Synthesis of melatonin analogues derived from furo[2,3-b]- and [2,3-c]pyridines by use of a palladium-copper catalyst system

Article abstract of DOI:10.3987/com-01-9363

2,3,5-Substituted furo[2,3-b]pyridine was synthesised by palladium-catalyzed reaction of 5-bromo-2-hydroxy-3-iodopyridine and phenylacetylene with (Ph₃P)₂PdCl₂, CuI in Et₃N. A carbonylative cyclization of 5-hydroxy-2-methoxy-4-(2-phenylethynyl)pyridine with carbon monoxide in methanol with PdCl₂, CuCl₂ under basic conditions, has been accomplished to prepare methyl 2,5-substituted furo[2,3-c]pyridine-3-carboxylate.

Full text of DOI:10.3987/com-01-9363

HHETEROCYCLES, Vol. 57, No. 1, 2002, pp. 55 - 71, Received, 15th October, 2001
SYNTHESIS OF MELATONIN ANALOGUES DERIVED FROM
FURO[2,3-b]- AND [2,3-c]PYRIDINES BY USE OF A PALLADIUM-
COPPER CATALYST SYSTEM
Hervé Van de Poël,a Gérald Guillaumet,a and Marie-Claude
Viaud-Massuardb*
aInstitut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, BP 6759, 45067
Orléans Cedex 2, France
b
EA 3247 Laboratoire de Chimie Organique, UFR des Sciences Pharmaceutiques, Université de Tours,
31 Avenue de Monge, 37200 Tours - France. Phone : 33 247 36 72 27 ; Fax : 33 247 36 72 29 ;
E-mail : mcviaud@univ-tours.fr
Abstract - 2,3,5-Substituted furo[2,3-b]pyridine was synthesised by palladium-catalyzed reaction
of 5-bromo-2-hydroxy-3-iodopyridine and phenylacetylene with (Ph3P)2PdCl2, CuI in Et3N. A
carbonylative cyclization of 5-hydroxy-2-methoxy-4-(2-phenylethynyl)pyridine with carbon
monoxide in methanol with PdCl2, CuCl2 under basic conditions, has been accomplished to
prepare methyl 2,5-substituted furo[2,3-c]pyridine-3-carboxylate.
In the course of our research on the synthesis of melatonin analogues,1 our attention has been focused on
developing a catalytic approach to the furopyridine derivatives (1) and (2). Several studies have shown
that 2-substituted melatonin analogues can be more potent than melatonin itself.2 This increase in potency
has been ascribed to the presence of a C-2 binding site. Thus, to take advantage of this increase in binding,
we envisaged to synthesize furopyridines analogues substituted with a phenyl group at the C-2 position
whilst keeping the 5-methoxy group and the 3-ethanamide side chain present in melatonin itself.
O
O
O
H
H
H
N
N
N
CH3
CH3
CH3
CH3O
CH3O
CH3O
N
O
N
H
O
N
1
2
Furo[2,3-b]pyridine derivative
Furo[2,3-c]pyridine derivative
Melatonin
It was reported that the reaction of 2-hydroxypyridinyl iodides with variety of 1-alkynes in the presence
of palladium (II) and copper iodide as co-catalyst provided 2-substituted furopyridines.3 The synthesis of
two kinds of furopyridines, which were expected to be obtainable by the above-mentioned method, was
examined. Initial studies were directed to the preparation of the suitable substrates

2-hydroxypyridinyl iodides (6) and (12) for palladium-catalyzed cyclizations.
RESULTS AND DISCUSSION
Synthesis of 2-hydroxy-3-iodo-5-methoxypyridine (6)
The synthesis of the 2-amino-5-methoxypyridine (4) was already described in a 2 or 3-step procedure4 but
when 2-amino-5-bromopyridine (3) was allowed to react with sodium methoxide in the presence of
copper in methanol, (4) can be directly obtained in moderate yield.5 Next, the amino group was converted
to the diazonium salt using sodium nitrite in sulfuric acid and then treated with copper sulfate to give the
corresponding pyridinol (5) in 72 % yield.6 The iodination of 5 was readily accomplished according the
procedure of Koch and Schnatterer7 for the halogenation of hydroxypyridine using one equivalent of
iodine in the presence of sodium carbonate in water (Scheme 1).
Scheme 1
CH ONa, Cu
3
1. NaNO , H SO4, 0 °C
2 2
Br
CH3O
CH OH, reflux
.
3
2. CuSO 5H2O, H O, 100 °C
4
2
N
NH2
N
NH2
44 %
72 %
3
4
I2
CH3O
CH3O
I
Na2CO , H O, rt
3
2
76 %
N
OH
N
OH
5
6
Synthesis of 5-hydroxy-4-iodo-2-methoxypyridine (12)
The required 5-hydroxy-2-methoxypyridine (9) was prepared in three steps from 5-amino-2-
methoxypyridine (7) by Holladay et al.8 For our purposes, a two-step sequence of 9 was carried out in
satisfactory yield from 7 by replacement of the amino group with bromine, according to the Sandmeyer
reaction,9 followed successively in one pot by lithiation, reaction of trimethylborate at low temperature,
and in situ oxidation of the boronic intermediate with peracetic acid10 in 55 % overall yield (Scheme 2). In
an attempt to prepare 9 directly from commercially available 5-amino-2-methoxypyridine (7) by a
diazotation reaction, a bipyridine product (structure not shown) was obtained as only product.11
In order to iodinate the C-4 position of compound (9), we used the MOM group to direct ortho
metallation of the aromatic compound.12 Thus, the MOM protected compound was prepared using
methoxymethyl chloride in the presence of sodium hydride in N,N-dimethylformamide and then treated
with 2 equivalents of tert-butyllithium at -78 °C in tetrahydrofuran. The lithio species was trapped with
1.5 equivalent of iodine to give the iodinated compound in 86 %. After the removal of the MOM group
by heating in hydrochloric acid and tetrahydrofuran at 60 °C, the 5-hydroxy-4-iodo-2-methoxypyridine
(12) was obtained in 92 % (Scheme 2).

