Straightforward access to ethyl 3-aminofuropyridine-2-carboxylates from 1-chloro-2-cyano- or 1-hydroxy-2-cyano-substituted pyridines

Article abstract of DOI:10.1055/s-2007-990810

The conditions of the synthesis of the four regioisomers of ethyl 3-aminofuropyridine-2-carboxylate are described and discussed in detail. The starting materials are either 1-chloro-2-cyanopyridines or 1-cyano-2- hydroxypyridines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990810

PAPER
3247
Straightforward Access to Ethyl 3-Aminofuropyridine-2-carboxylates from
1-Chloro-2-cyano- or 1-Hydroxy-2-cyano-Substituted Pyridines
E
thyl 3-Aminof
h
uropyridine-
o
2-carboxylat
m
es fromCyanopyrid
a
ines s Cailly, Stéphane Lemaître, Frédéric Fabis, Sylvain Rault*
Centre d’Etudes et de Recherche sur le Médicament de Normandie, U.F.R. des Sciences Pharmaceutiques,
Université de Caen Basse-Normandie, 5 rue Vaubénard, 14032 Caen Cedex, France
Fax +33(2)31931188; E-mail: sylvain.rault@unicaen.fr
Received 26 June 2007
CN
(N)
(N)
Abstract: The conditions of the synthesis of the four regioisomers
of ethyl 3-aminofuropyridine-2-carboxylate are described and dis-
cussed in detail. The starting materials are either 1-chloro-2-cyano-
pyridines or 1-cyano-2-hydroxypyridines.
a, c
b, d
HO
CO2Et
+
NH2
d
(N)
X
c
X = halogen
2
CO2Et
N
a
CN
(N)
b
O
Key words: fused-ring systems, cyclizations, nitriles, aryl alco-
hols, nucleophilic aromatic substitutions
X
CO2Et
+
OH
1
3
Scheme 1 Synthetic strategy for the preparation of the ethyl 3-ami-
nofuropyridine-2-carboxylate isomers 1a and 1c (a, c) and 1b and 1d
(b, d)
ortho-Amino esters are important scaffolds in medicinal
chemistry as the precursors of numerous bioactive hetero-
cyclic compounds. Many classes of pharmacologically
interesting heterocyclic derivatives such as benzo-
diazepines,1 quinazolines,2 and anthranilics3 are obtained
via ortho-amino esters. For example, in our laboratory,
they have been used with success for the synthesis of 5-
HT3 partial agonists,4 5-HT4 antagonists,5 kinase inhibi-
tors,6 and antitubulin agents.7 This is why new ortho-ami-
no esters are still of great interest as new, potent medicinal
chemistry building blocks. In this paper, we wish to de-
scribe a straightforward synthesis of the four furopyridine
ortho-amino esters 1 starting from cyanopyridines
(Scheme 1). Whereas several publications have dealt with
the synthesis of ethyl 3-aminofuro[2,3-b]pyridine-2-car-
boxylate (1a) and its substituted derivatives,8 only one
publication has reported the synthesis of ethyl 3-amino-
furo[3,2-b]pyridine-2-carboxylate (1d),8a and, to date, no
synthesis has been described for 1b and 1c at all.
possible with similar 3-halopyridines, we decided to in-
vestigate the synthesis of the corresponding
cyano(hydroxy)pyridines 3 to perform a cyclization with
ethyl bromoacetate to obtain isomers 1b and 1d
(Scheme 1).
We decided to start with the preparation of ethyl 3-amino-
furo[2,3-b]pyridine-2-carboxylate (1a) (Scheme 2).
Many conditions have been described for the preparation
of this amino ester and its substituted derivatives starting
from ethyl glycolate and 2a or its substituted derivatives.
These methods included the use of various bases, sol-
vents, and temperatures in one-pot or two-step proce-
dures. We therefore decided to reinvestigate the reaction
of commercially available 2-chloro-3-cyanopyridine (2a)
with ethyl glycolate under various conditions in a one-pot
procedure (Scheme 2, Table 1).
However, in our hands, none of the previous methods
have been able to give the unsubstituted amino esters 1
under acceptable conditions. For this reason, we decided
to investigate a general access applicable to the synthesis
of all four isomers 1a–d.
First, we performed the reaction of 2a and ethyl glycolate
in N,N-dimethylformamide at 70 °C in the presence of tri-
ethylamine (5 equiv), but, unfortunately, the starting ma-
terial was recovered completely (Table 1, entry 1). Under
the same conditions, but with replacement of triethyl-
amine by potassium tert-butoxide or sodium hydride (5
equiv), 1a and 2a decomposed (Table 1, entries 2 and 3).
