Synthesis of substituted oxazolo[4,5-b]-pyridine derivatives

Article abstract of DOI:10.3987/com-01-9213

Synthesis of new functionnalized oxazolo[4,5-b]pyridines was described. 5-Bromo-3-hydroxy-2-aminopyridine was heated, in the presence of PPSE or PPA, with 4-cyanobenzoic acid, (4-piperidinyl)acetic or propanoic acid to afford 1,3-oxazolo derivatives. Intr

Full text of DOI:10.3987/com-01-9213

HETEROCYCLES, Vol. 55, No. 7, 2001, pp. 1329 - 1345, Received, 30th March, 2001
SYNTHESIS OF SUBSTITUTED OXAZOLO[4,5-b]-
PYRIDINE DERIVATIVES
Valérie Grumel, Jean-Yves Mérour,* and Gérald Guillaumet
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université
*
d'Orléans, BP 6759, 45067 Orléans Cédex, France. Tel: (33) 238494592, Fax: (33)
238417281; e-mail jean-yves.merour@univ-orleans.fr
Abstract- Synthesis of new functionnalized oxazolo[4,5-b]pyridines was
described. 5-Bromo-3-hydroxy-2-aminopyridine was heated, in the presence of
PPSE or PPA, with 4-cyanobenzoic acid, (4-piperidinyl)acetic or propanoic acid
to afford 1,3-oxazolo derivatives. Introduction of a carboxylic acid moiety on the
pyridine framework was carried out using Heck reaction. The basic moiety, also
required for GPIIb/GPIIIa antagonism, was generated by guanylation.
In the search of new non-peptidic glycoprotein GPIIb/GPIIIa antagonists1,2 we have explored heterocyclic
scaffolds such as 1,4-benzoxazine or indole. In this paper we reported our results in the use of
oxazolo[4,5-b]pyridine as framework, having an acidic and a basic chains which may confer the
pharmacological properties to the desired molecules. Oxazolo[4,5-b]pyridines were usually obtained by
action of acid chloride3 or dithioketal4 on 2-amino-3-hydroxypyridine in a basic medium. Polyphosphoric
acid (PPA) or p-toluenesulfonic acid (PTSA) have been also used with aromatic carboxylic acid5-7 or
aliphatic acid8 to generate the oxazolo ring. For our own part, we have developped in our group9 a milder
synthesis using polyphosphoric acid trimethylsilyl ester (PPSE)10 instead of PPA. We planned to prepare
compounds (5) and (7) according to Scheme 1.
O
O
O
MeO
O
N
MeO
Br
CN
N
NHR
N
N
5 R = H
7 R = C(=NH)NH2
Br
OH
NH2
HO
O
O
+
CN
CN
N
N
N
Scheme 1

The starting material, 2-amino-5-bromo-3-hydroxypyridine (1) was not obtained by direct bromination of
2-amino-3-hydroxypyridine. In fact, oxazolo[4,5-b]pyridine-2(3H)-one11 which was a masked form of 2-
amino-3-hydroxypyridine was brominated according to our method12 (yield 90%); the oxazolone ring was
then hydrolyzed in basic medium to give compound (1) in 94 % yield (Scheme 2).
Br2, DMF
rt, 2 h
90%
10% NaOH
reflux, 8 h
Br
Br
O
N
OH
O
N
O
O
94%
NH2
N
N
N
H
H
1
Scheme 2
Formation of 1,3-oxazolo derivative (2) was obtained by heating pyridine (1) and 4-cyanobenzoic acid in
PPSE at 200°C in high yield (93 %) (Scheme 3).
R
Br
O
OH
PPSE
HO
200°C, 3 h
CN
+
CN
93%
N
NH2
O
N
N
2 R = Br
Pd(OAc)2
1
CH2=CH-COOMe
3 R = (E)CH=CH-COOMe
DMF
74%
Scheme 3
To introduce the acidic chain on the pyridine ring, a Heck reaction was performed between compound (2),
palladium acetate (1%), tri-o-tolylphosphine and methyl acrylate in DMF at reflux, for 24 h. Compound
(3) was obtained as an E isomer in 74% yield. Reduction of the double bond with hydrogen over
palladium on carbon, under 3 atm, in DMF, for 2 days afforded compound (4) in 88% yield.
Hydrogenation over Raney nickel of 4, under 35 atm in DMF, allowed the quantitative reduction of the
cyano group into the primary amino group (compound (5)), after 2 days (Scheme 4). This two-steps
procedure gave higher yield and easy purification than the one-step reduction of both the nitrile group and
ethylenic bond.
O
O
O
N
O
N
H2, Pd/C, 3 atm
DMF
MeO
MeO
R
CN
88%
N
N
4
R = CN
R = CH2NH2
H2, 35 atm
DMF, Raney Ni
3
5
100%
Scheme 4
In order to reinforce the basic character of the amino group and to mimic arginine residue, which was
involved in the binding with GPIIb/GPIIIa receptors, the guanylation of the amino group of 5 was
attempted. The use of 3,5-dimethyl-1-pyrazolecarboximidamide (6)13 gave an incomplete guanylation

reaction with difficulties to purify the desired compound (7), obtained as a nitrate salt (Scheme 5).
Me
O
EtOH, reflux, 20 h
< 10%
O
N
N
MeO
5
Me
+
N
NH
N
N
HN
NH2, HNO3
H
NH2, HNO3
6
7
Scheme 5
Reaction of 5 with N,N'-bis(tert-butoxycarbonyl)thiourea14,15 in presence of mercuric chloride and
triethylamine gave a mixture of two monoBoc derivatives and one diBoc derivative (9) in 15 and 18%
yields, respectively. Replacement of mercuric chloride with 2-chloro-N-methylpyridinium16 did not much
improved the yield of desired derivative (9) (22% yield), but the formation of monoBoc derivatives was
not observed in this case. Nevertheless we succeed in obtaining the diBoc derivative (9) by using the
method described by Miel and Rault.17,18 Thus treatment of 5 with N,N'-bis(tert-butoxycarbonyl)-S-
methylisothiourea (8) afforded 9 in excellent yield (91%) (Scheme 6).
O
HgCl2, Et3N
DMF, rt
91%
SMe
NBoc
O
N
5
MeO
+
NR
BocHN
N
N
H
NHR
8
9
R = Boc
R = H
1) SnCl4 , AcOEt
2) MeOH
7
71%
Scheme 6
Deprotection of the guanidino group of compound (9) was carried out using stannic chloride in ethyl
acetate,18 followed by treatment with methanol for 10 min. This procedure afforded directly in 71% yield
7 as hydrochloride salt, which was precipitated from the mixture by addition of ether.
In order to have more flexibility in the basic chain and also to modify the nature of the basic center, we
have decided to replace the guanidino group by a piperidino group. An other factor which was also of
interest was the distance between the oxazolo ring and the piperidino nitrogen atom. Thus we planned the
synthesis of 2-(2-piperidin-4-yl-alkyl)oxazolo[4,5-b]pyridine. For introducing the alkylpiperidino chain
we used the corresponding acids (11)19,20 and (12); (basic hydrolysis of ethyl 3-(1-benzyl-4-
piperidyl)propanoate (10) afforded acid (12). Oxazolo derivative (13) was obtained in only 22% yield,
from 11, by using PPSE at 200°C. The use of PPA instead of PPSE allowed us to obtain oxazolo
compounds (13) and (14), in 70 and 71% yields, respectively (Scheme 7). Introduction of ethyl
propenoate chain on the pyridine moiety was carried out using the same method as for 3. Heck reaction