Scheme 2
i) t-BuLi, THF, - 78 °C
ii) B(OCH3)3, - 78 °C
NaNO2, CuBr
48 % HBr , 10 °C
CH3O
CH3O
CH3O
iii)CH CO H, -10 °C
3
3
N
N
N
NH2
67 %
82 %
Br
OH
7
8
9
i)t-BuLi
THF, - 78 °C
ii)I2, - 78 °C
HCl, THF
60 °C
NaH,MOMCl
DMF, rt
CH3O
I
I
CH3O
CH3O
N
N
N
92 %
OH
86 %
OMOM
94 %
OMOM
10
11
12
Synthesis of compounds (13) and (14)
2-Phenyl-5-methoxyfuro[2,3-b]pyridine (13) and 2-phenyl-5-methoxyfuro[2,3-c]pyridine (14) were
directly obtained in good yield from 2-hydroxy-3-iodo-5-methoxypyridine (6) and 5-hydroxy-4-iodo-2-
methoxypyridine (12), respectively, by heating in a triethylamine solution in the presence of a catalytic
amount of dichlorobis(triphenylphosphine)palladium (5 mol %) and copper iodide (5 mol%) (Scheme 3).
Scheme 3
(Ph3P)2PdCl2
I
CH3O
CH3O
CuI, (C2H5)3N, 100 °C
+
Y
Y
O
X
OH
X
6 : X = N, Y = CH
12 : Y = N, X = CH
13 : X = N, Y = CH ; 65 %
14 : Y = N, X = CH ; 74 %
By the method described above, the compound (13) was prepared in 4 steps from 3 in 15 % yield.
However, a better overall yield (34 %) was obtained by reversing the order of the reactions (Scheme 4).
The iodination was performed with N-iodosuccinimide as the halogenating agent and the introduction of
the methoxy group was achieved in a 78 % yield by a copper-catalyzed reaction of sodium methoxide
with the 5-bromofuropyridine (17) in a mixture of methanol and N,N-dimethylformamide (3:1) .13 The
competitive reduction was also observed in 11 % yield.
Scheme 4
i) NaNO2, H2SO4, 0°C
I
Br
Br
ii) CuSO4.5H2O, H2O, 100 °C
NIS, CH3OH, 50 °C
3
82 %
74 %
N
OH
N
OH
15
16
, CuI
(Ph3P)2PdCl2
Ph
CH3ONa, CuBr
CH3OH, DMF
reflux
Br
CH3O
(C2H5)3N, 100 °C
Ph
Ph
Ph
+
O
O
O
72 %
N
N
N
17
13 : 78 %
18 : 11 %

To complete the synthesis of targets (1) and (2), the introduction of the N-ethylacetamido group at the C-3
position of 13 and 14 was now required.
Synthesis of compound (1)
The bromination14 of 13 with 1.2 mole of bromine in carbon tetrachloride afforded
the 2,3-dibromo-2-phenyl-5-methoxy-2,3-dihydrofuro[2,3-b]pyridine which was immediately treated with
sodium hydroxide in aqueous methanol to give the 3-bromofuropyridine derivative (19) in 93 % yield
(Scheme 5).
Scheme 5
Br
Br
H
Br2, CCl4, 0 °C
CH3O
CH3O
NaOH, CH3OH, 0 °C
13
Ph
Br
Ph
93 %
O
O
N
N
19
Subsequent chemical modifications converted the bromine atom to the side chain
N-ethylacetamide. Stille coupling of 19 with tetramethyltin gave the corresponding
3-methylfuropyridine (20) in 93 % yield. Treatment of 20 with N-bromosuccinimide and 2,2’-azobis(2-
methylpropionitrile) in refluxing carbon tetrachloride followed by a nucleophilic substitution with
potassium cyanide afforded the nitrile (22) which was converted to the final compound (1) by an
hydrogenation over Raney nickel and a concomitant N-acetylation in 87 % overall yield from 22
(Scheme 6).
Scheme 6
(CH ) Sn
3 4
Br
Ph
(Ph3P)2PdCl
CH3
2
NBS, AIBN, CCl
4
CH3O
CH3O
HMPA, 100 °C
reflux
19
Ph
93 %
O
O
N
N
20
21
NHCOCH3
Ph
CN
Ph
H2, Raney Ni
Ac2O, AcONa,50°C
CH3O
KCN, DMF, reflux
CH3O
87 %
41 % for 2 steps
O
N
O
N
22
1
Synthesis of compound (2)
Initial attempts for the synthesis of melatonin analogue (2) looked at the selective bromination of 14 in
the C-3 position. Unfortunately, the bromination of 14 provided the 4-bromo-substituted compound (23)
in 65 % yield. The β-free position of the nitrogen atom allowed the regioselective introduction of a
bromine atom to the C-4 position (Scheme 7).

Scheme 7
Br
Br2, CCl4, 0 °C
CH3O
CH3O
Ph
Ph
N
65 %
N
O
O
14
23
According the C-3 formylation of the benzofuran ring described in literature,15 we have also tried without
success to introduce a formyl group regioselectively at the C-3 position of the compound (14) under the
Gattermann-Adams conditions.
Finally, the synthesis of 2 was achieved using a closely related strategy which utilised the Sonogashira
coupling conditions described above. However, in this case the intermediate 2-(2-phenylethynyl)pyridinol
(25) was isolated prior to cyclisation and a palladium catalysed carbonylative cyclisation reaction was
used to form the furopyridine ring system with concomitant alkoxycarbonylation of the C-3 position. The
conditions used for this reaction were based on those developed in literature for the preparation of 2-
substituted benzofuran-3-carboxylate.15
The palladium-catalyzed cross-coupling reaction of 11 with the phenylacetylene followed by the removal
of the MOM protecting group using hydrochloric acid in methanol gave the
2-(2-phenylethynyl)pyridinol (25) in 71 % overall yield. When 25 was allowed to react with carbon
monoxide in methanol in the presence of palladium chloride, potassium carbonate and sodium acetate, the
5-methoxy-2-phenylfuro[2,3-c]pyridine-3-carboxylate (26) was obtained in 82 % (Scheme 8).
Scheme 8
Ph
HCl
Ph
(Ph3P)2PdCl , CuI
2
(C2H5)3N, 100 °C
CH3O
THF, 60 °C
11
92 %
77 %
N
OMOM
24
Ph
PdCl , CuCl
COOCH3
Ph
2
2
CH3O
N
CH3O
K2CO , AcONa, CHOH, CO, rt
3
3
N
O
82 %
OH
25
26
Thus, an ester function introduced into the C-3 position of the furopyridine ring allowed us to elaborate
the side chain. The compound (26) was reduced into the corresponding alcohol using lithium aluminum
hydride in tetrahydrofuran in good yield. The formation of tosylate from alcohol (27) followed by the
potassium cyanide displacement afforded the nitrile (29) in 22 % in two steps. This low yield was
probably due to the instability of the sulfonate. The desired melatonin analogue (2) was then obtained by
hydrogenation over Raney nickel and a concomitant N-acetylation in 75 % yield (Scheme 9).

