6726
J. Lazaar et al. / Tetrahedron 58 (2002) 6723–6728
(
25 g). The resin was removed by filtration 15 min later; the
(C ), 150.4 (C ), 165.6 (CO); IR (KBr) n 1254, 1401, 1407,
2 6
2
1
solvents were evaporated and the residue washed with
acetone (20 mL) to give after drying the pure halo picolinic
acid.
1725, 2455, 2584, 2713, 3078 cm ; mass (EI): m/z 157
þz
(M ).
1
b,13
4.3.2. 3-Iodoisonicotinic acid (6).
cedure 2, using I , initially gave 65% of 6a: H NMR
The general pro-
1
1
3
4
1
(
.2.1. 3-Chloropicolinic acid (2). The general procedure
1
2
, using C Cl , initially gave 72% of 2a: H NMR
2
(DMSO-d ) d 7.36 (d, 1H, J¼4.5 Hz, H ), 7.74 (d, 1H,
6
6
5
DMSO-d ) d 7.05 (dd, 1H, J¼7.9, 4.5 Hz, H ), 7.54 (dd,
J¼4.5 Hz, H ), 8.86 (s, 1H, H ). The lithium salt was then
6
5
6
2
1
The lithium salt was then converted in a 53% yield to 2:
beige powder; mp 150–1548C (dec.); H NMR (DMSO-d )
6
H, J¼7.9, 1.5 Hz, H ), 8.07 (dd, 1H, J¼4.5, 1.5 Hz, H ).
converted in a 45% yield to 6: beige powder; mp 205–
2108C; H NMR (DMSO-d ) d 7.44 (d, 1H, J¼4.5 Hz, H ),
4
6
1
6
5
1
8.47 (d, 1H, J¼4.5 Hz, H ), 8.86 (s, 1H, H ); IR (KBr) n
6
2
2
1
d 7.42 (dd, 1H, J¼7.9, 4.5 Hz, H ), 7.92 (dd, 1H, J¼7.9,
810, 1267, 1382, 1405, 1634, 2844, 3050, 3264 cm ; mass
(EI): m/z 249 (M ).
5
1
þz
1
data are in accordance with those of the literature);
.5 Hz, H ), 8.41 (dd, 1H, J¼4.5, 1.5 Hz, H ) (the H NMR
4
6
1
d 13
C
NMR (DMSO-d ) d 126.9 (C ), 128.1 (C ), 138.8 (C ),
4.4. General procedure 3: metallation of nicotinic acid
(7)
6
5
3
4
1
1
47.8 (C ), 149.9 (C ), 166.3 (CO); IR (KBr) n 806, 1287,
6 2
2
1
380, 1508, 1654, 1752, 3400 cm ; mass (EI): m/z 157
þz
(
M ).
A solution of BuLi (40 mmol) in hexane (16 mL) and
15 min later, nicotinic acid (1.2 g, 10 mmol) were added at
1
a,13
4
1
7
1
.2.2. 3-Iodopicolinic acid (3).
The general procedure
2758C to a solution of 2,2,6,6-tetramethylpiperidine
(5.1 mL, 30 mmol) in THF (50 mL). After 10 min at
2758C, the mixture was stirred for 30 min at 2558C and
transferred dropwise to a cooled (2558C) solution of the
required electrophile (30 mmol) in THF (50 mL). After
15 min at 2558C, the mixture was allowed to reach rt before
hydrolysis (5 mL), 1 h later, and removal of the solvents
under vacuum. The residue was dissolved in water (20 mL)
and the resulting solution washed with CH Cl (30 mL) and
1
, using I , initially gave 65% of 3a: H NMR (DMSO-d ) d
2
6
.15 (dd, 1H, J¼7.8, 4.5 Hz, H ), 8.28 (dd, 1H, J¼7.8,
5
.5 Hz, H ), 8.53 (dd, 1H, J¼4.5, 1.5 Hz, H ). The lithium
4
6
salt was then converted in a 55% yield to 3: beige powder;
mp 2108C; H NMR (DMSO-d ) d 8.13 (dd, 1H, J¼7.8,
1
6
4
.5 Hz, H ), 8.35 (dd, 1H, J¼7.8, 1.5 Hz, H ), 8.87 (dd, 1H,
5
4
J¼4.5, 1.5 Hz, H ); IR (KBr) n 630, 672, 1038, 1115, 1172,
6
2
1
1
2
280, 1383, 1501, 1593, 1753, 2944 cm ; mass (EI): m/z
49 (M ).