Then we retried the use of sodium hydride, but in tetrahy-
drofuran; this allowed us to isolate 1a in the very low yield
of 3% (Table 1, entry 4). At this stage, we have looked for
a base that could effect the deprotonation of the alcoholic
moiety, the cyclization, and would not lead to the degra-
dation of amino ester 1a. Cesium carbonate appeared to us
to be a good candidate for this. The first experiment with
five equivalents of cesium carbonate (Table 1, entry 5)
only led to the formation of side products, mainly due to
the production of dimethylamine from N,N-dimethyl-
formamide (LC/MS monitoring);9 replacement of N,N-
dimethylformamide by N-methylpyrrolidin-2-one result-
We reasoned that amino esters 1 could be obtained by the
use of the correctly substituted cyanopyridines 2 and 3
(Scheme 1). The envisaged strategy to obtain compounds
1a and 1c would use the ability of the 2- or 4-halopyridine
to undergo nucleophilic aromatic substitution smoothly.
By using ethyl glycolate as the nucleophile and 2-chloro-,
4-chloro-, or 4-iodo-3-cyanopyridine (2a, 2b, and 2c, re-
spectively) as the electrophiles, we wished to obtain iso-
mers 1a and 1c in one-pot procedures. Considering that
this nucleophilic aromatic substitution would be quite im-
SYNTHESIS 2007, No. 20, pp 3247–3251
x
x.
x
x
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-990810; Art ID: Z15507SS
© Georg Thieme Verlag Stuttgart · New York

3248
T. Cailly et al.
PAPER
Cl
ed in degradation of 1a (Table 1, entry 6), which, in this
case, was not the consequence of the reaction of N,N-dim-
ethylformamide. We then carried out microwave-assisted
experiments in the hope to avoid degradation. Two exper-
iments performed in N-methylpyrrolidin-2-one with five
and three equivalents of cesium carbonate allowed us, fi-
nally, to isolate 1a in 10% and 16% yield, respectively
(Table 1, entries 7 and 8). Regarding these two results, we
thought that the excess of base employed in all our exper-
iments was the cause of our difficulties, and therefore we
undertook a reaction with three equivalents of cesium car-
bonate in N-methylpyrrolidin-2-one at 70 °C for 12 hours;
this allowed us to improve the yield to 56% (Table 1, en-
try 9).
CN
CN
CN
i
+
N
4a
N
Cl
7%
N
2b
2a
37%
ii
iii 52%
19% overall
I
I
NH2
CN
CN
N
+
I
CO2Et
O
N
iii
23%
N
13% overall
2d
2c 56%
17%
1c
Scheme 3 Synthesis of ethyl 3-aminofuro[3,2-c]pyridine-2-car-
boxylate (1c). Reagents and conditions: (i) LTMP (2 equiv), THF,
–80 °C, 0.75 h, then C2Cl6 (2.1 equiv), –80 °C, 0.75 h; (ii) LTMP (2
equiv), THF, –80 °C, 0.75 h, then I2 (2.1 equiv), –80 °C, 0.75 h; (iii)
ethyl glycolate (1.1 equiv), Cs2CO3 (3 equiv), NMP, 70 °C, 12 h.
NH2
CN
O
CO2Et
HO
1.1 equiv
+
OEt
O
N
N
Cl
For the preparation of furopyridine isomers 1b and 1d, nu-
cleophilic aromatic substitution of the corresponding 3-
chloropyridines appeared to us to be problematic, and we
therefore decided to study the reactivity of the corre-
sponding cyano(hydroxy)pyridines 3a and 3b instead.
These compounds in the pyridine series can be obtained
easily from the corresponding boronic acid or one of its
esters by a hydroxydeboronation reaction. We decided to
carry out this reaction on (cyanopyridyl)boronic pinacol
esters 5a and 5b (Scheme 4), which are easy to handle,
and whose synthesis from the corresponding acids we de-
scribed recently.11 Begtrup et al. have also published the
synthesis of a (2-cyanopyridyl)boronic neopentyl glycol
ester, but in a one-pot procedure directly from the cyano-
pyridines.12 We used this latter methodology, using pina-
col instead of neopentyl glycol, to prepare 5a and 5b from
the corresponding cyanopyridines 4b and 4c in 55% and
53% yield, respectively (Scheme 4).