Scheme 9
p-TsCl, (C2H5)3N
LiAlH4
THF, rt
OH
OTs
Ph
CH2Cl2, rt
CH3O
CH3O
26
Ph
95 %
38 %
N
N
O
O
27
28
NHCOCH3
Ph
H2, Ni Raney
Ac2O, AcONa, 50 °C
CN
Ph
KCN, DMF, 0 °C
CH3O
CH3O
57 %
75 %
N
O
N
O
29
2
In summary, the palladium-catalyzed cross-coupling reactions provide a convenient route to synthesize
functionalized furopyridine derivatives. The procedure described herein offer much possibility for design
of 2-substituted furopyridines as melatonin analogues by the coupling of 10 or 11 with various of terminal
acetylenes.
EXPERIMENTAL
1
Melting points are uncorrected. H-NMR and 13C-NMR spectra were recorded on a Bruker Avance
DPX250 (250.131 Hz). The coupling constants are recorded in Hz and the chemical shifts are reported in
ppm (δ, ppm) downfield from TMS which was used a internal standard. IR spectra were obtained with a
Perkin-Elmer FT Paragon 1000 PC. MS spectra were registered on a Perkin-Elmer SCIEX API 3000
spectrometer. Reaction products were purified by flash chromatography using silica gel (Merck 230-400
mesh). Analytical thin-layer chromatography was carried out on silica gel F254 plates. All anhydrous
reactions were performed in oven-dried glassware under an atmosphere of argon. Anhydrous solvents
were transferred via syringe.
2-Amino-5-methoxypyridine (4)
A solution of 2-amino-5-bromopyridine (3) (0.50 g, 2.90 mmol) in 5 mL of methanol was heated in a
sealed tube for 12 h at 100 °C in the presence of sodium methoxide (0.47 g, 8.70 mmol) and copper
powder (0.185 g, 2.90 mmol). After cooling, dilution with dichloromethane, filtration under celite and
evaporation of solvent, water was added and the mixture was extracted with dichloromethane. The
combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (eluent : ethyl acetate/petroleum ether, 6/4) to
1
provide compound (4) (0.158 g, 44 %) as a brown oil : IR (NaCl) ν : 3202, 2925, 1612 cm-1. H-NMR
(CDCl3) δ : 3.77 (s, 3 H, OCH3), 4.13 (s, 2 H, NH2), 6.48 (d, J = 9.0 Hz, 1 H, H3), 7.08 (dd, J = 9.0 Hz,
J = 3.0 Hz, 1 H, H4), 7.77 (d, J = 3.0 Hz, 1 H, H6). 13C-NMR (CDCl3) δ : 56.2 (OCH3), 109.3 (C3), 125.5

(C4), 133.3 (C6), 149.5, 153.1. MS (IS) m/z: 125 (M+1). Anal. Calcd for C6H8N2O : C, 58.05 ; H, 6.50 ; N,
22.57. Found : C,58.00 ; H, 6.30 ; N, 22.20.
2-Hydroxy-5-methoxypyridine (5)
The compound (4) (5 g, 40.27 mmol) was dissolved in a mixture of concentrated sulfuric acid (8 mL) and
water (115 mL). The solution was cooled to 0 °C and treated dropwise with good stirring with a solution
of sodium nitrite (3 g, 44.88 mmol) in water (20 mL), keeping the temperature below 5 °C. After the
addition, the stirring was continued for 0.5 h at the temperature of diazotation. The solution was then
poured into a solution at 100 °C of copper sulfate (40.4 g, 161.08 mmol) in water (70 mL) and the heating
continued until the evolution of nitrogen ceased. The reaction solution was allowed to cool to rt,
dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to the mixture. The
organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined
organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent : ethyl acetate) to afford 5 (3.63 g, 72 %) as a
1
yellow solid : mp 94-95 °C (pentane). IR (KBr) ν : 3058 cm-1. H-NMR (CDCl3+D2O) δ : 3.65 (s, 3 H,
OCH3), 6.55 (d, J = 9.7 Hz, 1 H, H3), 6.95 (d, J = 3.0 Hz, 1 H, H6), 7.30 (dd, J = 9.7 Hz, J = 3.0 Hz, 1 H,
13
H4). C-NMR (CDCl3) δ : 56.4 (OCH3), 115.5 (C6), 120.7 (C3), 135.4 (C4), 144.3, 163.2. MS (IS) m/z:
126 (M+1). Anal. Calcd for C6H7NO2 : C, 57.59 ; H, 5.64 ; N, 11.19. Found : C, 57.40 ; H, 5.55 ; N,
11.10.
2-Hydroxy-3-iodo-5-methoxypyridine (6)
To a solution of 5 (0.20 g, 1.60 mmol) and sodium carbonate (0.34 g, 3.20 mmol) in water (5 mL) was
added iodine (0.407 g, 1.60 mmol) with stirring at 20 °C. After stirring for 45 min, the pH was adjusted to
3 with a solution of 5% hydrochloric acid and the reaction was extracted with ethyl acetate. The
combined organic extracts were washed with a saturated aqueous solution of sodium thiosulfate and dried
over MgSO4. After removal of the solvent, the residue was purified by flash chromatography on silica gel
(eluent : ethyl acetate) to afford (6) (0.305 g, 76 %) as a white solid : mp 104-105 °C (pentane). IR (KBr)
ν : 3110, 2932, 1611 cm-1. 1H-NMR (CDCl3+D2O) δ : 3.70 (s, 3 H, OCH3), 7.08 (d, J = 3.0 Hz, 1 H, H4),
7.95 (d, J = 3.0 Hz, 1 H, H6). 13C-NMR (CDCl3) δ : 56.8 (OCH3), 91.8 (C3), 116.5 (C4), 144.2 (C6), 144.4,
160.6. MS (IS) m/z: 252 (M+1). Anal. Calcd for C6H6NO2I : C, 28.71 ; H, 2.41 ; N, 5.58. Found : C,
28.65 ; H, 2.35 ; N, 5.42.
5-Bromo-2-methoxypyridine (8)
Copper(I) bromide (17.0 g, 120.96 mmol) was dissolved in 48 % hydrobromic acid (25 mL).
To this solution, 5-amino-2-methoxypyridine (7) (6.0 g, 48.40 mmol) was added with stirring. The
mixture was cooled to 10 °C and sodium nitrite (4.35 g, 63.04 mmol), dissolved in water (30 mL) , was
added dropwise maintaining the temperature between 10 and 15 °C. After the addition was completed, the

