F. Mongin et al. / Tetrahedron 58 (2002) 309±314
313
oil; 1H NMR (CDCl3) d 3.65 (s, 3H, CH2OMe), 3.87 (s, 3H,
OMe), 5.17 (s, 2H, CH2), 6.76 (d, 1H, J5.4 Hz, H5),
8.00 (d, 1H, J5.4 Hz, H6); 13C NMR (CDCl3) d 56.2
(CH2OMe), 58.8 (OMe), 98.9 (CH2), 108.1 (C5), 117.2
(C2), 143.2 (C3), 147.4 (C6), 157.9 (C4); IR (KBr) n 2918,
C20H37NO3Sn (458.23): C, 52.42; H, 8.14; N, 3.06. Found:
C, 52.33; H, 8.15; N, 2.91%.
4.5. General procedure 4: cross-coupling from 2-lithio-
pyridines
2848, 1568, 1477, 1380, 1296, 1158, 1027, 927, 817 cm21
.
Anal. calcd for C8H10INO3 (295.08): C, 32.56; H, 3.42; N,
4.75. Found: C, 32.43; H, 3.38; N, 4.53%.
After 15 min at 2758C, an anhydrous solution of ZnCl2
(0.82 g, 6.0 mmol) in THF (20 mL) was added to the
required 2-lithiopyridine (2.0mmol) at the same tempera-
ture. The reaction mixture was then warmed to rt. After the
addition of the required 2-halopyridine (4.0mmol) and
Pd(PPh3)4 (69 mg, 60 mmol), the mixture was re¯uxed for
20h, cooled and evaporated to dryness. The residue was
dissolved in conc. NH4OH (20mL) and CH 2Cl2 (50mL)
containing EDTA (3.7 g, 10mmol). The mixture was
re¯uxed for 1 h.
4.3.2. 2-Iodo-3-methoxy-4-methoxymethoxypyridine (7a).
The general procedure 2, starting from 5 and using
MeOCH2Cl, gave 7a (eluent: CH2Cl2/Et2O 80:20). Yield:
69%; colorless oil; 1H NMR (CDCl3) d 3.37 (s, 3H,
CH2OMe), 3.76 (s, 3H, OMe), 5.15 (s, 2H, CH2), 6.88 (d,
1H, J5.5 Hz, H5), 7.84 (d, 1H, J5.5 Hz, H6); 13C NMR
(CDCl3) d 57.0(CH 2OMe), 61.1 (OMe), 94.7 (CH2), 111.1
(C5), 117.3 (C2), 146.6 (C3), 147.4 (C6), 155.8 (C4); IR
(KBr) n 2933, 2829, 1566, 1474, 1382, 1281, 1154, 1089,
975 cm21. Anal. calcd for C8H10INO3 (295.08): C, 32.56; H,
3.42; N, 4.75. Found: C, 32.77; H, 3.20; N, 4.73%.
4.5.1. 3-Hydroxy-2,20-bipyridine (10). The general pro-
cedure 4, starting from 3a and 2-bromopyridine gave 32%
of 10 (eluent: CH2Cl2/Et2O 90:10); mp 91±938C (lit.15
13
928C); C NMR (CDCl3) d 121.1 (C5 ), 123.3 (C3 ), 125.0
0
0
4.3.3. 2-Iodo-3,4-dimethoxypyridine (7b). The general
procedure 2, starting from 5 and using MeI, gave 7b (eluent:
CH2Cl2/Et2O 80:20). Yield: 71%; mp 89±908C (lit.6 908C).
0
and 126.1 (C4 and C5), 137.1 (C3), 138.2 (C4 ), 140.2 (C6),
0
145.6 (C6 ), 156.9 (C2), 158.5 (C2 ).
0
4.5.2. 4,40-Dihydroxy-3,30-dimethoxy-2,20-bipyridine (1b).
The general procedure 4, starting from 7a and using 7a
(halopyridine), followed by subsequent treatment of the
crude compound (eluent: CH2Cl2/MeOH 50:50) in a 50:50
mixture (20mL) of aqueous 10% HCl and THF at 50 8C for
7 h, gave 60% of 1b (eluent: CH2Cl2/MeOH 90:10); mp
4.4. General procedure 3: iodine±lithium exchange of
2-iodopyridines (3a, 6)
At 2758C, the required 2-iodopyridine (2.0mmol) was
added to a solution of BuLi (4.0mmol) in hexane (1.6
mL) and THF (10mL). After 15 min at 2758C, Bu3SnCl
(0.60 mL, 2.0 mmol) was added at 2758C with subsequent
warming at rt.