2a
1a
Scheme 2 Synthesis of ethyl 3-aminofuro[2,3-b]pyridine-2-car-
boxylate (1a)
Table 1 Conditions Used for the Synthesis of Ethyl 3-Amino-
furo[2,3-b]pyridine-2-carboxylate (1a)
Entry Solvent Time
(h)
Temp
(°C)
Base
Amount base Yield
(equiv)
(%)
1
2
3
DMF
DMF
DMF
12
12
12
70
70
Et3N
5
5
5
0
t-BuOK
NaH
0
r.t.,
then 70 °C
0
4
5
6
7
8
9
THF
12
12
12
70
70
NaH
5
5
5
5
3
3
3
0
DMF
NMP
NMP
NMP
NMP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
70
0
CN
CN
1.5a
1.5a
12
150
150
70
10
16
56
iv
N
N
O
B
4b
5a
55%
N
O
a Sealed-tube microwave heating.
CN
N
CN
iv
O
B
4-Chloro- and 4-iodo-3-cyanopyridine (2b and 2c), not
available commercially, were needed to prepare the 1c
isomer (Scheme 3). We recently described an ortho-lithi-
ation method leading to these compounds from nicotino-
nitrile (4a) (Scheme 3);10 thus, 2b and 2c can be obtained
in 37% and 56% yield, respectively, accompanied by two
side products 2a and 2d (Scheme 3). From 2b and 2c, we
then applied the above-described cyclization promoted by
cesium carbonate, and could isolate 1c from 2b in 52%
yield, and 1c from 2c in 23% yield. The pathway from 4a
via 4-chloronicotinonitrile (2b) in 19% overall yield is
slightly better than the pathway from 4a via 4-iodonicoti-
nonitrile (2c) with its 13% overall yield.
53%
O
4c
5b
Scheme 4 One-pot synthesis of (cyanopyridyl)boronic pinacol
esters 5a and 5b. Reagents and conditions : (iv) 1. LTMP (1.2 equiv),
(i-PrO)3B (1.3 equiv), THF, –80 °C, overnight; 2. AcOH (1.4 equiv),
pinacol (1.5 equiv), THF, r.t., 2 h.
Our research group has recently reported the hydroxy-
deboronation reaction of pyridineboronic acids or their
esters using either hydrogen peroxide or m-chloro-
peroxybenzoic acid.13 However, the use of these oxidants
on 5a and 5b only gave mixtures, probably due to the ox-
idation of the nitrile moiety. We then turned to the proce-
Synthesis 2007, No. 20, 3247–3251 © Thieme Stuttgart · New York

PAPER
Ethyl 3-Aminofuropyridine-2-carboxylates from Cyanopyridines
3249
1
ed on a Perkin-Elmer BX FTIR spectrometer. H and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively, on a Jeol
Lambda 400-NMR spectrometer. HRMS was carried out on a Jeol
JMS GCMate spectrometer. Elemental analyses were performed at
the ‘Institut de Recherche en Chimie Organique fine’ (Rouen,
France). The microwave reactions were performed in a Biotage Ini-
tiator microwave oven. Temperatures were measured with an IR
sensor and the reaction times given are hold times.
dure of Webb and Levy,14 who used Oxone as the oxidant
in the phenyl series, and we obtained cyano(hydroxy)py-
ridines 3a and 3b in 100% and 93% yield, respectively
(Scheme 5), without a trace of oxidized product at the lev-
el of the nitrogen atom or the cyano group.
CN
CN
v
N
N
O
Halonicotinonitriles 2; General Procedure
B
OH
A soln of n-BuLi (2.5 M in n-hexane; 7.7 mL, 19.2 mmol) was add-
ed to a stirred soln of 2,2,6,6-tetramethylpiperidine (3.4 mL, 20.2
mmol) in THF (40 mL) under N2 at –30 °C. The soln was allowed
to reach 0 °C, kept stirring for 15 min, and then cooled to –80 °C. A
soln of nicotinonitrile (4a; 1 g, 9.6 mmol) in THF (20 mL) was
slowly added to the mixture over 15 min. After the mixture had
stirred for 30 min at –80 °C, a soln of the chosen electrophile (C2Cl6
or I2) (20.2 mmol) in THF (10 mL) was slowly added over 15 min,
and the resulting mixture was stirred for 30 min. The soln was then
allowed to warm slowly to r.t. The mixture was quenched with sat.
aq NH4Cl (40 mL). The soln was extracted with EtOAc (3 × 100
mL). The combined organic layers were washed with brine (2 × 100
mL), dried (MgSO4), filtered, evaporated under vacuum, and puri-
fied by chromatography (silica gel).
5a
3a
100%
O
N
CN
N
CN
v
O
B
OH
93%
5b
3b
O
Scheme 5 Synthesis of cyano(hydroxy)pyridines 3a and 3b.