mixture was allowed to stand for 1 h at 10-15 °C and was then heated on a steam bath for 10 min. It was
finally made basic by the addition of 50 % potassium hydroxide solution. The solution was filtered under
celite and washed with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel
(eluent : petroleum ether/ethyl acetate, 95/5) to provide compound (8) (6.09 g, 67 %) as a colorless oil :
IR (NaCl) ν : 2945, 1585 cm-1. 1H-NMR (CDCl3) δ : 3.82 (s, 3 H, OCH3), 6.77 (d, J = 8.6 Hz, 1 H, H3),
13
7.81 (dd, J = 8,6 Hz, J = 2,6 Hz, 1 H, H4), 8.21 (d, J = 2,6 Hz, 1 H, H6). C-NMR (CDCl3) δ : 53.4
(OCH3), 111.5, 112.4 (C3), 140.7 (C4), 147.3 (C6), 162.7. MS (IS) m/z: 188 (M) 190 (M+1). Anal. Calcd
for C6H6NOBr : C, 38.33 ; H, 3.22 ; N, 7.45. Found : C, 38.20 ; H, 3.15 ; N, 7.40.
5-Hydroxy-2-methoxypyridine (9)
To a solution of 8 (2.60 g, 13.83 mmol) in dry tetrahydrofuran (100 mL) at - 78 °C under argon was
added a solution of n-butyllithium in hexane (13.1 mL of a 1.6 M solution, 20.90 mmol) and the mixture
was stirred for 20 min before addition at - 78 °C of trimethyl borate (2.37 mL, 20.90 mmol). After 2 h of
stirring, a solution of peracetic acid (32 wt % in dilute acetic acid) (4.4 mL, 20.90 mmol) was then added,
and the mixture was warmed to 0 °C under stirring for 1 h and then cooled to - 10 °C, whereupon an
aqueous solution of sodium hydrogenosulfite (10 mL) was poured dropwise. The mixture was warmed to
rt and then extracted with dichloromethane. The organic layer was separated, dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent : petroleum
ether/ethyl acetate, 7/3) to provide 9 (1.41g, 82 %) as a yellow solid : mp 77-78 °C (ethyl acetate). IR
(KBr) ν : 3180, 1585 cm-1. 1H-NMR (CDCl3) δ : 3.84 (s, 3 H, OCH3), 6.65 (d, J = 8.9 Hz, 1 H, H3), 7.26
13
(dd, J = 8.9 Hz, J = 2.9 Hz, 1 H, H4), 7.75 (d, J = 2.9 Hz, 1 H, H6), 9.38 (sl, 1 H, OH). C-NMR
(CDCl3) δ : 54.1 (OCH3), 110.6 (C3), 128.6 (C4), 132.2 (C6), 148.3, 158.1. MS (IS) m/z: 126 (M+1). Anal.
Calcd for C6H7NO2 : C, 57.59 ; H, 5.64 ; N, 11.19. Found : C, 57.62 ; H, 5.70 ; N, 11.30.
2-Methoxy-5-(methoxymethoxy)pyridine (10)
A mixture of compound (9) (1.80 g, 14.40 mmol) and sodium hydride (60 % ,0.69 g, 17.28 mmol) in
N,N-dimethylformamide (20 mL) was stirred at rt for 45 min. To the mixture, methoxymethyl chloride
(1.25 mL, 16.56 mmol) was added and the solution was stirred at rt for 2 h. After dilution with water, the
reaction mixture was extracted with ethyl acetate. The organic layer was separated, washed with water (4
times) dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography
on silica gel (eluent : petroleum ether/ethyl acetate, 95/5) to afford 10 (2.31 g, 94 %) as a colorless oil. IR
(NaCl) ν : 2946, 1280, 1233 cm-1. 1H-NMR (CDCl3) δ : 3.42 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 5.03
(s, 2 H, CH2), 6.62 (d, J = 8.2 Hz, 1H, H3), 7.27 (dd, J = 8.2 Hz, J = 2.7 Hz, H4), 7.89 (d, J = 2.7 Hz, 1 H,
H6). 13C-NMR (CDCl3) δ : 53.1 (OCH3), 55.6 (OCH3), 95.4 (CH2), 110,6 (C3), 128.4 (C4), 134.7 (C6),
148.5, 159.3. MS (IS) m/z: 170 (M+1). Anal. Calcd for C8H11NO3 : C, 56.80 ; H, 6.55 ; N, 8.28. Found :

C, 56.60 ; H, 6.50 ; N, 8.19.
2-Methoxy-4-iodo-5-methoxymethoxypyridine (11)
To a solution of 10 (0.20 g, 1.18 mmol) in dry tetrahydrofuran (6 mL) at - 78 °C under argon was added a
solution of tert-butyllithium in pentane (1.4 mL of a 1.7 M solution, 2.37 mmol). The mixture was stirred
for 35 min before addition at - 78 °C of a solution of iodine (0.45 g, 1.77 mmol) in tetrahydrofuran
(3 mL). After 1 h of stirring, water was added, and the mixture was warmed to rt and then extracted with
ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium thiosulfate and
dried over MgSO4. After removal of the solvent, the residue was purified by flash chromatography on
silica gel (eluent : petroleum ether/ethyl acetate, 95/5) to afford 11 (0.30 g, 86 %) as a brown solid : mp
1
46-47 °C (pentane). IR (KBr) ν : 2947, 1582 cm-1. H-NMR (CDCl3) δ : 3.50 (s, 3 H, OCH3), 3.84 (s,
3 H, OCH3), 5.12 (s, 2 H, CH2), 7.19 (s, 1 H, H3), 7.83 (s, 1 H, H6). 13C-NMR (CDCl3) : δ = 53.8 (OCH3),
56.5 (CH3), 96.3 (CH2), 102.0, 120.9 (C3), 133.1 (C6), 148.3, 159.5. MS (IS) m/z: 296 (M+1). Anal.
Calcd for C8H10NO3I : C, 32.56 ; H, 3.42 ; N, 4.75. Found : C, 32.43 ; H, 3.33 ; N, 4.68.
5-Hydroxy-4-iodo-2-methoxypyridine (12)
A solution of compound (11) (2.10 g, 7.12 mmol) in 3 N hydrochloric acid (15 mL) and tetrahydrofuran
(10 mL) was heated at 60°C for 3 h, cooled to rt and then extracted with ethyl acetate. The combined
organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 7/3) to provide
compound 12 (1.64 g, 92 %) as a yellow solid : mp 122-123 °C (pentane). IR (KBr) ν : 3330 cm-1.
1H-NMR (CDCl3) δ : 3.88 (s, 3 H, OCH3), 5.28 (s, 1 H, OH), 7.14 (s, 1 H, H3), 7.81 (s, 1 H, H6).
13C-NMR (CDCl3) δ : 54.3 (OCH3), 100.4, 119.9 (C3), 131.9 (C6), 149.3, 157.6. MS (IS) m/z: 252 (M+1).
Anal. Calcd for C6H6NO2I : C, 28.71 ; H, 2.41 ; N, 5.58. Found : C, 28.82 ; H, 2.52 ; N, 5.54.
5-Methoxy-2-phenylfuro[2,3-b]pyridine (13)
Method A : A mixture of 2-hydroxy-3-iodo-5-methoxypyridine (6) (0.22 g, 0.88 mmol), phenylacetylene
(0.116 mL, 1.05 mmol), bis(triphenylphosphine)palladium chloride (0.031 g, 0.04 mmol) and copper
iodide (0.008 g, 0.04 mmol) in triethylamine (5 mL) was heated under argon at 100 °C for 10 h. After
cooling at rt and evaporating of the solvent, the residue was diluted with water and extracted with
dichloromethane. The combined organic extracts were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent : petroleum
ether/ethyl acetate, 95/5) to give compound (13) (0.143 g, 65 %) as a white solid.
Method B : A mixture of compound (17) (2.40 g, 8.76 mmol), sodium methoxide (23.60 g, 436.90 mmol)
and copper(I) bromide (2.50 g, 17.42 mmol) in methanol (75 mL) was heated under argon at reflux for
1 h before addition of N,N-dimethylformamide (25 mL). The mixture was heated at reflux for 12 h. After
cooling at rt and evaporation of solvents, the residue was diluted with water and ethyl acetate and filtered