2
2
þz
Et O (2£30 mL). The aqueous phase was then evaporated to
2
dryness and the residue chromatographed on a silica gel
column (eluent: CH Cl and then CH Cl /MeOH 70:30) to
4
.3. General procedure 2: metallation of isonicotinic acid
2
2
2
2
(
4)
give the corresponding lithium nicotinate. It was dissolved
in MeOH (30 mL) and treated for 15 min with Amberlystw
IR-120 (25 g). The resin was removed by filtration; the
solvents were evaporated and the residue washed with
acetone (20 mL) to give after drying the pure halo nicotinic
acid.
A solution of BuLi (40 mmol) in hexane (16 mL) and
5 min later, isonicotinic acid (1.2 g, 10 mmol) were added
at 2758C to a solution of 2,2,6,6-tetramethylpiperidine
5.1 mL, 30 mmol) in THF (50 mL). After 10 min at
758C, the mixture was stirred for 30 min at 2208C and
1
(
2
transferred dropwise to a cooled (2208C) solution of the
required electrophile (30 mmol) in THF (50 mL). After
4.4.1. 4-Chloronicotinic acid (8). The general procedure 3,
1
using C Cl , initially gave 79% of 8a: H NMR (DMSO-d )
2
6
6
1
5 min at 2208C, the mixture was allowed to reach rt before
d 7.33 (d, 1H, J¼5.1 Hz, H ), 8.27 (d, 1H, J¼5.1 Hz, H ),
8.51 (s, 1H, H ). The lithium salt was then converted in a
2
5
6
hydrolysis (5 mL), 1 h later, and removal of the solvents
under vacuum. The residue was dissolved in water (20 mL)
and the resulting solution washed with CH Cl (30 mL) and
1
5
75% yield to 8: beige powder; mp 205–2088C (lit. 207–
1
2108C); H NMR (DMSO-d ) d 7.52 (d, 1H, J¼4.9 Hz, H ),
2
2
6
5
Et O (2£30 mL). The aqueous phase was then evaporated to
8.46 (d, 1H, J¼4.9 Hz, H ), 8.71 (s, 1H, H ) (the spectral
2
6
2
1
c
dryness and the residue chromatographed on a silica gel
column (eluent: CH Cl and then CH Cl /MeOH 70:30) to
data are in accordance with those of the literature).
2
2
2
2
1
6
give the corresponding lithium isonicotinate. It was
dissolved in MeOH (30 mL) and treated for 15 min with
Amberlystw IR-120 (25 g). The resin was removed by
filtration; the solvents were evaporated and the residue
washed with acetone (20 mL) to give after drying the pure
halo isonicotinic acid.
4.4.2. 4-Iodonicotinic acid (9). The general procedure 3,
1
using I , initially gave 71% of 9a: H NMR (DMSO-d ) d
2
6
7.55 (d, 1H, J¼5.2 Hz, H ), 7.74 (d, 1H, J¼5.2 Hz, H ),
5
6
8.22 (s, 1H, H ). The lithium salt was then converted to 9,
2
which was found to be unstable.
4.5. General procedure 4: metallation of 5-bromo-
nicotinic acid (10)
1
3
4
cedure 2, using C Cl , initially gave 53% of 5a: H NMR
.3.1. 3-Chloroisonicotinic acid (5). The general pro-
1
2
6
(
DMSO-d ) d 7.39 (d, 1H, J¼4.7 Hz, H ), 8.52 (d, 1H,
A solution of BuLi (4.4 mmol) in hexane (1.8 mL) and,
5 min later, 5-bromonicotinic acid (0.40 g, 2.0 mmol) were
added at 2508C to a solution of 2,2,6,6-tetramethylpiperi-
dine (0.81 mL, 4.8 mmol) in THF (10 mL). The mixture was
stirred for 30 min at 2508C.
6
5
J¼4.7 Hz, H ), 8.61 (s, 1H, H ). The lithium salt was then
6
2
1
converted in a 49% yield to 5: beige powder; mp 2208C; H
NMR (DMSO-d ) d 7.55 (d, 1H, J¼4.9 Hz, H ), 8.47 (d, 1H,
6
5
1
J¼4.9 Hz, H ), 8.61 (s, 1H, H ) (the H NMR data are in
6
2
1
4 13
accordance with those of the literature);
(
C NMR
DMSO-d ) d 124.1 (C ), 128.5 (C ), 139.3 (C ), 148.7
4.5.1. 5-Bromo(4-D)nicotinic acid (11a). The lithio
6
5
3
4