.41 (d, J¼7.8 Hz,1H,
PhNHAceH), 7.50 (s, 1H, eCONH2), 7.66 (s, 1H, eCONH2), 8.32 (d,
J¼2.0 Hz,1H, furo[3,2-b]pyridineeH), 8.68 (d, J¼2.0 Hz,1H, furo[3,2-
b]pyridineeH), 9.55 (s, 1H, eNHCOCH3); 13C NMR (100 MHz): 23.5,
43.6, 117.9, 119.5, 122.6, 125.5, 127.2, 128.3, 130.6, 134.5, 135.7, 135.9,
140.0, 146.1, 146.3, 162.9, 168.6; MS (ESI) m/z (%): 402.9 [(MþH)þ,
100], 404.9 [(MþH)þ2,100]. Anal. Calcd for C17H15BrN4O3: C, 50.64;
H, 3.75; N, 13.89. Found: C, 50.70; H, 3.78; N, 13.83.
4.1.14. tert-Butyl 2-(acetylamino)benzyl[2-(aminocarbonyl)-6-bromo-
furo[3,2-b]pyridin-3-yl]carbamate (15). Acetyl chloride (0.025 mL,
0.35 mmol) was added dropwise to a cold solution of 14 (161 mg,
0.35 mmol) in pyridine (1.6 mL). The reaction mixture was stirred at
room temperature for 18 h. Ethyl acetate was added. The organic
layers were washed with HCl 1 M, dried over Na2SO4, filtered, and
evaporated to dryness afforded 15 (158 mg, 90%) as a beige solid.
Mp 186e187 ꢀC; IR (KBr): 3324, 3234, 3151, 2978, 1674, 1612, 1543,
1434, 1369, 1301, 1160 cmꢂ1; 1H NMR (400 MHz): 1.35 (s, 9H, Boc),
2.05 (s, 3H, eNHCOCH3), 5.10 (s, 2H, eCH2PhNHAc), 6.97 (m, 1H,
PhNHAceH), 7.15 (dd, J¼7.2, 7.6 Hz, 1H, PhNHAceH), 7.31 (d,
J¼6.8 Hz, 1H, PhNHAceH), 7.39 (d, J¼7.6 Hz, 1H, PhNHAceH), 8.02
(s, 1H, eCONH2), 8.18 (s, 1H, eCONH2), 8.46 (d, J¼1.8 Hz, 1H, furo
[3,2-b]pyridineeH), 8.82 (d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH),
9.41 (s, 1H, eNHCOCH3); 13C NMR (100 MHz): 23.4, 27.8, 47.7, 81.0,
117.6,121.0,119.7,123.0,125.0,125.2,127.8,129.3,130.5,136.5,138.8,
145.3, 148.1, 159.3, 160.1, 168.3; MS (ESI) m/z (%): 502.9 [(MþH)þ,
100], 505.0 [(MþH)þ2,100]. Anal. Calcd for C22H23BrN4O5: C, 52.50;
H, 4.61; N, 11.13. Found: C, 52.38; H, 4.57; N, 11.09.
References and notes
1. Kawaguchi, T.; Akatsuka, H.; Iijima, T.; Watanabe, T.; Murakami, J; Mitsui, T.
Preparation of fused furan compounds as inhibitors of activated blood
coagulation factor X PCT Int. Appl. WO 2004/063202, 2004.
2. Shiohara, H.; Nakamura, T.; Mukaiyama, H.; Kobayashi, S.; Jo, K. Preparation of
furopyridine derivatives as adenosine A2A receptor antagonists PCT Int. Appl.
WO 2006/137350, 2006.
3. Leger, S.; Hutchinson, J.H. Preparation of furo[3,2-b]pyridines and thieno[3,2-
b]pyridines as inhibitors of leukotriene biosynthesis PCT Int. Appl. WO
9422869, 1994.
4. 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.
5. Chartoire, A.; Comoy, C.; Fort, Y. Tetrahedron 2008, 64, 10867e10873.
6. Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Synlett 2002,
453e457.
7. Cailly, T.; Lemaître, S.; Fabis, F.; Rault, S. Synthesis 2007, 20, 3247e3251.
8. (a) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Tetrahedron Lett. 2004, 45,
3607e3610; (b) Morgentin, R.; Jung, F.; Lamorlette, M.; Maudet, M.; Ménard,
M.; Plé, P.; Pasquet, G.; Renaud, F. Tetrahedron 2009, 65, 757e764.