under celite. The organic layer was separated, washed with water (4 times) dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent : petroleum
ether/ethyl acetate, 95/5) to afford 13 (1.54 g, 78 %) as a white solid and 18 ( 19 mg, 11 %) as a white
solid.
5-Methoxy-2-phenylfuro[2,3-b]pyridine (13) : mp 90-91 °C (pentane). IR (KBr) ν : 2942, 1612 cm-1.
1H-NMR (CDCl3) δ : 3.90 (s, 3 H, OCH3), 6.94 (s, 1 H, H3), 7.38 (d, J = 2.6 Hz, 1 H, H4), 7.38-7.50
13
(m, 3 H, Harom), 7.87-7.91 (m, 2 H, Harom), 8.01 (d, J = 2.6 Hz, 1 H, H6). C-NMR (CDCl3) δ : 56.4
(OCH3), 100.1 (C3), 113.1 (C4), 121.5, 125.1 (2 Carom), 128.9 (2 Carom), 129.2 (Carom), 129.7, 132.5 (C6),
153.6, 156.8, 156.9. MS (IS) m/z: 226 (M+1). Anal. Calcd for C14H11NO2 : C, 74.65 ; H, 4.92 ; N, 6.22.
Found : C, 74.00 ; H, 4.85 ; N, 6.42.
1
2-Phenylfuro[2,3-b]pyridine (18): mp 89-90 °C (pentane). IR (KBr) ν : 1596 cm-1, H-NMR (CDCl3)
δ : 6.98 (s, 1 H, H3), 7.20 (dd, J = 7.6 Hz, J= 4.8 Hz, 1 H, H5), 7.37-7.49 (m, 3 H, Harom), 7.85-7.91 (m,
3 H, Harom, H4), 8.28 (dd, J = 4.8 Hz, J= 1.5 Hz, 1 H, H6). 13C-NMR (CDCl3) δ : 100.1 (C3), 113.1 (C4),
121.5, 125.1 (2 Carom), 128.9 (2 Carom), 129.2 (Carom), 129.7, 132.5 (C6), 153.6, 156.8, 156.9. MS (IS)
m/z: 196 (M+1). Anal. Calcd for C13H9NO : C, 79.98 ; H, 4.65 ; N, 7.17. Found : C, 79.82 ; H, 4.85 ; N,
7.07.
5-Methoxy-2-phenylfuro[2,3-c]pyridine (14)
Compound (14) was prepared from 12 (0.22 g, 0.88 mmol) according to the procedure used for 13,
purification by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 95/5) gave
compound (14) (0.146 g, 74 %) as a yellow solid. mp 104-105 °C (pentane). IR (KBr) ν : 2949,
1585 cm-1. 1H-NMR (CDCl3) δ : 3.98 (s, 3 H, OCH3), 6.90 (s, 1 H, H3), 7.34-7.39 (m, 3 H, Harom), 7.55-
13
7.60 (m, 3 H, Harom, H4), 8.38 (s, 1 H, H7). C-NMR (CDCl3) δ : 54.4 (OCH3), 99.8 (C4), 101.1 (C3),
128.1 (2 Carom), 129.3 (C7), 129.4 (2 Carom), 130.1 (Carom), 132.4, 133.9, 148.7, 151.3, 159.9. MS (IS)
m/z: 226 (M+1). Anal. Calcd for C14H11NO2 : C, 74.65 ; H, 4.92 ; N, 6.22. Found : C, 74.35 ; H, 4.85 ;
N, 5.98.
5-Bromo-2-hydroxypyridine (15)
Prepared in 82 % yield following the procedure used for the preparation of 5.
mp 180-182 °C (ethyl acetate). IR (KBr) ν : 3052 cm-1. 1H-NMR (DMSO-d6) δ : 6.33 (d, J = 9.5 Hz, 1 H,
H3), 7.52 (dd, J = 9.5 Hz, J= 2.7 Hz, 1 H, H4), 7.66 (d, J= 2.7 Hz, 1 H, H6), 11.7 (s, 1 H, OH). 13C-NMR
(DMSO-d6) δ : 99.9, 121.1 (C3), 138.5 (C4), 144.1 (C6), 162.1. MS (IS) m/z: 174 (M) 176 (M+1). Anal.
Calcd for C5H4NOBr : C, 34.52 ; H, 2.32 ; N, 8.05. Found : C, 34.45 ; H, 2.23 ; N, 7.91.
5-Bromo-2-hydroxy-3-iodopyridine (16)
N-Iodosuccinimide (846 mg, 3.75 mmol) was added under inert atmosphere to a stirred solution of
5-bromo-2-hydroxypyridine (15) (500 mg, 2.88 mmol) in methanol (12 mL), and stirring was continued