1
1518C; H NMR (CDCl3) d 3.95 (s, 6H, 2OMe), 6.74 (d,
0
0
J5.8 Hz, 2H, H5,5 ), 7.74 (d, J5.8 Hz, 2H, H6,6 ), 8.50(s,
2H, OH); 13C NMR (DMSO-d6) d 60.1 (2OMe), 113.8
0
(C5,5 ), 145.6 (C3,3 ), 146.7 (C6,6 ), 153.8 (C2,2 ), 158.0
0
0
0
0
(C4,4 ); IR (KBr) n 2926, 2824, 1609, 1505, 1382, 1318,
. Anal. calcd for C12H12N2O4
(248.24): C, 58.06; H, 4.87; N, 11.28. Found: C, 57.82; H,
4.83; N, 11.09%.
1208, 991, 898 cm21
4.4.1. Tributyl-3-methoxymethoxypyridine-2-stannane
(8). The general procedure 3, starting from 3a, gave 8
(neutral alumina instead of silica gel, eluent: petroleum
1
ether/CH2Cl2 50:50). Yield: 68%; colorless oil; H NMR
4.5.3. 3,30,4,40-Tetramethoxy-2,20-bipyridine (tetramethyl-
orelline) (1d). The general procedure 4, starting from 7b
and using 7b (halopyridine), gave 59% of 1d (eluent:
CHCl3/MeOH 90:10); mp 1868C (lit.6 186±1878C).
(CDCl3) d 0.80 (t, 9H, J7.2 Hz, Me), 1.06 (m, 6H,
CH2), 1.25 (m, 6H, CH2), 1.51 (m, 6H, CH2), 3.39 (s, 3H,
OMe), 5.09 (s, 2H, CH2), 7.00 (dd, 1H, J7.7, 4.6 Hz, H5),
7.16 (dd, 1H, J7.7, 1.2 Hz, H4), 8.34 (dd, 1H, J4.6,
1.2 Hz, H6); 13C NMR (CDCl3) d 10.4 (3Me), 14.1
(3CH2), 27.7 (3CH2), 29.6 (3CH2), 56.4 (OMe), 94.6
(CH2), 117.7 (C4), 122.7 (C5), 144.8 (C6), 159.0(C 3),
164.7 (C2); IR (KBr) n 3436, 2955, 2928, 1412, 1397,
1252, 1154, 1063, 994, 796 cm21. Anal. calcd for
C19H35NO2Sn (428.21): C, 53.29; H, 8.24; N, 3.27. Found:
C, 52.98; H, 8.15; N, 3.03%.
4.6. General procedure 5: cross-coupling from tributyl-
pyridine-2-stannanes 8±9
Pd(PPh3)4 (0.12 g, 0.10 mmol) and CuBr (20 mg, 0.14
mmol) were added to a solution of the required stannane
(2.0mmol) and 2-halopyridine (2.0mmol) in dioxane
(20mL) at rt. The mixture was re¯uxed for 15 h, cooled
and evaporated to dryness. The residue was dissolved in
conc. NH4OH (20mL). The compound was then dissolved
in Et2O (50mL) and treated with aqueous 10% HCl
(25 mL). The mixture was stirred at rt for 15 h and neutra-
lized to pH 5 with NaHCO3.
4.4.2. Tributyl-4-methoxy-3-methoxymethoxypyridine-
2-stannane (9). The general procedure 3, starting from 6,
gave 9 (neutral alumina instead of silica gel, eluent: CH2Cl2/
Et3N 90:10). Yield: 65%; colorless oil; 1H NMR (CDCl3) d
0.87 (t, 9H, J7.3 Hz, Me), 1.14 (m, 6H, CH2), 1.32 (m, 6H,
CH2), 1.56 (m, 6H, CH2), 3.55 (s, 3H, OMe), 3.87 (s, 3H,
4.6.1. 3-Hydroxy-2,20-bipyridine (10). The general pro-
cedure 5, starting from 8 and 2-bromopyridine, gave crude
OMe), 5.10(s, 2H, CH ), 6.72 (d, 1H, J5.4 Hz, H5), 8.41
2
(d, 1H, J5.4 Hz, H6); 13C NMR (CDCl3) d 10.7 (3Me),
14.1 (3 CH2), 27.7 (3CH2), 29.6 (3CH2), 55.7 (CH2OMe),
58.0(OMe), 99.2 (CH 2), 106.7 (C5), 148.1 (C3), 148.3 (C6),
156.2 (C4), 167.4 (C2); IR (KBr) n 2956, 2923, 1565, 1462,
1376, 1289, 1154, 1073, 961, 673 cm21. Anal. calcd for
3-methoxymethoxy-2,20-bipyridine
(neutral
alumina,
eluent: CH2Cl2/MeOH 95:5); viscous oil; 1H NMR
(CDCl3) d 3.56 (s, 3H, OMe), 5.14 (s, 2H, CH2), 7.22 (m,
0
2H, H5,5 ), 7.52 (dd, J8.4, 1.3 Hz, 1H, H4), 7.70(td, J7.4,