between compounds (13) or (14) and methyl acrylate in presence of palladium acetate afforded
compounds (15) and (16), respectively in 70 and 88% yields.
Br
O
Br
OH
PPA, 130°C, 2 h
N
( )n
O
( )n
+
Ph
HO
N
N
NH2
N
1
N
11 n=1
12 n=2
Ph
13 n = 1 70%
14 n = 2 71%
Scheme 7
The hydrogenation of the double bond of 16 was achieved with palladium, under 2 atm of hydrogen, to
afford 17 in 83 % yield, without loss of the benzyl group (Scheme 8).
O
Br
O
N
Pd(OAc)2 , DMF
CH2=CH-COOMe
O
N
MeO
Ph
Ph
( )n
N
( )n
N
N
N
13, 14
15 n = 0 70% 16 n = 1 88 %
H2 2 atm
Pd/C, MeOH
O
O
MeO
Ph
N
N
N
83%
17
Scheme 8
All attempts of deprotection of the nitrogen atom in compound (17) were unfruitful. Hydrogenolysis over
palladium on carbon or Pd(OH)2, in ethyl acetate or acetic acid leave 17 unchanged; a large excess of
palladium on carbon afforded in an unreproductive manner compound (18) in 15-22% yield. Palladium
with ammonium formate gave a degradation of the mixture. 1-Chloroethyl chloroformate21-25 in 1,2-
dichloroethane followed by methanolysis afforded a mixture of the expected debenzylated product (18), in
26% yield and compound (19), resulting of an oxazolo ring opening, in 30% yield (Scheme 9). Structure
13
of 19 was in agreement, inter alia, with C NMR data which indicated two CO (ester group) with
chemical shift of 172.1 and 173.6 ppm respectively.
Benzyl group as protective group was inadequate, so we switched with the Boc group since we need to
protect nitrogen atom for performing the Heck reaction; but in the oxazolo ring synthesis the Boc group
did not survive during the PPA cyclization. Recently the reaction of 4-piperidinecarboxylic acid with 2-
aminophenol have been reported26 so we planned a such cyclization on 4-piperidinylacetic acid (20) or 3-
(4-piperidinyl)propanoic acid (21), followed by introduction of the Boc group.

O
O
N
MeO
ClCH2CH2Cl
reflux, 1 h
1)
N
H
N
O
Cl
2) SiO2/MeOH
reflux, 2 h
26%
18
17
+
Cl
O
+
O
H
N
O
MeO
O
N
NH2
19
30%
Scheme 9
Reaction of 1 with acids (20) and (21) afforded the oxazolo derivatives (22) and (23), in 42 and 53 %
yields, respectively (Scheme 10). These yields were lower than those obtained with the N-benzyl
protected acids (11) and (12).
Br
O
N
H
( )n
O
PPA, 140°C, 14 h
( )n
1
HO
+
N
N
n=1
n=2
20
21
N
R
R = H , 22 n = 1 (42%), 23 n = 2 (53%)
R = Boc, 24 n = 1 (78%), 25 n = 2 (63%)
Boc2O
rt, CHCl3
Scheme 10
Compounds (22) and (23) were reacted with Boc2O in chloroform to give derivatives (24) and (25)
respectively in 78 and 63 % yields. The desired compounds (18) and (28) were obtained using the same
methodology reported for compound (3) (Scheme 11).
Heck reaction, with palladium acetate in DMF and methyl acrylate, on compounds (24) and (25), followed
by hydrogenation of the double bond afforded compounds (26) and (27) in a two-steps overall yield of
59% and 54%, respectively. N-Boc protected derivatives (24) and (25) gave better yields in the Heck
reaction than for compounds (22) and (23). Clean cleavage of the Boc group was carried out with formic
acid at rt for 1 h, furnishing 18 and 28, respectively in 68 and 72% yields as formate salt.

O
1) Pd(OAc)2, DMF
CH2=CH-COOMe
2) H2 /Pd, MeOH , 2 atm
O
N
MeO
24, 25
( )n
N
N
R
R = Boc 26 n = 1 (59%), 27 n = 2 (54%)
R = H 28 n = 1 (72%), 18 n = 2 (68%)
HCOOH, rt
Scheme 11
This paper describes a new series of functionnalized oxazolo[4,5-b]pyridines with basic and acidic
appendages. Since benzoxazole analogues have been reported28 to possess activity as GPIIb/GPIIIa
antagonists these compounds can be considered as potential antithrombotics.
EXPERIMENTAL
Melting points were determined using a Büchi MSP-20 melting point apparatus and were uncorrected.
The IR spectra of compounds were recorded on a Perkin Elmer FT IR paragon 1000 spectrophotometer.
NMR spectra were recorded at 300°K in CDCl3 or DMSO-d6 on a Bruker Avance DPX 250. Chemical
shifts were expressed in parts per million and referenced to TMS. MS spectra were recorded on Perkin-
Elmer SCIEX API 300 using ionspray methodology. Thin layer chromatography was performed on
precoated plate of silica gel 60F254 (Merck) and the spots visualized using an ultraviolet lamp. Flash
chromatography was conducted on Merck silica gel 60 (0.040 mm-0.063 mm) as the stationary phase; the
ratio of eluents was indicated as volume. All air and moisture sensitive reactions were conducted under a
prepurified argon atmosphere. Anhydrous solvents or reagents were transferred via syringe.
2-Amino-5-bromo-3-hydroxypyridine (1)
A suspension of 6-bromooxazolo[4,5-b]pyridin-2(3H)-one11,12 (14.2 g, 66 mmol) in a 10% aqueous
sodium hydroxide solution (160 mL) was refluxed for 8 h. After cooling, addition of 10% aqueous HCl
solution gave a precipitate; the solid was filtered, washed with water and dried over phosphorus pentoxide
to afford 1 (11.9 g, 94%), mp > 250 °C. IR (KBr) ν (cm-1) : 3500-2900 (OH); 3450 and 3340 (NH2) .
1H NMR (DMSO-d6 + D2O) δ (ppm) 7.93 (d, 1H, H4, J = 2.0 Hz); 7.46 (d, 1H, H2, J = 2.0 Hz). MS (IS) :
m/z 189, 191 (MH+).
4-(6-Bromooxazolo[4,5-b]pyridin-2-yl)benzonitrile (2)
A solution of phosphorus pentoxide (15.77 g, 111 mmol) and hexamethyldisiloxane (40 mL, 185 mmol,
30.1 g) in dichloroethane (100 mL) was heated at reflux for 2 h. The solvent was evaporated and 2-amino-
5-bromo-3-hydroxypyridine (1) (5 g, 26 mmol) and 4-cyanobenzoic acid (5.74 g, 39 mmol) were added to