9. (a) Lin, W.; Chen, L.; Knochel, P. Tetrahedron 2007, 63, 2787e2797; (b) Koch, V.;
Schnatterer, S. Synthesis 1990, 497e498.
4.1.15. 6-Bromo-3-[(3-chlorobenzyl)amino]furo[3,2-b]pyridine-2-
carboxamide (16). Trifluoroacetic acid (1.23 mL, 16.57 mmol) was
added dropwise to a cold solution of 12 (0.40 g, 0.83 mmol) in CH2Cl2
(1.3 mL). The reaction mixture was stirred at room temperature for
2 h. The reaction mixture was evaporated to dryness. The resulting
solid was recrystallized in Et2O to give 16 (247 mg, 78%) as a beige
solid. Mp 183e184 ꢀC; IR (KBr): 3451, 3341, 3133, 1666, 1602, 1452,
10. Harris, N.; Higgs, C.; Wren S.; Dyke, H.J.; Price, S.; Cramp, S. Pyrimidine com-
pounds as histamine modulators PCT Int. Appl. WO 2006/050965, 2006.
11. Zhang, H.-Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.; Ollis-Mason, K.; Qiu, L.;
Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2005, 48, 5215e5223.
12. (a) Vicini, P.; Geronikaki, A.; Incerti, M.; Busonera, B.; Poni, G.; Cabras, C. A.; La
Colla, P. Bioorg. Med. Chem. 2003, 11, 4785e4789; (b) Nawrocka, W.; Sztuba, B.;
1372 cmꢂ1
;
1H NMR (400 MHz): 5.09 (d, J¼7.2 Hz, 2H, eCH2PhCl),
6.96 (dd, J¼J0¼7.2 Hz, 1H, PhCleH), 7.31 (m, 3H, PhCleH), 7.41 (d,
J¼7.2 Hz,1H, eNH), 7.70 (s, 1H, eCONH2), 7.54 (s, 1H, eCONH2), 8.32
(d, J¼1.8 Hz, 1H, furo[3,2-b]pyridineeH), 8.68 (d, J¼1.8 Hz, 1H, furo
[3,2-b]pyridineeH); 13C NMR (100 MHz): 46.3, 113.7, 115.0, 116.3,
118.1,126.0,127.2,130.5,130.7,133.8,133.0,135.4,144.4,146.4,163.0;
MS (ESI) m/z (%): 380.1 [(MþH)þ, 76], 382.1 [(MþH)þ2, 100], 484.1
[(MþH)þ4, 29]. Anal. Calcd for C15H11BrClN3O2: C, 47.33; H, 2.91; N,
11.04. Found: C, 47.45; H, 2.93; N, 11.07.
ꢀ
Kowalska, M. W.; Liszkiewicz, H.; Wietrzyk, J.; Nasulewicz, A.; Pe1czynska, M.;
Opolski, A. II Farmaco 2004, 59, 83e91.
13. (a) Abarghaz, M.; Kerbal, A.; Bourguignon, J.-J. Tetrahedron Lett. 1995, 36,
6463e6466; (b) Mederski, W. W. K. R.; Osswald, M.; Dorsch, D.; Christadler, M.;
Schmitges, C.-J.; Wilm, C. Bioorg. Med. Chem. Lett. 1999, 9, 619e622.
14. (a) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368e6380; (b) Boger, D. L.;
McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1996, 118, 2301e2302.
15. Hernández, J. N.; Crisóstomo, F. R. P.; Martín, T.; Martín, V. S. Eur. J. Org. Chem.
2007, 5050e5058.
16. (a) Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189e191; (b) Ji, J.; Schrimpf, M.
R.; Sippy, K. B.; Bunnelle, W. H.; Li, T.; Anderson, D. J.; Faltynek, C.; Surowy, C. S.;
Dyhring, T.; Ahring, P. K.; Meyer, M. D. J. Med. Chem. 2007, 50, 5493e5508.
4.1.16. 3-{[2-(Acetylamino)benzyl]amino}-6-bromofuro[3,2-b]pyri-
dine-2-carboxamide (17). The title compound was prepared in 86%