Reagents and conditions: (v) Oxone (0.7 equiv), NaHCO3 (7 equiv),
H2O–acetone, 0 °C, 20 min.
From cyano(hydroxy)pyridines 3a and 3b thus prepared,
we could synthesize furopyridine isomers 1b and 1d
(Scheme 6). A two-step sequence from salicylonitrile has
been reported to give the corresponding aminobenzofuran
ester in an overall yield of 50%.15 To improve this proce-
dure, we decided to transpose the same sequence to a one-
pot procedure, using an excess of potassium carbonate
and microwave heating. In a sealed tube, with ethanol as
2-Chloro- and 4-Chloronicotinonitrile (2a and 2b)
Chloronicotinonitriles 2a (7%) and 2b (37%) were obtained when
hexachloroethane (4.78 g, 20.2 mmol) was used as the electrophile.
Chromatography (silica gel, EtOAc–cyclohexane, 1:4).
2-Chloronicotinonitrile (2a)
Yield: 7%; white powder; mp 104 °C.
the solvent, and at 150 °C, the reaction was complete after IR (KBr): 3065, 2236 (CN), 1578, 1554, 1407, 1399, 1145, 1133,
1080, 1071, 809, 736, 673, 571, 471 cm–1.
half an hour (by TLC). These conditions allowed us to iso-
1H NMR (400 MHz, CDCl3): d = 7.40 (dd, 3J = 4.9 Hz, 3J = 7.8 Hz,
1 H), 8.02 (dd, 3J = 7.8 Hz, 4J = 1.9 Hz, 1 H), 8.62 (dd, 3J = 4.9 Hz,
4J = 1.9 Hz, 1 H).
late 1b and 1d in 54% and 58% yield, respectively
(Scheme 6).
NH2
4-Chloronicotinonitrile (2b)
CN
vi
Yield: 37%; pale yellow powder; mp 86 °C.
CO2Et
N
N
O
IR (KBr): 3091, 2926, 2236 (CN), 1572, 1549, 1473, 1404, 1291,
1187, 1101, 844, 798, 728, 700, 571, 476 cm–1.
OH
CN
OH
3a
1b
54%
NH2
1H NMR (400 MHz, CDCl3): d = 7.51 (d, 3J = 5.3 Hz, 1 H), 8.71 (d,
N
N
vi
3J = 5.3 Hz, 1 H), 8.86 (s, 1 H).
CO2Et
13C NMR (100 MHz, CDCl3): d = 111.4, 113.8, 124.6, 146.5, 153.4,
153.8.
O
3b
1d
58%
Anal. Calcd. for C6H3N2Cl: C, 52.01; H, 2.18; N, 20.22. Found: C,
52.31; H, 2.07; N, 19.93.
Scheme 6 Synthesis of ethyl 3-aminofuro[2,3-c]pyridine-2-car-
boxylate (1b) and ethyl 3-aminofuro[3,2-b]pyridine-2-carboxylate
(1d). Reagents and conditions: (vi) ethyl bromoacetate (1.1 equiv),
K2CO3 (2.5 equiv), EtOH, MW, sealed tube, 150 °C, 30 min.
4-Iodo- and 2,4-Diiodonicotinonitrile (2c and 2d)
Nicotinonitriles 2c (56%) and 2d (17%) were obtained when I2
(5.12 g, 20.2 mmol) was used as the electrophile; sat. aq NH4Cl (40
mL) and then sat. aq Na2S2O3 (40 mL) were used to quench the mix-
ture. Chromatography (silica gel, CHCl3–Et3N, 99.5:0.5).
In conclusion, we have described a scalable access to the
four isomers 1a–d of ethyl 3-aminofuropyridine-2-car-
boxylate. A new, easy synthesis of 2- or 4-cyano-3-hy-
droxypyridine (3a and 3b) is also reported. We are
currently evaluating amino esters 1a–d as starting materi-
4-Iodonicotinonitrile (2c)
Yield: 56%; pale yellow powder; mp 128 °C.
als for the synthesis of potential antitumor agents such as IR (KBr): 3073, 2229 (CN), 1563, 1461, 1396, 1283, 1187, 1061,
935, 847, 722, 661, 462 cm–1.
pyridofuropyrrolizinones, but they could also be powerful
building blocks for other medicinal chemistry groups.
1H NMR (400 MHz, CDCl3): d = 7.91 (d, 3J = 5.3 Hz, 1 H), 8.39 (d,
3J = 5.3 Hz, 1 H), 8.73 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 109.7, 117.3, 118.8, 134.1, 152.2,
153.1.