the residue. The mixture was heated for 3 h at 200°C. After cooling, ice and water were added and the pH
adjusted to 7-8 with a saturated aqueous solution of sodium hydrogencarbonate. The solid was filtered,
washed several times with water and dried over phosphorus pentoxide to give 2 (7.4 g, 93%) as yellow
solid, mp 239°C (EtOH). IR (KBr) ν (cm-1) : 2236 (C≡N). 1H NMR (CDCl3) δ (ppm) 7.88 (d, 2H, Harom, J
= 8.5 Hz); 8.12 (d, 1H, H7, J = 2.0 Hz); 8.44 (d, 2H, Harom, J = 8.5 Hz); 8.72 (d, 1H, H5, J = 2.0
Hz).13C NMR (CDCl3) δ (ppm) 115.1 (C); 116.0 (C); 117.0 (C); 120.7 (CH); 127.6 (2 CH); 129.0 (C);
132.0 (2 CH); 142.6 (C); 147.9 (CH); 153.7 (C); 163.1 (O-C=N). MS (IS) : m/z 300, 302 (MH+). Anal.
Calcd for C13H6N3OBr: C, 52.03; H, 2.02; N, 14.00. Found: C, 52.33; H, 2.14; N, 14.20.
Methyl (E)-3-[2-(4-Cyanophenyl)oxazolo[4,5-b]pyridin-6-yl]-2-propenoate (3)
Methyl acrylate (360 µL, 4 mmol, 344 mg), palladium acetate (8 mg, 0.033 mmol), tri-o-tolylphosphine
(41 mg, 0.13 mmol), triethylamine (560 µL, 4 mmol, 404 mg), were successively added to thebromide (2)
(1 g, 3.33 mmol) in DMF (40 mL). After refluxing for 24 h, the mixture was concentrated in vacuo and
dichloromethane was added to the residue. The organic layer was washed with brine and dried over
magnesium sulfate. Evaporation leave a residue which was purified by column chromatography (silica
gel, eluent : CH2Cl2/ MeOH, 95 : 5) to give 3 (750 mg, 74 %) as yellow solid, mp 155 °C (decomp)
1
(MeOH/H2O). IR (KBr) ν (cm-1) : 2221 (C≡N); 1734 (C=O). H NMR (CDCl3) δ (ppm) 3.86 (s, 3H,
OCH3); 6.69 (d, 1H, CO-CH=, J = 16.0 Hz); 6.84 (d, 1H, =CH, J = 16.0 Hz); 7.87 (dd, 2H, Harom, J = 6.7
Hz, J = 1.7 Hz); 8.06 (d, 1H, H7, J = 1.9 Hz); 8.45 (dd, 2H, Harom, J = 6.7, 1.7 Hz); 8.78 (d, 1H, H5, J =
1.9 Hz). 13C NMR δ (ppm) 52.3 (OCH3); 115.3 (C); 116.1 (CH); 117.2 (C); 120.5 (CH); 126.1 (C);127.7
(2 CH); 129.1 (C); 132.2 (2 CH); 141.3 (CH); 142.9 (C); 148.0 (CH); 153.8 (C); 163.3 (O-C=N), 170.2
(C=O). MS (IS) : m/z 306 (MH+). Anal. Calcd for C17H11N3O3: C, 66.88; H, 3.63; N, 13.76. Found: C,
67.26; H, 3.49; N,13.57.
Methyl 3-[2-(4-Cyanophenyl)oxazolo[4,5-b]pyridin-6-yl]propanoate (4)
A suspension of compound (3) (600 mg, 1.97 mmol) and 10% Pd/C (60 mg) in DMF (60 mL) was shaken
for 2 days at rt under 3 atm of hydrogen in a Parr apparatus. After filtration over a pad of celite the solvent
was evaporated to leave a solid which was purified by column chromatography (silica gel, eluent : CH2Cl2
/ MeOH, 97 : 3) to give 4 (530 mg, 88%) as yellow solid, mp 182 °C (MeOH). IR (KBr) ν (cm-1) : 2228
1
(C≡N); 1737 (C=O). H NMR (CDCl3) δ (ppm) 2.73 (t, 2H, CH2, J = 7.4 Hz); 3.14 (t, 2H, CH2, J = 7.4
Hz); 3.68 (s, 3H, OCH3); 7.80 (d, 1H, H7, J = 1.5 Hz); 7.83 (d, 2H, Harom, J = 8.3 Hz); 8.40 (d, 2H, Harom
,
13
J = 8.3 Hz); 8.50 (d, 1H, H5, J = 1.5 Hz). C NMR (CDCl3) δ (ppm) 29.6 (CH2); 36.8 (CH2); 53.2
(OCH3); 116.8 (C); 119.3 (C); 119.9 (CH); 129.7 (2 CH); 131.8 (C); 134.1 (2 CH); 135.7 (C);
144.7 (C); 149.2 (CH); 155.8 (C); 164.6 (O-C=N); 173.9 (C=O). MS (IS) : m/z 308 (MH+). Anal. Calcd
for C17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.35; H, 4.14; N, 13.51.

Methyl 3-{2-[4-(Aminomethyl)phenyl]oxazolo[4,5-b]pyridin-6-yl}propanoate (5)
A suspension of compound (4) (100 mg, 0.33 mmol) and Raney nickel (30 mg) in DMF (30 mL) was
shaken under 35 atm of hydrogen. After 48 h at rt the mixture was filtered and the solvent evaporated. The
residue was purified by column chromatography (silica gel, eluent : CH2Cl2 / MeOH / 30% NH4OH, 100 :
10 : 1) to give 5 (100 mg, 100%) as yellow solid, mp 160 °C (decomp) (EtOH/H2O). IR (KBr) ν (cm-1) :
3345 and 3196 (NH2); 1732 (C=O). 1H NMR (CDCl3) δ (ppm) 1.66 (br s, 2H, NH2); 2.74 (t, 2H, CH2, J =
7.4 Hz); 3.14 (t, 2H, CH2, J = 7.4 Hz); 3.70 (s, 3H, OCH3); 4.00 (s, 2H, NCH2); 7.51 (d, 2H, Harom, J = 8.2
Hz); 7.75 (d, 1H, H7, J = 1.6 Hz); 8.28 (d, 2H, Harom, J = 8.2 Hz); 8.45 (d, 1H, H5, J = 1.6 Hz). 13C NMR
(CDCl3) δ (ppm) 28.7 (CH2); 36.0 (CH2); 46.6 (CH2); 52.2 (OCH3); 118.3 (CH); 125.4 (C); 128.0 (2 CH);
128.7 (2 CH); 133.5 (C); 141.9 (C); 147.3 (CH); 148.3 (C); 155.5 (C); 165.9 (O-C=N); 171.5 (C=O). MS
(IS) : m/z 312 (MH+). Anal. Calcd for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.92; H, 5.44;
N, 13.65.
Methyl 3-{2-[4-({[Amino(imino)methyl]amino}methyl)phenyl]oxazolo[4,5-b]pyridin-6-
yl}propanoate (7) hydrochloride
To a solution of di-Boc derivative (9) (360 mg, 0.65 mmol) in ethyl acetate (5 mL), stannic tetrachloride
(300 µL, 2.6 mmol, 677 mg) was added and the mixture stirred at rt for 2 h. Methanol was added andafter
stirring for 10 min the hydrochloride salt of 7 was precipitated by addition of ether. Filtration afforded 7,
HCl (180 mg, 71%) as white solid, mp 216 °C (decomp) (EtOH). IR (KBr) ν (cm-1) : 3331 and 3165
(NH2, NH); 1750 (C=O). 1H NMR (CD3OD) δ (ppm) 2.82 (t, 2H, CH2, J = 7.4 Hz); 3.18 (t, 2H, CH2, J =
7.4 Hz); 3.68 (s, 3H, OCH3); 4.59 (d, 2H, NCH2, J = 6.0 Hz); 7.61 (d, 2H, Harom, J = 8.4 Hz); 8.14 (d, 1H,
H7, J = 1.7 Hz); 8.36 (d, 2H, Harom, J = 8.4 Hz); 8.49 (d, 1H, H5, J = 1.7 Hz). 13C NMR (CD3OD) δ (ppm)
25.7 (CH2); 32.9 (CH2); 42.2 (CH2); 49.2 (OCH3); 118.0 (CH); 123.3 (C); 125.7 (2 CH); 126.3 (2 CH);
132.9 (C); 139.9 (C); 143.6 (C); 143.8 (CH); 151.5 (C); 155.5 (N-C(NH)); 164.1 (O-C=N); 171.7 (C=O).
MS (IS) : m/z 354 (MH+). Anal. Calcd for C18H19N5O3, HCl: C, 55.46; H, 5.17; N, 17.96. Found: C,
55.06; H, 5.33; N, 18.17.
Methyl 3-(2-{4-[({[(tert-Butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-
amino)methyl]phenyl}oxazolo[4,5-b]pyridin-6-yl)propanoate (9)
Triethylamine (360 µL, 2.56 mmol, 259 mg), N, N'-bis-(tert-butoxycarbonyl)-S-methylisothiourea (8)17,18
(339 mg, 1.17 mmol), mercuric chloride (333 mg, 1.22 mmol) were added to a solution of amine (5) (400
mg, 1.28 mmol) in DMF (25 mL). After stirring for 4.5 h at rt ethyl acetate (50 mL) was added and the
mixture was filtered over celite. The filtrate was washed successively with a 5% aqueous solution of
sodium hydrogencarbonate, water and brine. The organic layer was dried over magnesium sulfate and
evaporated. The residue was purified by column chromatography (silica gel, eluent : CH2Cl2 / MeOH,