for 10 h at 50 °C. After cooling at rt and evaporating of the solvent, the residue was diluted with water
and extracted with ethyl acetate. The combined organic extracts were washed with aqueous 10% Na2S2O3
solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (eluent : ethyl acetate/petroleum ether, 6/4) to give compound (16)
1
(638 mg, 74 %) as a white solid. mp 253-254 °C (ethyl acetate). IR (KBr) ν : 3051 cm-1. H-NMR
(DMSO-d6) δ : 7.72 (d, J= 2.5 Hz, 1 H, H4), 8.19 (d, J= 2.5 Hz, 1 H, H6), 12.21 (s, 1 H, OH). 13C-NMR
(DMSO-d6) δ : 94.5, 97.9, 137.6 (C4), 151.5 (C6), 159.8. MS (IS) m/z: 300/302 (M+1). Anal. Calcd for
C5H3NOBrI : C, 20.03 ; H, 1.01 ; N, 4.67. Found : C, 19.93 ; H, 1.01 ; N, 4.63.
5-Bromo-2-phenylfuro[2,3-b]pyridine (17)
This compound was prepared in 72 % yield following the general procedure used for the preparation of
1
13 and 14. mp 204-205 °C (pentane). IR (KBr) cm-1 : ν = 1596 (C=C, Ar). H-NMR (CDCl3) δ : 6.93
(s, 1 H, H3), 7.40-7.49 (m, 3 H, Harom), 7.86-7.89 (m, 2 H, Harom), 7.98 (d, J = 3.0 Hz, 1 H, H4), 8.31
(d, J = 3.0 Hz, 1 H, H6). 13C-NMR (CDCl3) δ : 99.4 (C3), 115.3, 123.3, 125.3 (2 Carom), 128.9 (2 Carom),
129.1, 129.8 (Carom), 131.6 (C4), 144.3 (C6), 157.2, 160.4. MS (IS) m/z: 274 (M), 276 (M+1). Anal. Calcd
for C13H8NOBr : C, 56.96 ; H, 2.94 ; N, 5.11. Found : C, 56.89 ; H, 2.87 ; N, 5.00.
3-Bromo-2-methoxyfuro[2,3-b]pyridine (19)
To a solution of compound (13) (1.50 g, 6.67 mmol) in carbon tetrachloride (30 mL) at - 15 °C was added
a solution of bromine (0.5 mL, 9.62 mmol) in carbon tetrachloride (5 mL). The mixture was stirred for 10
min at this temperature. The solvent was then removed under reduced pressure at rt. The residue was
taken up in methanol (30 mL) and a 20 % sodium hydroxide solution (20 mL) was added. After being
stirred for 10 min at rt, the solution was evaporated and the residue was taken up in dichloromethane and
washed with water. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 95/5) to
afford 19 (1.88 g, 93 %) as a white solid : mp 126-127 °C (pentane). IR (KBr) ν : 2945, 1592 cm-1.
1H-NMR (CDCl3) δ : 3.96 (s, 3 H, OCH3), 7.35 (d, J = 2.8 Hz, 1 H, H4), 7.47-7.56 (m, 3 H, Harom), 8.07
(d, J = 2.8 Hz, 1 H, H6), 8.20-8.24 (m, 2 H, Harom). 13C-NMR (CDCl3) δ : 56.4 (OCH3), 111.4 (C4), 122.1,
125.8, 126.9 (2 Carom), 128.6 (2 Carom), 128.9, 129.6 (Carom), 134.6 (C6), 151.1, 154.1, 154.5. MS (IS)
m/z: 304 (M), 306 (M+1). Anal. Calcd for C14H10NO2Br : C, 55.29 ; H, 3.31 ; N, 4.61. Found :
C, 55.10 ; H, 3.07 ; N, 4.49.
5-Methoxy-3-methyl-2-phenylfuro[2,3-b]pyridine (20)
Bis(triphenylphosphine)palladium chloride (0.135 g, 0.19 mmol) and tetramethyltin (0.530 mL,
3.79 mmol) were respectively added to a solution of compound (19) (0.960 g, 3.16 mmol) in
hexamethylphosphoramide (5 mL). The mixture was stirred at 110 °C for 3 h. After cooling to rt, the
reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated,

washed with water (4 times) dried over MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 95/5) and further purified by
recrystallization (petroleum ether/ ether, 2/1) to afford 20 (0.700 g, 93 %) as a white solid.
1
mp 178-179 °C . IR (KBr) ν : 2939, 1583 cm-1. H-NMR (CDCl3) δ : 2.47 (s, 3 H, CH3), 3.92 (s, 3 H,
OCH3), 7.33 (d, J = 2.9 Hz, 1 H, H4), 7.35-7.52 (m, 3 H, Harom), 7.82-7.85 (m, 2 H, Harom), 8.01
(d, J = 2.9 Hz, 1 H, H6), 13C-NMR (CDCl3) δ : 10.0 (CH3), 56.8 (OCH3), 110.8, 112.1 (C4), 123.7, 127.3
(2 Carom), 128.8 (2 Carom), 129.1 (Carom), 131.7, 132.9 (C6), 151.9, 153.7, 156.4. MS (IS) m/z: 240 (M+1).
Anal. Calcd for C15H13NO2 : C, 75.30 ; H, 5.48 ; N, 5.85. Found : C, 75.12 ; H, 5.39 ; N, 5.78.
2-(5-Methoxy-2-phenylfuro[2,3-b]pyridin-3-yl)acetonitrile (22)
A solution of 20 (0.240 g, 1.0 mmol) in carbon tetrachloride (10 mL) was heated to reflux after which the
N-bromosuccinimide (0.186 g, 1.06 mmol) and a catalytic amount of AIBN were added. The heating was
continued during 3 h. The mixture was then cooled to rt. The succinimide produced as a byproduct was
filtered off and washed with cold carbon tetrachloride. The filtrates were combined, and the solvent was
removed under reduced pressure. The residue was taken up in N,N-dimethylformamide (10 mL) and
potassium cyanide (0.105 g, 1.61 mmol) was added at 0 °C. The solution which resulted was stirred at
this temperature for 2 h. After dilution with water, the reaction mixture was extracted with ethyl acetate.
The organic layer was separated, washed with water (4 times) dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl
acetate, 8/2) to afford 22 (0.110 g, 41 %) as a white solid. mp 169-170 °C (pentane). IR (KBr) ν : 2945,
2248, 1583 cm-1. 1H-NMR (CDCl3) δ : 3.94 (s, 3 H, OCH3), 3.95 (s, 2 H, CH2), 7.48-7.58 (m, 4 H, Harom
,
13
H4), 7.70-7.73 (m, 2 H, Harom), 8.08 (d, J = 2.8 Hz, 1 H, H6). C-NMR (CDCl3) δ : 13.7 (CH2), 56.3
(OCH3), 103.6, 111.2 (C4), 116.3, 120.4, 127.4 (2 Carom), 128.5, 129.0 (2 Carom), 129.8 (Carom), 133.8
(C6), 153.4, 153.6, 155.5. MS (IS) m/z: 265 (M+1). Anal. Calcd for C16H12N2O2 : C, 72.72 ; H, 4.58 ;
N, 10.60. Found : C, 72.69 ; H, 4.50 ; N, 10.51.
N-[2-(5-Methoxy-2-phenylfuro[2,3-b]pyridin-3-yl)ethyl]acetamide (1)
A solution of compound (22) (0.20 g, 0.75 mmol) in acetic anhydride (10 mL) was hydrogenated over
Raney nickel (0.03 g) in the presence of sodium acetate (0.092 g, 1.12 mmol) for 12 h at 50 °C. The
reaction was cooled to rt and the catalyst was filtered on Celite and the filtrate concentrated in vacuo. The
residue was taken up in dichloromethane, washed with water and dried over MgSO4. After removal of the
solvent, the crude residue was chromatographed over silica gel (eluent : ethyl acetate) and purified by
recrystallization (pentane/ether, 2/1) to afford 1 (0.202 g, 87 %) as a white solid : mp 134-135 °C.
IR (KBr) ν : 3283, 2934, 1669, 1585 cm-1. 1H-NMR (CDCl3) δ : 1.92 (s, 3 H, COCH3), 3.20 (t, J = 7 Hz,
2 H, CH2-CH2-N), 3.61 (td, J = 7 Hz, J = 5 Hz, 2 H, CH2-CH2-N), 3.95 (s, 3 H, OCH3), 6.61-6.63
(m, 1 H, NH), 7.41-7.61 (m, 4 H, Harom, H4), 7.84-7.87 (m, 2 H, Harom), 8.01 (d, J = 2.8 Hz, 1 H, H6).