All commercial reagents were used as received except THF, which
was distilled from Na/benzophenone. Melting points were deter-
mined on a Kofler melting point apparatus. IR spectra were record-
Synthesis 2007, No. 20, 3247–3251 © Thieme Stuttgart · New York

3250
T. Cailly et al.
PAPER
Anal. Calcd. for C6H3N2I: C, 31.39; H, 1.31; N, 12.18. Found: C,
31.78; H, 1.12; N, 12.05.
mmol) in THF (50 mL) over 15 min. The mixture was then allowed
to warm slowly to r.t. overnight. The resulting soln was quenched
with glacial AcOH (2 mL, 35 mmol) and pinacol (4.43 g, 37.5
mmol). After 2 h, a 10% KH2PO4 soln (75 mL) was added. The soln
was washed with CH2Cl2 (3 × 50 mL), acidified with a 3 M HCl
soln, and extracted with CH2Cl2 (3 × 50 mL). The combined organ-
ic layers were then washed with H2O (3 × 10 mL), dried (MgSO4),
filtered, and evaporated under reduced pressure.
2,4-Diiodonicotinonitrile (2d)
Yield: 17%; white powder; mp 128 °C.
IR (KBr): 3097, 2225 (CN), 1532, 1517, 1415, 1344, 1191, 1180,
1075, 1061, 836, 706, 571, 510 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, 3J = 5.3 Hz, 1 H), 8.08 (d,
3J = 5.3 Hz, 1 H).
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)isonicotino-
nitrile (5a)
Compound 5a was prepared from 4b (2.5 g, 25 mmol).
13C NMR (100 MHz, CDCl3): d = 110.6, 119.1, 121.0, 127.1, 133.2,
151.7.
Yield: 55%; mp 102 °C.
Anal. Calcd. for C6H2N2I2: C, 20.25; H, 0.57; N, 7.87. Found: C,
20.60; H, 0.20; N, 7.64.
IR (KBr): 2970, 2928, 2231 (CN), 1607, 1542 1469, 1408, 1386,
1374, 1363, 1275, 1189, 1159, 1035, 878, 845, 777, 764, 714, 667,
581 cm–1.
3-Aminofuropyridine-2-carboxylates 1a and 1c from Halo-
nicotinonitriles 2a–c; General Procedure
1H NMR (400 MHz, CDCl3): d = 1.40 (s, 12 H), 7.54 (d, J = 5.1
3
Cs2CO3 (7.05 g, 21.6 mmol), NMP (20 mL), ethyl glycolate (0.76
mL, 7.9 mmol), and one of the halonicotinonitriles 2a–c (7.2 mmol)
were introduced into a round-bottomed flask. The mixture was then
heated at 70 °C for 12 h. After cooling, the soln was poured into
H2O (100 mL) and extracted with Et2O (3 × 100 mL). The com-
bined organic phases were washed with H2O (3 × 20 mL), dried
(MgSO4), filtered, evaporated under reduced pressure, and purified
by chromatography (silica gel).
Hz, 1 H), 8.82 (d, 3J = 5.1 Hz, 1 H), 9.09 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.8, 85.2, 116.7, 125.3, 126.3,
152.3, 156.5 (the quaternary C bonded to B was missing).
HRMS (EI): m/z calcd for C12H15N2O2B: 230.1226; found:
230.1230.
3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine-2-car-
bonitrile (5b)
Compound 5b was prepared from 4c (2.5 g, 25 mmol).
Ethyl 3-Aminofuro[2,3-b]pyridine-2-carboxylate (1a)
Compound 1a was prepared from 2a by the above general proce-
dure and purified by chromatography (silica gel, EtOAc–cyclohex-
ane, 1:4).
Yield: 53%; mp 66 °C.
IR (KBr): 3053, 2979, 2238 (CN), 1582, 1557, 1458, 1361, 1145,
1130, 1074, 1041, 962, 837, 778, 662, 561 cm–1.
Yield: 56%; mp 134 °C.
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 12 H), 7.48 (dd, 3J = 4.8
Hz, 3J = 7.8 Hz, 1 H), 8.18 (dd, 3J = 7.8 Hz, 4J = 1.7 Hz, 1 H), 8.75
(dd, 3J = 4.8 Hz, 4J = 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.8, 85.3, 117.2, 125.7, 138.3,
143.4, 152.3 (the quaternary C bonded to the B was missing).