99 : 1) to give 9 (590 mg, 91%) as white solid, mp 104 °C (decomp) (EtOH/H2O). IR (KBr) ν (cm-1) :
3322 (NH); 1742 (C=O); 1652 (C=O). 1H NMR (CDCl3) δ (ppm) 1.49 (s, 18H, 2 t-Bu); 2.73 (t, 2H, CH2,
J = 7.3 Hz); 3.14 (t, 2H, CH2, J = 7.3 Hz); 3.69 (s, 3H, OCH3); 4.75 (d, 2H, NCH2, J = 5.4 Hz); 7.49 (d,
2H, Harom, J = 8.2 Hz); 7.76 (d, 1H, H7, J = 1.6 Hz); 8.28 (d, 2H, Harom, J = 8.2 Hz); 8.45 (d, 1H, H5, J =
13
1.6 Hz); 8.75 (br s, 1H, NH); 11.57 (sl, 1H, NH). C NMR (CDCl3) δ (ppm) 28.4 (CH2 and C(CH3)3);
28.7 (C(CH3)3); 35.9 (CH2); 46.8 (CH2); 52.2 (OCH3); 82.8 (C(CH3)3); 83.9 (C); 118.6 (CH); 126.1 (C);
128.5 (2 CH); 128.8 (2 CH); 133.7 (C); 142.5 (C); 143.6 (C); 147.3 (CH); 153.6 (C); 155.4 (N-C=O);
156.7 (N-C=O); 163.8 (N-C-NBoc); 165.7 (O-C=N); 173.0 (C=O). MS (IS) : m/z 554.5 (MH+). Anal.
Calcd for C28H35N5O7: C, 60.75; H, 6.37; N, 12.65. Found: C, 60.48; H, 6.46; N, 12.80.
Ethyl 3-(1-Benzyl-4-piperidyl)propanoate (10)
Same procedure as for ethyl 2-(1-benzyl-4-piperidyl)acetate,19 starting from ethyl 2-(4-
piperidyl)propanoate (7.32 g, 39.5 mmol); oil; (8.72 g, 81%). IR (film) ν (cm-1) : 1735 (C=O).1H NMR
(CDCl3) δ (ppm) 1.21-1.27 (m, 6H, H3a-5a, H4, CH3); 1.52-1.65 (m, 4H, H3b-5b and CH2-CH2CO); 1.87-
1.96 (m, 2H, H2a-6a); 2.27-2.33 (m, 2H, CH2CO); 2.84-2.89 (m, 2H, H2b-6b); 3.47 (s, 2H, N-CH2Ph); 4.12
(q, 2H, O-CH2, J = 7.2 Hz); 7.21-7.29 (m, 5H, Ph). MS (IS) : m/z 276 (MH+). Anal. Calcd for
C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.42; H, 9.01; N, 5.13
3-(1-Benzyl-4-piperidyl)propanoic acid (12)
A solution of compound (10) (3.03 g, 11 mmol) in methanol (12 mL) and a 1N aqueous solution of
sodium hydroxide (33 mL, 33 mmol) were stirred at rt for 12 h. After evaporation, the crude residue was
dissolved in water and the pH adjusted to 4-5. Extraction with dichloromethane, drying over magnesium
sulfate and evaporation leave a yellow solid, (2.25 g, 79%), mp 78 °C (EtOH). IR (KBr) ν (cm-1) : 3500-
1
2900 (OH); 1731 (C=O). H NMR (CDCl3 + D2O) δ (ppm) 1.45-1.57 (m, 2H, H3a-5a); 1.60-1.75 (m, 3H,
H4, CH2-CH2CO); 1.95-2.05 (m, 2H, H3b-5b); 2.34-2.41 (m, 2H, CH2CO); 2.99-3.09 (m, 2H, H2a-6a); 3.47-
3.53 (m, 2H, H2b-6b); 4.34 (s, 2H, NCH2-Ph); 7.45-7.62 (m, 5H, Ph). MS (IS) : m/z 248 (MH+). Anal.
Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.50; H, 8.67; N, 5.49.
2-[(1-Benzyl-4-piperidinyl)methyl]-6-bromooxazolo[4,5-b]pyridine (13)
2-Amino-5-bromo-3-hydroxypyridine (1) (140 mg, 0.74 mmol) and acid (11)20 (250 mg, 1.11 mmol) in
PPA (1 g) were heated at 130°C for 2 h. After cooling, ice was added and the pH adjusted to 7-8 with a
saturated solution of sodium hydrogencarbonate. Extraction with dichloromethane, drying over
magnesium sulfate and evaporation leave a residue. Purification by column chromatography (silica gel,
eluent : CH2Cl2 / MeOH, 95 : 5) afforded 13 (200 mg, 70%) as solid, mp 165 °C (EtOH/H2O). IR (KBr) ν
1
(cm-1) : 1604 (C=N). H NMR (CDCl3) δ (ppm) 1.38-1.54 (m, 2H, H3’a-5’a); 1.74-1.80 (m, 2H, H3’b-5’b);
1.80-2.10 (m, 3H, H2’a-6’a , H4’); 2.87-2.91 (m, 2H, H2’b-6’b); 2.91 (d, 2H,CH2C=N, J = 7.1 Hz); 3.51 (s,

2H, NCH2Ph); 7.26-7.32 (m, 5H, Ph); 7.93 (d, 1H, H7, J = 2.0 Hz); 8.59 (d, 1H, H5, J = 2.0 Hz).
13C NMR (CDCl3) δ (ppm) 32.5 (2 CH2); 34.9 (CH); 36.1 (CH2); 53.7 (2 CH2); 63.7 (CH2); 115.8 (C);
121.3 (CH); 127.4 (CH); 128.6 (2 CH); 129.5 (2 CH); 138.7 (C); 143.5 (C); 147.6 (CH); 155.1 (C); 170.5
(O-C=N). MS (IS) : m/z 386, 388 (MH+). Anal. Calcd for C19H20N3OBr: C, 59.08; H, 5.22; N, 10.88.
Found: C, 59.45; H, 5.36; N, 11.03.
2-[(1-Benzyl-4-piperidinyl)ethyl]-6-bromooxazolo[4,5-b]pyridine (14)
Same procedure as for 13 starting from acid (12) (1.96 g, 7.96 mmol). Solid, (1.51 g, 71%), mp 146 °C
(EtOH/H2O). IR (KBr) ν (cm-1) : 1605 (C=N). 1H NMR (CDCl3) δ (ppm) 1.28-1.39 (m, 3H, H3’a-5’a , H4’);
1.72-1.76 (m, 2H, H3’b-5’b); 1.83-2.01 (m, 4H, H2’a-6’a, CH2-CH2C=N); 2.89-2.94 (m, 2H, H2’b-6’b); 3.01 (t,
2H, CH2C=N, J = 7.5 Hz); 3.52 (s, 2H, NCH2Ph); 7.23-7.33 (m, 5H, Ph); 7.94 (d, 1H, H7, J = 2.0 Hz);
13
8.59 (d, 1H, H5, J = 2.0 Hz). C NMR (CDCl3) δ (ppm) 26.8 (CH2); 32.3 (2 CH2); 33.3 (CH); 35.5
(CH2); 54.0 (2 CH2); 63.8 (CH2); 115.7 (C); 121.2 (CH); 127.3 (CH); 128.5 (2 CH); 129.6 (2 CH); 138.8
(C); 143.5 (C); 147.6 (CH); 155.1 (C); 171.7 (O-C=N). MS (IS) : m/z 400 and 402 (MH+). Anal. Calcd
for C20H22N3OBr: C, 60.01; H, 5.54; N, 10.50. Found: C, 59.85; H, 5.39; N, 10.41.
Methyl (E)-3-{2-[(1-Benzyl-4-piperidinyl)methyl]oxazolo[4,5-b]pyridin-6-yl}-2-propenoate (15)
Methyl acrylate (45 µL, 0.52 mmol, 44 mg), palladium acetate (6 mg, 0.026 mmol), tri-o-tolylphosphine
(32 mg, 0.10 mmol), triethylamine (70 µL, 0.52 mmol, 52 mg), were sucessively added to the bromide
(13) (100 mg, 0.26 mmol) in DMF (3 mL). After refluxing for 24 h, the mixture was concentrated in
vacuo and dichloromethane was added to the residue. The organic layer was washed with brine and dried
over magnesium sulfate. Evaporation leave a residue which was purified by column chromatography
(silica gel, eluent : CH2Cl2/ MeOH, 95 : 5) to afford 15 (70 mg, 70 %) as brown solid, mp 152 °C
(EtOH/H2O). IR (KBr) ν (cm-1) : 1710 (C=O); 1605 (C=N). 1H NMR (CDCl3) δ (ppm) 1.49-1.59 (m, 2H,
H3’a-5’a); 1.62-1.67 (m, 1H, H4’); 1.78-1.83 (m, 2H, H3’b-5’b); 2.01-2.09 (m, 2H, H2’a-6’a); 2.91-2.96 (m, 2H,
H2’b-6’b); 2.97 (d, 2H, CH2-C=N, J = 7.0 Hz); 3.54 (s, 2H, NCH2Ph); 3.87 (s, 3H, OCH3); 6.54 (d, 1H,
=CH-CO, J = 16.0 Hz); 7.29-7.35 (m, 5H, Ph); 7.83 (d, 1H, CH=, J = 16.0 Hz); 7.93 (d, 1H, H7, J = 1.8
Hz); 8.69 (d, 1H, H5, J = 1.8 Hz). 13C NMR (CDCl3) δ (ppm) 32.4 (2 CH2); 34.7 (CH); 35.9 (CH2); 52.4
(OCH3); 53.6 (2 CH2); 63.5 (CH2); 115.7 (CH); 120.3 (CH); 127.3 (CH); 127.5 (C); 128.4 (2 CH); 129.5
(2 CH); 138.6 (C); 141.4 (CH); 143.5 (C); 147.6 (CH); 155.5 (C); 168.5 (O-C=N); 172.4 (C=O). MS
(IS) : m/z 392 (MH+). Anal. Calcd for C23H25N3O3: C, 70.57; H, 6.44; N, 10.73. Found: C, 70.24; H, 6.45;
N, 10.92.
Methyl (E)-3-{2-[(1-Benzyl-4-piperidinyl)ethyl]oxazolo[4,5-b]pyridin-6-yl}-2-propenoate (16)
Same procedure as for 15, starting from bromide (14) (900 mg, 2.37 mmol). Brown solid, (850 mg, 88 %),
1
mp 136 °C (EtOH/H2O). IR (KBr) ν (cm-1) : 1707 (C=O); 1603 (C=N). H NMR (CDCl3) δ (ppm) 1.40-