13C-NMR (CDCl3) δ : 23.1 (COCH3), 24.3 (CH2-CH2-N), 38.9 (CH2-CH2-N), 56.3 (OCH3), 111.7 (C4),
112.2, 122.6, 126.7 (2 Carom), 128.7 (2 Carom), 128.8 (Carom), 130.0, 132.7 (C6), 152.4, 153.5, 155.8,
170.6 (CO). MS (IS) m/z: 311 (M+1). Anal. Calcd for C18H18N2O3 : C, 69.66; H, 5.85; N, 9.03. Found : C,
69.27; H, 5.87; N, 8.80.
4-Bromo-5-methoxy-2-phenylfuro[2,3-c]pyridine (23)
This compound was prepared according the same methodology described for derivative (19). The crude
mixture was purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 99/1)
to afford 23 in 65 % yield as a white solid : mp 127-128 °C (pentane). IR (KBr) ν : 2942, 1588 cm-1.
1H-NMR (CDCl3) δ : 4.11 (s, 3 H, OCH3), 7.12 (s, 1 H, H3), 7.42-7.49 (m, 3 H, Harom), 7.79-7.84
13
(m, 2 H, Harom), 8.01 (s, 1 H, H7). C-NMR (CDCl3) δ : 54.7 (OCH3), 101.4 (C3), 101.7, 125.1 (C7),
125.8 (2 Carom), 128.8 (2 Carom), 129.1 (Carom), 129.4, 144.3, 145.6, 157.1, 159.9. MS (IS) m/z: 304 (M),
306 (M+1). Anal. Calcd for C14H10NO2Br : C, 55.29 ; H, 3.31 ; N, 4.61. Found : C, 55.00 ; H, 3.28 ;
N, 4.58.
2-Methoxy-5-methoxymethoxy-4-(2-phenylethynyl)pyridine (24)
A mixture of compound (11) (3.16 g, 10.71 mmol), phenylacetylene (1.41 mL, 12.86 mmol),
bis(triphenylphosphine)palladium chloride (0.376 g, 0.54 mmol) and copper iodide (0.102 g, 0.54 mmol)
in triethylamine (50 mL) was heated under argon at 100 °C for 4 h. After cooling at rt and evaporating of
the solvent, the residue was diluted with water and extracted with dichloromethane. The combined
organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 95/5) to afford 24
(2.64 g, 92 %) as a brown solid : mp 35-36 °C (ether). IR (KBr) ν : 2946, 1604 cm-1.
1H-NMR (CDCl3) δ : 3.55 (s, 3 H, CH2-O-CH3), 3.89 (s, 3 H, OCH3), 5.20 (s, 2 H, CH2), 6.84 (s, 1 H,
13
H3), 7.33-7.36 (m, 3 H, Harom), 7.52-7.56 (m, 2 H, Harom), 8.02 (s, 1 H, H6). C-NMR (CDCl3) δ : 54.2
(OCH3), 55.8 (CH2-O-CH3), 83.4, 96.8 (CH2), 113.5 (C3), 122.4, 126.2, 128.7 (2 Carom), 129.5 (Carom),
132.2 (2 Carom), 135.3 (C6), 135.8, 148.4, 159.6. MS (IS) m/z: 270 (M+1). Anal. Calcd for C16H15NO3 :
C, 71.36 ; H, 5.61 ; N, 5.20. Found : C, 71.12 ; H, 5.49 ; N, 5.08.
5-Hydroxy-2-methoxy-4-(2-phenylethynyl)pyridine (25)
A solution of compound (24) (2.60 g, 9.66 mmol) in 3 N hydrochloric acid (20 mL) and tetrahydrofuran
(15 mL) was heated at 60 °C for 3 h, cooled to rt and then extracted with ethyl acetate. The combined
organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 7/3) to provide
compound (25) (2.11 g, 77 %) as a brown solid : mp 118-119 °C (ether). IR (KBr) ν : 3100, 2965,
1605 cm-1. 1H-NMR (CDCl3 + D2O) δ : 3.88 (s, 3 H, OCH3), 6.78 (s, 1 H, H3), 7.33-7.40 (m, 3 H, Harom),
7.51-7.55 (m, 2 H, Harom), 7.92 (s, 1 H, H6). 13C-NMR (CDCl3) δ : 54.1 (OCH3), 81.4, 98.8, 111.6 (C3),