IR (KBr): 3403, 3353, 2976, 1678 (CO), 1631, 1600, 1443, 1332,
1294, 1214, 1156, 1132, 775, 757 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (t, 3J = 7.1 Hz, 3 H), 4.44 (q,
3J = 7.1 Hz, 2 H), 5.03 (br s, 2 H), 7.25 (dd, 3J = 7.8 Hz, 3J = 4.7 Hz,
1 H), 7.95 (dd, 3J = 7.8 Hz, 4J = 1.7 Hz, 1 H), 8.50 (dd, 3J = 4.7 Hz,
4J = 1.7 Hz, 1 H).
Anal. Calcd. for C12H15N2O2B: C, 62.65; H, 6.57; N, 12.18. Found:
C, 62.41; H, 6.88; N, 11.74.
13C NMR (100 MHz, CDCl3): d = 14.5, 60.7, 114.2, 118.7, 124.4,
129.7, 137.1, 148.8, 159.9, 161.6.
Cyano(hydroxy)pyridines 3a and 3b; General Procedure
NaHCO3 (0.88 g, 10.4 mmol) and the appropriate boronic ester 5a
or 5b (0.3 g, 1.5 mmol) were added to a mixture of H2O (15 mL) and
acetone (5 mL), and the mixture was cooled to 0 °C. Oxone (0.72 g,
1.1 mmol) was added dropwise while the temperature of the mixture
was maintained between 0 and 8 °C. The mixture was allowed to
stir for 20 min at the same temperature, and NaHSO3 (3 g) in H2O
(6 mL) was added. The soln was acidified with a 3 M HCl soln and
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (MgSO4), filtered, evaporated under reduced pressure,
and purified by chromatography (silica gel, CH2Cl2, then CH2Cl2–
MeOH, 19:1).
HRMS (EI): m/z calcd for C10H10N2O3: 206.0691; found: 206.0694.
Ethyl 3-Aminofuro[3,2-c]pyridine-2-carboxylate (1c)
Compound 1c was prepared from 2b or 2c by the above general pro-
cedure and purified by chromatography (silica gel, EtOAc–cyclo-
hexane, 1:4 + 3% MeOH).
Yield: 52% (from 2b) and 23% (from 2c); mp 185 °C.
IR (KBr): 3422, 3317, 3184, 2977, 2927, 1728, 1674 (CO), 1636,
1613, 1462, 1428, 1323, 1299, 1175, 1137, 1106, 885, 815, 760,
659 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45 (t, 3J = 7.3 Hz, 3 H), 4.45 (q,
3J = 7.3 Hz, 2 H), 5.13 (br s, 2 H), 7.40 (dd, 3J = 5.8 Hz, 4J = 0.7 Hz,
1 H), 8.60 (d, 3J = 5.8 Hz, 1 H), 8.95 (d, 4J = 0.7 Hz, 1 H).
3-Hydroxyisonicotinonitrile (3a)
Compound 3a was prepared from 5a.
13C NMR (100 MHz, CDCl3): d = 14.6, 60.8, 108.0, 119.5, 125.7,
137.0, 143.5, 148.0, 158.1, 161.2.
Yield: 100%; mp 166 °C.
IR (KBr): 3227 (OH), 2219 (CN), 2159, 1600, 1537, 1477, 1410,
1281, 1114, 1054, 862, 810, 744, 699, 608, 594, 572, 502, 477 cm–1.
HRMS (EI): m/z calcd for C10H10N2O3: 206.0691; found: 206.0687.
1H NMR (400 MHz, CDCl3): d = 7.61 (dd, 3J = 4.8 Hz, 4J = 0.7 Hz,
(2-Cyanopyridyl)boronic Esters 5a and 5b; General Procedure
A soln of n-BuLi (2.5 M in n-hexane; 12 mL, 30 mmol) was added
to a stirred soln of 2,2,6,6-tetramethylpiperidine (5.06 mL, 30
mmol) in THF under N2 (50 mL) at –30 °C. The soln was allowed
to reach 0 °C, kept stirring for 15 min, and cooled to –80 °C. (i-
PrO)3B (8.08mL, 34 mmol) was added and the soln was stirred for
5 min before addition of the appropriate cyanopyridine 4b or 4c (25
1 H), 8.16 (d, 3J = 4.8 Hz, 1 H), 8.41 (s, 1 H), 11.72 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 105.5, 114.8, 125.6, 139.3, 140.5,
154.8.
HRMS (EI): m/z calcd for C6H4N2O: 120.0324; found 120.0324.
Synthesis 2007, No. 20, 3247–3251 © Thieme Stuttgart · New York

PAPER
Ethyl 3-Aminofuropyridine-2-carboxylates from Cyanopyridines
3251
3-Hydroxypyridine-2-carbonitrile (3b)
Compound 3b was prepared from 5b.