1.53 (m, 3H, H3’a-5’a, H4’); 1.77-1.81 (m, 2H, H3’b-5’b); 1.91-2.11 (m, 4H, H2’a-6’a and CH2); 2.95-3.03
(m, 2H, H2’b-6’b); 3.05 (t, 2H, CH2-C=N, J = 7.5 Hz); 3.67 (s, 2H, N-CH2Ph); 3.87 (s, 3H, OCH3); 6.54 (d,
1H, =CH-CO, J = 16.0 Hz); 7.33-7.43 (m, 5H, Ph); 7.82 (d, 1H, CH=, J = 16.0 Hz); 7.93 (d, 1H, H7, J =
13
1.6 Hz); 8.69 (d, 1H, H5, J = 1.6 Hz). C NMR(CDCl3) δ (ppm) 27.0 (CH2); 32.3 (2 CH2); 33.4 (CH2);
35.5 (CH); 52.3 (OCH3); 54.0 (2 CH2); 63.8 (CH2); 115.7 (CH); 119.9 (CH); 127.4 and 127.5 (CH and
C); 128.5 (2 CH); 129.6 (2 CH); 138.7 (C); 141.5 (CH); 143.6 (C); 147.6 (CH); 157.8 (C); 167.1 (O-
C=N); 172.9 (C=O). MS (IS) : m/z 406 (MH+). Anal. Calcd for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.42; H, 6.58; N, 10.52.
Methyl 3-{2-[(1-Benzyl-4-piperidinyl)ethyl]oxazolo[4,5-b]pyridin-6-yl}propanoate (17)
A suspension of compound (16) (400 mg, 0.99 mmol) and 10% Pd/C (40 mg) in methanol (10 mL) was
shaken under 2 atm of hydrogen in a Parr apparatus. After 24 h at rt the catalyst was filtered off and the
solution evaporated. The residue was purified by column chromatography (silica gel, eluent : CH2Cl2 /
MeOH, 95 : 5) to afford 17 (335 mg, 83%) as grey solid, mp 124 °C (MeOH/H2O). IR (KBr) ν (cm-1) :
1
1730 (C=O); 1607 (C=N). H NMR (CDCl3) δ (ppm) 1.29-1.34 (m, 3H, H3’a-5’a, H4’); 1.70-1.74 (m, 2H,
H3’b-5’b); 1.80-1.88 (m, 2H, CH2); 1.91-1.99 (m, 2H, H2’a-6’a); 2.68 (t, 2H, CH2, J = 7.5 Hz); 2.87-2.92 (m,
2H, H2’b-6’b); 2.97 (t, 2H, CH2, J = 7.5 Hz); 3.08 (t, 2H, CH2, J = 7.5 Hz); 3.50 (s, 2H, NCH2Ph); 3.66 (s,
3H, OCH3); 7.23-7.31 (m, 5H, Ph); 7.63 (d, 1H, H7, J = 1.7 Hz); 8.37 (d, 1H, H5, J = 1.7 Hz). 13C NMR
(CDCl3) δ (ppm) 26.7 (CH2); 28.5 (CH2); 32.1 (2 CH2); 33.3 (CH2); 35.3 (CH); 35.9 (CH2); 52.2 (OCH3);
53.9 (2 CH2); 63.7 (CH2); 118.2 (CH); 127.4 (CH); 128.5 (2 CH); 129.7 (2 CH); 133.1 (C); 138.2 (C);
143.3 (C); 146.6 (CH); 154.8 (C); 170.7 (O-C=N); 173.0 (C=O). MS (IS) : m/z 408 (MH+). Anal. Calcd
for C24H29N3O3: C, 70.74; H, 7.17; N, 10.31. Found: C, 70.53; H, 6.99; N, 10.48.
Methyl 3-{2-[2-(4-Piperidinyl)ethyl]oxazolo[4,5-b]pyridin -6-yl}propanoate (18)
A suspension of compound (17) (50 mg, 0.12 mmol) and 10% Pd/C (130 mg) in acetic acid (2 mL) was
shaken under 1 atm of hydrogen in a Parr apparatus. After 3 days at rt the catalyst was filtered and the
solution evaporated. The residue was purified by column chromatography (silica gel, eluent : CH2Cl2 /
MeOH / NH4OH 30%, 100 : 20 : 2) to afford 18 (10 mg, 26%) as brown solid, mp 96 °C (decomp)
(MeOH/H2O). IR (KBr) ν (cm-1) : 3429 (NH); 1727 (C=O); 1604 (C=N). 1H NMR (CDCl3) δ (ppm) 1.26-
1.35 (m, 2H, H3’a-5’a); 1.47-1.55 (m, 1H, H4’); 1.77-1.83 (m, 2H, H3’b-5’b); 1.89 (t, 2H, CH2, J = 7.3 Hz);
2.40 (br s, 1H, NH); 2.58 - 2.67 (m, 2H, H2’a-6’a); 2.70 (t, 2H, CH2, J = 7.5 Hz); 3.00 (t, 2H, CH2, J = 7.5
Hz); 3.10 (t, 2H, CH2, J = 7.3 Hz); 3.12-3.18 (m, 2H, H2’b-6’b); 3.68 (s, 3H, OCH3); 7.64 (d, 1H, H7, J =
1.8 Hz); 8.39 (d, 1H, H5, J = 1.8 Hz). 13C NMR (CDCl3) δ (ppm) 26.1 (CH2); 28.1 (CH2); 28.2 (2 CH2);
33.4 (CH2); 35.2 (CH); 35.6 (CH2); 46.1 (2 CH2); 51.8 (OCH3); 117.8 (CH); 132.7 (C); 143.0 (C); 146.4