121.4, 121.9, 128.4 (2 Carom), 129.4 (Carom), 131.8 (2 Carom), 132.8 (C6), 147.3, 158.0. MS (IS) m/z: 226
(M+1). Anal. Calcd for C14H11NO2 : C, 74.65 ; H, 4.92 ; N, 6.22. Found : C, 74.49 ; H, 4.81 ; N, 6.08.
Methyl 5-methoxy-2-phenylfuro[2,3-c]pyridine-3-carboxylate (26)
A mixture of compound (25) (0.165 g, 0.74 mmol), sodium acetate (0.121 g, 1.47 mmol), potassium
carbonate (0.203 g, 1.47 mmol), copper(II) dichloride (0.375 g, 2.22 mmol) and palladium chloride
(0.010 g, 0.05 mmol) in methanol (10 mL) was vigorously stirred under carbon monoxide atmosphere at
rt for 3 h. After removal of the solvent, the residue was diluted with water and extracted with ethyl acetate.
The combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash
chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 9/1) to afford compound (26) (0.170
g, 82 %) as a yellow solid : mp 96-97 °C (pentane). IR (KBr) ν : 2953, 1726, 1586 cm-1.
1H-NMR (CDCl3) δ : 3.92 (s, 3 H, OCH3), 3.99 (s, 3 H, COOCH3), 7.29 (s, 1 H, H4), 7.49-7.52 (m, 3 H,
Harom), 8.03-8.07 (m, 2 H, Harom), 8.44 (s, 1 H, H7). 13C-NMR (CDCl3) δ : 51.8 (COOCH3), 54.2 (OCH3),
101.6 (C4), 108.0, 128.3 (2 Carom), 128.7, 129.1 (Carom), 129.8 (2 Carom), 131.3 (C7), 137.6, 147.6, 160.7,
163.7, 165.2. MS (IS) m/z: 284 (M+1). Anal. Calcd for C16H13NO4 : C, 67.84 ; H, 4.63 ;
N, 4.94. Found : C, 67.78 ; H, 4.50 ; N, 4.79.
3-Hydroxymethyl-5-methoxy-2-phenylfuro[2,3-c]pyridine (27)
To a suspension of lithium aluminum hydride (0.102 g, 2.67 mmol) in tetrahydrofuran
(10 mL) cooled at 0 °C, was added a solution of compound (26) (0.630 g, 2.23 mmol) in tetrahydrofuran
(10 mL). The reaction was stirred at rt for 1 h before being quenched with ethyl acetate (5 mL) and water
(5 mL). The reaction was filtered and washed with water. The organic layer was then dried over MgSO4
and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel
(eluent : petroleum ether/ethyl acetate, 7/3) to afford compound (27) (0.540 g, 95 %) as a white solid :
1
mp 145-146 °C (pentane). IR (KBr) ν : 3300 cm-1. H-NMR (CDCl3) δ : 3.93 (s, 3 H, OCH3), 4.89
(s, 2 H, CH2), 6.92 (s, 1 H, H4), 7.45-7.53 (m, 3 H, Harom), 7.84-7.88 (m, 2 H, Harom), 8.35 (s, 1 H, H7).
13C-NMR (CDCl3) δ : 54.2 (OCH3), 55.2 (CH2), 98.1 (C4), 113.9, 127.9 (2 Carom), 128.8 (Carom), 128.9
(2 Carom), 129.4, 130.1 (C7), 139.9, 147.8, 158.1, 159.9. MS (IS) m/z: 256 (M+1). Anal. Calcd for
C15H13NO3 : C, 70.58 ; H, 5.13 ; N, 5.13. Found : C, 70.18 ; H, 4.95 ; N, 4.98.
5-Methoxy-2-phenylfuro[3,2-c]pyridin-3-ylmethyl 4-toluenesulfonate (28)
A solution of p-toluenesulfonyl chloride (0.560 g, 2.93 mmol) in dichloromethane (6 mL) was added
dropwise to an ice cold solution of 27 (0.500 g, 1.96 mmol) and triethylamine (0.82 mL, 5.88 mmol) in
dichloromethane (12 mL). The solution was stirred for 24 h at rt, then the solvents were evaporated. The
residue was purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 9/1) to
afford compound (28) (0.305 g, 38 %) as a white solid : mp 55-56 °C (ether). IR (KBr) cm-1 ν : 1358,
1
1177 cm-1. H-NMR (CDCl3) : δ : 2.42 (s, 3 H, CH3), 3.67 (s, 3 H, OCH3), 4.82 (s, 2 H, CH2), 6.96 (s,

1 H, H4), 7.40 (d, J = 8.3 Hz, 2 H, Htosyl), 7.53-7.56 (m, 3 H, Harom), 7.77-7.80 (m, 2 H, Harom), 7.89 (d,
J = 8,3 Hz, 2 H, Htosyl), 8.42 (s, 1 H, H7). MS (IS) m/z: 410 (M+1). Anal. Calcd for C22H19NO5S :
C, 64.53 ; H, 4.68 ; N, 3.42. Found : C, 64.37 ; H, 4.55 ; N, 3.18.
2-(5-Methoxy-2-phenylfuro[2,3-c]pyridin-3-yl)acetonitrile (29)
To a solution of tosylate (28) (0.112 g, 0.24 mmol) in N,N-dimethylformamide (5 mL) at 0°C was added
potassium cyanide (0.029 g, 0.44 mmol). The solution which resulted was stirred at this temperature for
5 h. After dilution with water, the reaction mixture was extracted with ethyl acetate. The organic layer
was separated, washed with water (4 times) dried over MgSO4 and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (eluent : petroleum ether/ethyl acetate, 9/1) to afford
29 (0.041 g, 57 %) as a white solid : mp 164-165 °C (ether). IR (KBr) ν : 2946, 2249, 1618 cm-1.
1H-NMR (CDCl3) δ : 3.86 (s, 2 H, CH2), 3.98 (s, 3 H, OCH3), 6.96 (s, 1 H, H4), 7.52-7.55 (m, 3 H,
Harom), 7.70-7.73 (m, 2 H, Harom), 8.44 (s, 1 H, H7). 13C-NMR (CDCl3) δ : 13.7 (CH2), 54.2 (OCH3), 98.1
(C4), 103.5, 116.3, 120.4, 127.8 (2 Carom), 128.6, 129.2 (3 Carom), 130.5 (C7), 147.6, 160.1, 178.1.
MS (IS) m/z: 265 (M+1). Anal. Calcd for C16H12N2O2 : C, 72.72 ; H, 4.58 ; N, 10.60. Found : C, 72.60 ; H,
4.48 ; N, 10.49
N-[2-(5-Methoxy-2-phenylfuro[2,3-c]pyridin-3-yl)ethyl]acetamide (2)
A solution of compound (29) (0.08 g, 0.30 mmol) in acetic anhydride (4 mL) was hydrogenated over
Raney nickel (0.012 g) in the presence of sodium acetate (0.037 g, 0.45 mmol) for 12 h at 50 °C. The
reaction was cooled to rt and the catalyst was filtered on Celite and the filtrate concentrated in vacuo. The
residue was taken up in dichloromethane, washed with water and dried over MgSO4. After removal of the
solvent, the crude residue was chromatographed over silica gel (eluent : ethyl acetate) and purified by
recrystallization (pentane/ ether, 2/1) to afford 2 (0.070 g, 74 %) as a white solid : mp 157 - 158 °C.
1
IR (KBr) ν : 3295, 2949, 1644, 1619 cm-1. H-NMR (CDCl3) δ : 1.84 (s, 3 H, COCH3), 3.08
(t, J = 7.1 Hz, 2 H, CH2-CH2-N), 3.54 (td, J = 7.1 Hz, J = 5.4 Hz, 2 H, CH2-CH2-N), 3.93 (s, 3 H, OCH3),
6.16-6.19 (m, 1 H, NH), 6.83 (s, 1 H, H4), 7.41-7.52 (m, 3 H, Harom), 7.81-7.84 (m, 2 H, Harom), 8.34 (s,
13
1 H, H7). C-NMR (CDCl3) δ : 23.1 (COCH3), 24.3 (CH2-CH2-N), 38.9 (CH2-CH2-N), 54.1 (OCH3),
98.4 (C4), 111.9, 127.3 (2 Carom), 129.1 (C7), 129.3 (2 Carom), 129.9 (Carom), 130.0, 140.7, 147.6, 156.3,
159.7, 170.5 (CO). MS (IS) m/z: 311 (M+1). Anal. Calcd for C18H18N2O3 : C, 69.66; H, 5.85; N, 9.03.
Found : C, 69.37; H, 5.82; N, 8.92.
ACKNOWLEDGEMENTS
We are grateful to A.D.I.R. Company (Courbevoie, France) for its multiform support.
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