References
(1) (a) Gogerty, J. H.; Griot, R. G.; Habeck, D.; Iorio, L. C.;
Houlihan, W. J. J. Med. Chem. 1977, 20, 952. (b) Peet, N.
P.; Sunder, S. J. Heterocycl. Chem. 1977, 14, 561.
(c) Hirayama, F.; Koshio, H.; Katayama, N.; Ishihara, T.;
Kaizawa, H.; Taniuchi, Y.; Sato, K.; Sakai-Moritani, Y.;
Kaku, S.; Kurihara, H.; Kawasaki, T.; Matsumoto, Y.;
Sakamoto, S.; Tsukamoto, S. Bioorg. Med. Chem. 2003, 11,
367.
Yield: 93%; mp 205 °C.
IR (KBr): 3078 (OH), 2999, 2893, 2775, 2579, 2238 (CN), 1579,
1467, 1365, 1310, 1277, 1242, 1155, 1119, 1063, 873, 808, 739,
576 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (dd, 3J = 8.8 Hz, 4J = 1.9 Hz,
1 H), 7.54 (dd, 3J = 8.8 Hz, 3J = 4.5 Hz, 1 H), 8.17 (dd, 3J = 4.5 Hz,
4J = 1.9 Hz, 1 H), 11.69 (br s, 1 H).
(2) (a) Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.;
Fennell, M.; Green, T. P.; Lambert van der Brempt, C.;
Morgentin, R.; Norman, R. A.; Olivier, A.; Otterbein, L.;
Plé, P. A.; Warin, N.; Costello, G. J. Med. Chem. 2006, 49,
6465. (b) Desroses, M.; Laconde, G.; Depreux, P.;
Henichart, J. P. Org. Prep. Proced. Int. 2004, 36, 445.
(c) Wright, S. W.; Carlo, A. A.; Carty, M. D.; Danley, D. E.;
Hageman, D. L.; Karam, G. A.; Levy, C. B.; Mansour, M.
N.; Mathiowetz, A. M.; McClure, L. D.; Nestor, N. B.;
McPherson, R. K.; Pandit, J.; Pustilnik, L. R.; Schulte, G. K.;
Soeller, W. C.; Treadway, J. L.; Wang, I. K.; Bauer, P. H. J.
Med. Chem. 2002, 45, 3865.
(3) (a) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem.
Res., Synop. 1986, 5, 155. (b) Elliott, R. L.; O’Hanlon, P. J.;
Rogers, N. H. Tetrahedron 1987, 43, 3295. (c) Danswan,
G.; Kennewell, P. D.; Tully, W. R. J. Heterocycl. Chem.
1989, 26, 293.
13C NMR (100 MHz, CDCl3): d = 116.2, 120.5, 124.6, 129.1, 142.3,
157.9.
Anal. Calcd. for C6H4N2O: C, 60.00; H, 3.36; N, 23.32. Found: C,
59.84; H, 3.01; N, 22.93.
3-Aminofuropyridine-2-carboxylates 1b and 1d from
Cyano(hydroxy)pyridines 3a and 3b; General Procedure
The appropriate cyano(hydroxy)pyridine 3a or 3b (0.3 g, 2.5
mmol), ethyl bromoacetate (0.3 mL, 2.7 mmol), K2CO3 (0.86 g, 6.2
mmol), and EtOH (5 mL) were placed in a sealed tube. The resulting
mixture was heated at 150 °C for 30 min under microwave irradia-
tion, diluted with H2O (50 mL), and then extracted with EtOAc
(3 × 100 mL). The combined organic layers were dried (MgSO4),
filtered, evaporated under reduced pressure, and purified by chro-
matography (silica gel, CH2Cl2, then CH2Cl2 + 3% MeOH). The re-
sulting oil was then precipitated with PE.
(4) Prunier, H.; Rault, S.; Lancelot, J. C.; Robba, M.; Renard, P.;
Delagrange, P.; Pfeiffer, B.; Caignard, D. H.; Misslin, R.;
Guardiola-Lemaitre, B.; Hamon, M. J. Med. Chem. 1997,
40, 1808.
(5) Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.;
Dumuis, A.; Dauphin, F.; Bureau, R.; Pfeiffer, B.; Renard,
P.; Rault, S. J. Med. Chem. 2003, 46, 138.
Ethyl 3-Aminofuro[2,3-c]pyridine-2-carboxylate (1b)
Compound 1b was prepared from 3a.
Yield: 0.27 g (54%); mp 146 °C.