(CH); 154.6 (C); 170.2 (O-C=N); 172.6 (C=O). MS (IS) : m/z 318 (MH+). Anal. Calcd for C17H23N3O3:
C, 64.33; H, 7.30; N, 13.24. Found: C, 64.68; H, 7.26; N, 13.14.
18, HCOOH was directly obtained from 27 using the same procedure as for compound (28); (100 mg,
68%); solid, mp 96 °C (MeOH).
Methyl 3-(6-Amino-5-{[3-(4-piperidyl)propanoyl]oxy}-3-pyridyl)propanoate (19)
To a solution of 17 (100 mg, 0.25 mmol) in refluxing dichloroethane (2 mL) was added ethyl 1-
chloroethyl chloroformate (39 µL, 0.27 mmol, 38 mg). After stirring for 1 h at reflux, methanol (1 mL)
and silica gel (100 mg) were added. After stirring for 2 h at reflux the mixture was evaporated and
purified by column chromatography (silica gel, eluent : CH2Cl2 / MeOH / 30% NH4OH, 100 : 10 : 1 then
100 : 20 : 2); two solids were obtained: 18, (20 mg, 26%) and 19, (25 mg, 30%), mp 174 °C (decomp)
1
(AcOEt). IR (KBr) ν (cm-1) : 3405 (NH2); 3133 (NH); 1728 (C=O). H NMR (CD3OD) δ (ppm) 1.31-
1.49 (m, 2H, H3’a-5’a); 1.67-1.77 (m, 3H, piperidyl-CH2, H4’); 2.00-2.05 (m, 2H, H3’b-5’b); 2.59 (t, 2H,
piperidyl-CH2-CH2, J = 7.2 Hz); 2.68 (t, 2H, CH2CH2CO, J = 7.5 Hz); 2.92 (t, 2H, CH2CO, J = 7.5 Hz);
2.96-3.08 (m, 2H, H2’a-6’a); 3.39-3.45 (m, 2H, H2’b-6’b); 3.70 (s, 3H, OCH3); 7.22 (s, 1H, H4); 7.79 (s, 1H,
13
H6). C NMR (CD3OD) δ (ppm) 26.0 (CH2); 27.2 (CH2); 28.8 (2 CH2); 31.5 (CH2); 33.4 (CH); 35.9
(CH2); 44.2 (2 CH2); 51.1 (OCH3); 119.5 (CH); 125.8 (CH); 139.4 (C); 142.5 (C); 149.6 (C); 172.1
(C=O); 173.6 (C=O). MS (IS) : m/z 336 (MH+). Anal. Calcd for C17H25N3O4: C, 60.88; H, 7.51; N, 12.53.
Found: C, 60.52; H, 7.67; N, 12.44.
3-(4-Piperidyl)propanoic Acid (21)29,30
Ethyl 3-[1-(tert-Butoxycarbonyl)-4-piperidyl]propanoate
To a solution of ethyl 3-(4-piperidyl)propanoate (3.66 g, 19.8 mmol) in dioxane / water (1 : 1) (40 mL)
were added triethylamine (8.3 mL, 59,2 mmol, 5.99 g) and di-tert-butyloxycarbonyl carbonate (6.03 g,
27.6 mmol). After stirring for 96 h at rt the solvent was evaporated to leave a residue; water was added
and the mixture extracted with ethyl acetate. Drying over magnesium sulfate and evaporation leave an oil;
(5.5 g, 97%). IR (film) ν (cm-1) : 1735 (C=O); 1695 (C=O). 1H NMR (CDCl3) δ (ppm) 1.03-1.18 (m, 2H,
H3a-5a); 1.27 (t, 3H, CH3, J = 7.1 Hz); 1.37-1.42 (m, 1H, H4); 1.46 (s, 9H, t-Bu); 1.58-1.64 (m, 2H, CH2);
1.68-1.78 (m, 2H, H3b-5b); 2.33 (t, 2H, CH2-CO, J = 7.4 Hz); 2.62-2.72 (m, 2H, H2a-6a); 4.06-4.12 (m, 2H,
H2b-6b); 4.15 (q, 2H, O-CH2, J = 7.1 Hz). MS (IS) : m/z 286 (MH+).
3-[1-(tert-Butoxycarbonyl)-4-piperidyl]propanoic Acid
A solution of ethyl 3-[1-(tert-butoxycarbonyl)-4-piperidyl]propanoate (5 g, 17.5 mmol) in ethanol (20
mL) and aqueous 1N sodium hydroxide (52.5 mL, 52.5 mmol) was stirred for 12 h at rt; after evaporation,
the residue was taken in water. Washing with ether was followed by acidification of the aqueous layer;
extraction with ether gave after drying over magnesium sulfate and evaporation a white solid; (4.1 g,

1
91%), mp 123 °C. IR (KBr) ν (cm-1) : 2900-3500 (OH); 1726 (C=O); 1623 (C=O). H NMR (CDCl3 +
D2O) δ (ppm) 1.02-1.18 (m, 2H, H3a-5a); 1.36-1.41 (m, 1H, H4); 1.45 (s, 9H, t-Bu); 1.56-1.62 (m, 2H,
CH2); 1.63-1.68 (m, 2H, H3b-5b); 2.39 (t, 2H, -CH2-CO, J = 7.4 Hz); 2.62-2.72 (m, 2H, H2a-6a); 4.06-4.11
(m, 2H, H2b-6b). MS (IS) : m/z 258 (MH+).
3-(4-Piperidyl)propanoic Acid
A solution of 3-[1-(tert-butoxycarbonyl)-4-piperidyl]propanoic acid (700 mg, 2.72 mmol) in dioxan (5
mL) containing 4N HCl was stirred for 1 h at 0°C. Ethyl acetate was added to the mixture and a solid
precitated. After filtration, a white solid (525 mg, 99 %) was obtained, mp 242 °C (lit.,28 244 °C). IR
1
(KBr) ν (cm-1) : 3500-2900 (OH); 3426 (NH); 1723 (C=O). H NMR (CD3OD) δ (ppm) 1.12-1.28 (m,
3H, H3a-5a, H4); 1.33-1.42 (m, 2H, CH2); 1.63-1.68 (m, 2H, H3b-5b); 2.15 (t, 2H, CH2-CO, J = 7.4 Hz);
13
2.70-2.82 (m, 2H, H2a-6a); 3.16-3.21 (m, 2H, H2b-6b). C NMR (CD3OD) δ (ppm) 28.7 (2 CH2); 30.7
(CH2); 30.9 (CH2); 33.3 (CH); 44.2 (2 CH2); 174.5 (C=O). MS (IS) : m/z 158 (MH+).
6-Bromo-2-(4-piperidinylmethyl)oxazolo[4,5-b]pyridine (22)
A mixture of 2-amino-5-bromo-3-hydroxypyridine (1) (490 mg, 2.60 mmol) and acid (20)27 (560 mg, 3.90
mmol) in PPA (4 g) was stirred for 14 h at 140°C. After cooling, ice was added and pH adjusted to 12
with 5% aqueous sodium hydroxide. Extraction with dichloromethane, drying over magnesium sulfate
and evaporation leave a residue which was purified by column chromatography (silica gel, eluent :
CH2Cl2 / MeOH /30% NH4OH, 100 : 20 : 2) to give 22 (320 mg, 42%) as grey solid, mp 184°C (EtOH).
IR (KBr) ν (cm-1) : 3373 (NH); 1601 (C=N). 1H NMR (CDCl3) δ (ppm) 1.20-1.35 (m, 2H, H3’a-5’a); 1.73-
1.77 (m, 2H, H3’b-5’b); 1.88-1.94 (m, 1H, H4’); 2.23 (br s, 1H, NH); 2.58-2.68 (m, 2H, H2’a-6’a); 2.88 (d,
2H, CH2-C=N, J = 7.1 Hz); 3.04-3.09 (m, 2H, H2’b-6’b); 7.92 (d, 1H, H7, J = 2.0 Hz); 8.56 (d, 1H, H5, J =
2.0 Hz). 13C NMR (CDCl3) δ (ppm) 34.0 (2 CH2); 35.8 (CH); 37.1 (CH2); 49.2 (2 CH2); 116.3 (C); 121.8
(CH); 144.0 (C); 148.1 (CH); 155.5 (C); 170.8 (O-C=N). MS (IS) : m/z 296 and 298 (MH+). Anal. Calcd
for C12H14N3OBr: C, 48.67; H, 4.76; N, 14.19. Found: C, 48.32; H, 4.70; N, 14.35.
6-Bromo-2-[2-(4-piperidinyl)ethyl]oxazolo[4,5-b]pyridine (23)
Same procedure as for 22 starting from acid (21)29,30 (526 mg, 2.72 mmol). Solid, (300 mg, 53%), mp 166 °C
1
(EtOH). IR (KBr) ν (cm-1) : 3429 (NH); 1600 (C=N). H NMR (CDCl3) δ (ppm) 1.09-1.25 (m, 2H,
H3’a-5’a); 1.42-1.52 (m, 1H, H4’); 1.72-1.77 (m, 2H, H3’b-5’b); 1.85 (q, 2H, CH2-CH2-C=N, J = 7.5 Hz);
2.53-2.63 (m, 3H, H2’a-6’a, NH); 3.01 (t, 2H, CH2-C=N, J = 7.5 Hz); 3.05-3.11 (m, 2H, H2’b-6’b); 7.93 (d,
13
1H, H7, J = 2.2 Hz); 8.59 (d, 1H, H5, J = 2.2 Hz). C NMR (CDCl3) δ (ppm) 26.2 (CH2); 33.4 (2 CH2);
33.5 (CH2); 35.6 (CH); 46.6 (2 CH2); 115.4 (C); 120.9 (CH); 143.2 (C); 147.3 (CH); 154.7 (C); 171.3 (O-
C=N). MS (IS) : m/z 310, 312 (MH+). Anal. Calcd for C13H16N3OBr: C, 50.34; H, 5.20; N, 13.55. Found:
C, 50.31; H, 5.04; N, 13.72.

tert-Butyl 4-[2-(6-Bromooxazolo[4,5-b]pyridin-2-yl)methyl]-1-piperidinecarboxylate (24)
A solution of compound (22) (250 mg, 0.84 mmol), diisopropylethylamine (320 µL, 1.85 mmol, 240 mg),
di-tert-butyl dicarbonate (370 mg, 1.69 mmol) in chloroform (5 mL) was stirred for 24 h at rt. Dichloro-
methane and water were added to the mixture; the organic layer was then washed with water. Drying of
the organic extracts over magnesium sulfate and evaporation leave a residue which was purified by
column chromatography (silica gel, eluent : EtOAc / petroleum ether, 1 : 1) to give 24 (250 mg, 78%) as
1
grey solid, mp 163 °C (EtOAc). IR (KBr) ν (cm-1) : 1687 (C=O). H NMR (CDCl3) δ (ppm) 1.26-1.45
(m, 2H, H3’a-5’a); 1.50 (s, 9H, t-Bu); 1.75-1.81 (m, 2H, H3’b-5’b); 2.13-2.22 (m, 1H, H4’); 2.70-2.79 (m, 2H,
H2’a-6’a); 2.92 (d, 2H, CH2-C=N, J = 7.1 Hz); 4.10-4.15 (m, 2H, H2’b-6’b); 7.96 (d, 1H, H7, J = 2.0 Hz); 8.59
(d, 1H, H5, J = 2.0 Hz). 13C NMR δ (ppm) 28.8 (C(CH3)3); 32.2 (2 CH2); 35.0 (CH); 36.0 (CH2); 44.1 (2
CH2); 79.8 (C); 115.9 (C); 121.4 (CH); 143.5 (C); 147.7 (CH); 155.0 (C); 155.1 (C=O); 169.9 (O-C=N).
MS (IS) : 396, 398 (MH+). Anal. Calcd for C17H22N3O3Br: C, 51.53; H, 5.60; N, 10.60. Found: C, 51.91;
H, 5.78; N, 10.43.
tert-Butyl 4-[2-(6-Bromopyrido oxazolo[4,5-b]pyridin-2-yl)ethyl]-1-piperidinecarboxylate (25)
Same procedure as for 24, starting from 23 (300 mg, 0.97 mmol). Solid, (250 mg, 63%), mp 145 °C
(EtOAc). IR (KBr) ν (cm-1) : 1686 (C=O). 1H NMR (CDCl3) δ (ppm) 1.13-1.26 (m, 2H, H3’a-5’a); 1.45 (s,
9H, t-Bu); 1.49-1.58 (m, 1H, H4’); 1.70-1.77 (m, 2H, H3’b-5’b); 1.87 (q, 2H, CH2-CH2C=N, J = 7.4 Hz);
2.63-2.72 (m, 2H, H2’a-6’a); 3.01 (t, 2H, CH2-C=N, J = 7.4 Hz); 4.08-4.14 (m, 2H, H2’b-6’b); 7.94 (d, 1H,
13
H7, J = 2.0 Hz); 8.59 (d, 1H, H5, J = 2.0 Hz). C NMR (CDCl3) δ (ppm) 26.6 (CH2); 28.8 (C(CH3)3);
32.1 (2 CH2); 33.2 (CH2); 35.7 (CH); 44.1 (2 CH2); 79.7 (C); 115.8 (C); 121.3 (CH); 143.5 (C); 147.6
(CH); 155.0 (C); 155.2 (N-C=O); 171.4 (O-C=N). MS (IS) : 410 and 412 (MH+) . Anal. Calcd for
C18H24N3O3Br: C, 52.69; H, 5.90; N, 10.24. Found: C, 52.31; H, 5.74; N, 10.40.
tert-Butyl 4-{2-[6-(3-Methoxy-3-oxopropyl] oxazolo[4,5-b]pyridin-2-yl}methyl)-1-piperidine-
carboxylate (26)
tert-Butyl 4-({6-[(E)-3-Methoxy-3-oxo-1-propenyl]oxazolo[4,5-b]pyridin-2-yl}methyl)-1-
piperidinecarboxylate
Same procedure as for 15 starting from 24 (300 mg, 0.79 mmol). Solid, (290 mg, 95%), mp 157 °C
1
(MeOH). IR (KBr) ν (cm-1) : 1711 (C=O); 1688 (C=O). H NMR (CDCl3) δ (ppm) 1.12-1.28 (m, 2H,
H3’a-5’a); 1.45 (s, 9H, t-Bu); 1.75-1.81 (m, 2H, H3’b-5’b); 2.16-2.20 (m, 1H, H4’); 2.69-2.79 (m, 2H, H2’a-6’a);
2.94 (d, 2H, CH2-C=N, J = 7.1 Hz); 3.83 (s, 3H, OCH3); 4.08-4.14 (m, 2H, H2’b-6’b); 6.51 (d, 1H, =CH-
CO, J = 16.0 Hz); 7.79 (d, 1H, CH=, J = 16.0 Hz); 7.92 (d, 1H, H7, J = 1.9 Hz); 8.67 (d, 1H, H5, J = 1.9
Hz). 13C NMR (CDCl3) δ (ppm) 28.8 (C(CH3)3); 32.2 (2 CH2); 35.1 (CH); 36.2 (CH2); 44.2 (2 CH2); 52.4
(OCH3); 79.9 (C); 115.8 (CH); 120.1 (CH); 127.7 (CH); 141.4 (CH); 143.5 (C); 147.7 (CH); 155.1 (C);