IR (KBr): 3419, 3309, 3029, 1678, 1645, 1588, 1562, 1475, 1452,
1327, 1292, 1237, 1183, 1133, 1029, 826, 759, 580, 549, 482 cm–1.
(6) Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. Bioorg.
1H NMR (400 MHz, CDCl3): d = 1.46 (t, 3J = 7.1 Hz, 3 H), 4.46 (q,
3J = 7.1 Hz, 2 H), 5.00 (br s, 2 H), 7.52 (d, 3J = 5.3 Hz, 1 H), 8.47
(d, 3J = 5.3 Hz, 1 H), 8.90 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 61.1, 114.2, 127.2, 127.9,
135.7, 136.8, 141.5, 150.1, 161.4.
Med. Chem. 2006, 14, 8162.
(7) Lisowski, V.; Leonce, S.; Kraus-Berthier, L.; Sopkova-
de Oliveira Santos, J.; Pierre, A.; Atassi, G.; Caignard, D.
H.; Renard, P.; Rault, S. J. Med. Chem. 2004, 47, 1448.
(8) (a) Dunn, A. D.; Norrie, R. J. Prakt. Chem. 1996, 338, 663.
(b) Zheng, G. Z.; Bhatia, P.; Daanen, J.; Kolasa, T.; Patel,
M.; Latshaw, S.; El Kouhen, O. F.; Chang, R.; Uchic, M. E.;
Miller, L.; Nakane, M.; Lehto, S. G.; Honore, M. P.;
Moreland, R. B.; Brioni, J. D.; Stewart, A. O. J. Med. Chem.
2005, 48, 7374. (c) Sauter, F.; Froehlich, J.; Ahmed, E. K.
Monatsh. Chem. 1995, 26, 945. (d) Narsaiah, B.;
Sivaprasad, A.; Venkataratnam, R. V. J. Fluorine Chem.
1994, 69, 139. (e) Wagner, G.; Prantz, J. Pharmazie 1993,
48, 250. (f) Kamal El-Dean, A. M.; Abdel Hafez, A. A.;
Attallah, A. A. Phosphorus, Sulfur Silicon Relat. Elem.
1989, 46, 1. (g) Gewald, K.; Jaensch, H. J. J. Prakt. Chem.
2004, 318, 313.
HRMS (EI): m/z calcd for C10H10N2O3: 206.0691; found: 206.0694.
Ethyl 3-Aminofuro[3,2-b]pyridine-2-carboxylate (1d)
Compound 1d was prepared from 3b.
Yield: 0.30 g (58%); mp 117 °C.
IR (KBr): 3447, 3305, 3082, 2980, 1681 (CO), 1633, 1587, 1561,
1478, 1454, 1371, 1337, 1270, 1182, 1106, 1024, 930, 880, 799,
759, 601, 559 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45 (t, 3J = 7.0 Hz, 3 H), 4.46 (q,
3J = 7.0 Hz, 2 H), 5.23 (br s, 2 H), 7.38 (dd, 3J = 8.5 Hz, 3J = 4.6 Hz,
1 H), 7.75 (dd, 3J = 8.5 Hz, 4J = 1.2 Hz, 1 H), 8.55 (dd, 3J = 4.6 Hz,
4J = 1.2 Hz, 1 H).
(9) Cho, Y. H.; Park, J. H. Tetrahedron Lett. 1997, 38, 8331.
(10) Cailly, T.; Fabis, F.; Lemaître, S.; Bouillon, A.; Rault, S.
Tetrahedron Lett. 2005, 46, 135.
13C NMR (100 MHz, CDCl3): d = 14.6, 60.7, 119.8, 122.9, 140.3,
142.0, 142.9, 145.5, 147.8, 161.3.
(11) Cailly, T.; Fabis, F.; Lemaître, S.; Bouillon, A.; Sopkova, J.;
Rault, S. Synlett 2006, 53.
(12) Hansen, H. M.; Lysén, M.; Begtrup, M.; Kristensen, J.
Tetrahedron 2005, 61, 9955.
Anal. Calcd. for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59. Found:
C, 58.32; H, 4.56; N, 13.28.
(13) Voisin, A. S.; Bouillon, A.; Lancelot, J. C.; Rault, S.
Tetrahedron 2005, 61, 1427.
Acknowledgment
(14) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
(15) Sangapure, S. S.; Agasimundin, Y. S. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1975, 14, 688.
We thank the Servier Laboratories, the ‘Conseil Régional de Basse-
Normandie’ and ‘Les Sapins de l’Espoir’ for their financial support.
We thank Dr. R. Legay for carrying out the mass analyses.
Synthesis 2007, No. 20, 3247–3251 © Thieme Stuttgart · New York