157.7 (N-C=O); 167.1 (O-C=N); 171.1 (C=O). MS (IS) : m/z 402 (MH+). Anal. Calcd for C21H27N3O5: C,
62.83; H, 6.78 N, 10.47. Found: C, 62.56; H, 6.72; N, 10.35.
A suspension of tert-butyl 4-({6-[(E)-3-methoxy-3-oxo-1-propenyl]oxazolo[4,5-b]pyridin-2-yl}methyl)-
1-piperidinecarboxylate (290 mg, 0.72 mmol) and 10% Pd/C (30 mg) in methanol (7 mL) was shaken
under 2 atm of hydrogen in a Parr apparatus. After 24 h at rt, the catalyst was filtered and the solution
evaporated. The residue was purified by column chromatography (silica gel, eluent : EtOAc / petroleum
ether, 4 : 6) to afford 26 (180 mg, 62%) as grey solid, mp 148 °C (MeOH/H2O). IR (KBr) ν (cm-1) : 1730
1
(C=O); 1687 (C=O). H NMR (CDCl3) δ (ppm) 1.17-1.32 (m, 2H, H3’a-5’a); 1.45 (s, 9H, t-Bu); 1.75-1.81
(m, 2H, H3’b-5’b); 2.16-2.20 (m, 1H, H4’); 2.70 (t, 2H, CH2, J = 7.4 Hz); 2.72 - 2.79 (m, 2H, H2’a-6’a); 2.91
(d, 2H, CH2, J = 7.1 Hz); 3.10 (t, 2H, CH2, J = 7.4 Hz); 3.68 (s, 3H, OCH3); 4.09-4.14 (m, 2H, H2’b-6’b);
7.65 (d, 1H, H7, J = 1.9 Hz); 8.40 (d, 1H, H5, J = 1.9 Hz). 13C NMR (CDCl3) δ (ppm) 28.5 (2 CH2); 28.8
(C(CH3)3); 32.2 (2 CH2); 35.1 (CH); 36.0 (CH2); 44.1 (2 CH2); 52.2 (OCH3); 79.8 (C); 118.2 (CH); 133.2
(C); 143.3 (C); 146.9 (CH); 154.9 (C); 155.1 (N-C=O); 169.0 (O-C=N); 173.0 (C=O). MS (IS) : m/z; 404
(MH+). Anal. Calcd for C21H29N3O5: C, 62.51; H, 7.24; N, 10.11. Found: C, 62.90; H, 7.33; N, 10.02.
tert-Butyl 4-{2-[6-(3-Methoxy-3-oxopropyl]oxazolo[4,5-b]pyridin-2-yl}ethyl)-1-piperidine-
carboxylate (27)
tert-Butyl (4-({6-[(E)-3-Methoxy-3-oxo-1-propenyl]oxazolo[4,5-b]pyridin-2-yl}ethyl)-1-piperidine-
carboxylate
Same procedure as for 16, starting from 25 (340 mg, 0.83 mmol). A brown solid (310 mg, 90%) was
1
obtained, mp 138 °C (MeOH). IR (KBr) ν (cm-1) : 1709 (C=O); 1662 (C=O). H NMR (CDCl3) δ (ppm)
1.15-1.26 (m, 2H, H3’a-5’a); 1.47 (s, 9H, t-Bu); 1.50-1.58 (m, 1H, H4’); 1.71-1.77 (m, 2H, H3’b-5’b); 1.90 (q,
2H, CH2-CH2-C=N, J = 7.5 Hz); 2.64-2.74 (m, 2H, H2’a-6’a); 3.05 (t, 2H, CH2-C=N, J = 7.5 Hz); 3.85 (s,
3H, OCH3); 4.08-4.14 (m, 2H, H2’b-6’b); 6.53 (d, 1H, =CH-CO, J = 16.0 Hz); 7.81 (d, 1H, CH=, J = 16.0
13
Hz); 7.93 (d, 1H, H7, J = 1.8 Hz); 8.68 (d, 1H, H5, J = 1.8 Hz). C NMR (CDCl3) δ (ppm) 26.3 (CH2);
28.4 (C(CH3)3); 31.7 (2 CH2); 32.8 (CH2); 35.3 (CH); 43.8 (2 CH2); 51.9 (OCH3); 79.3 (C); 115.3 (CH);
119.5 (CH); 127.1 (CH); 141.0 (CH); 143.1 (C); 147.2 (CH); 154.7 (C); 157.3 (N-C=O); 166.6 (O-C=N);
172.1 (C=O). MS (IS) : m/z 416.5 (MH+). Anal. Calcd for C22H29N3O5: C, 63.60; H, 7.04; N, 10.11.
Found: C, 63.23; H, 6.89; N, 10.22.
A suspension of tert-butyl (4-({6-[(E)-3-methoxy-3-oxo-1-propenyl] oxazolo[4,5-b]pyridin-2-yl}ethyl)-
1-piperidinecarboxylate (350 mg, 0.84 mmol) and 10% Pd/C (35 mg) inmethanol (8 mL) was stirred under
2 atm of hydrogen in a Parr apparatus. After 24 h at rt the catalyst was filtered and the solution
evaporated. The residue was purified by column chromatography (silica gel, eluent : EtOAc / petroleum
ether, 4 : 6) to give 27 (210 mg, 60%) as grey solid, mp 130 °C (MeOH/H2O). IR (KBr) ν (cm-1) : 1727

1
(C=O); 1694 (C=O). H NMR (CDCl3) δ (ppm) 1.11-1.20 (m, 2H, H3’a-5’a); 1.47 (s, 9H, t-Bu); 1.51-1.58
(m, 1H, H4’); 1.72-1.76 (m, 2H, H3’b-5’b); 1.87 (q, 2H, CH2-CH2-C=N, J = 7.5 Hz); 2.71 (t, 2H, CH2-
CH2CO, J = 7.5 Hz); 2.58-2.68 (m, 2H, H2’a-6’a); 3.02 (t, 2H, CH2-C=N, J = 7.5 Hz); 3.11 (t, 2H, CH2-
CO, J = 7.5 Hz); 3.69 (s, 3H, OCH3); 4.09-4.14 (m, 2H, H2’b-6’b); 7.66 (d, 1H, H7, J = 1.8 Hz); 8.41 (d,
13
1H, H5, J = 1.8 Hz). C NMR (CDCl3) δ (ppm) 26.5 (CH2); 28.5 (CH2); 28.8 (C(CH3)3); 32.1 (2 CH2);
33.3 (CH2); 35.6 (CH); 36.0 (CH2); 44.2 (2 CH2); 52.2 (OCH3); 79.7 (C); 118.2 (CH); 133.1 (C); 143.3
(C); 146.7 (CH); 154.9 (C); 155.2 (N-C=O); 170.4 (O-C=N); 173.0 (C=O). MS (IS) : m/z 418.5 (MH+).
Anal. Calcd for C22H31N3O5: C, 63.29; H, 7.48; N, 10.06. Found: C, 63.56; H, 7.67; N, 10.24.
Methyl 3-[2-(4-Piperidinylmethyl)oxazolo[4,5-b]pyridin-6-yl]propanoate (28), HCOOH salt
A solution of compound (26) (160 mg, 0.37 mmol) in formic acid (3 mL) was stirred for 1 h at rt.
Evaporation of the solvent under vacuo leave a solid which was crystallized in ether to give 28 (100 mg,
1
72%), mp 95 °C (decomp). IR (KBr) ν (cm-1) : 3500-2900 (OH); 3426 (NH); 1730 (C=O). H NMR
(CDCl3) δ (ppm) 1.77-1.86 (m, 2H, H3’a-5’a); 2.05-2.11 (m, 2H, H3’b-5’b); 2.34-2.40 (m, 1H, H4’); 2.74 (t,
2H, CH2-CH2CO, J = 7.3 Hz); 2.97-3.05 (m, 4H, H2’a-6’a, CH2-C=N); 3.14 (t, 2H, CH2-CO, J = 7.3 Hz);
3.49-3.54 (m, 2H, H2’b-6’b); 3.71 (s, 3H, OCH3); 7.69 (s, 1H, H7); 8.42 (br s, 2H, H5, HC=O); 9.65 (br s,
2H, NH, OH). 13C NMR (CDCl3) δ (ppm) 28.5 (CH2); 28.9 (CH2); 33.1 (2 CH2); 35.3 (CH); 36.0 (CH2);
43.8 (2 CH2); 52.2 (OCH3); 118.5 (CH); 133.6 (C); 143.4 (C); 147.0 (CH); 154.6 (C); 168.1 (HC=O);
168.2 (O-C=N); 173.0 (C=O). MS (IS) : m/z 304 (MH+). Anal. Calcd for C16H21N3O3, HCOOH: C, 58.43;
H, 6.63; N, 12.03. Found: C, 58.79; H, 6.78; N, 12.15.
ACKNOWLEDGEMENTS
We thank Laboratoire L. Lafon, Maisons-Alfort, France, for financial support of this work. We are also
grateful to Dr B. Lesur and Dr A. Frydman for helpful discussions.
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