E. Wolińska: Novel aza-Smiles rearrangementꢀꢂꢁꢁꢁꢀ2ꢃ1
1
37.5, 126.9, 118.6, 114.9, 108.8. Anal. Calcd for C H N ClO: C, 48.55; H, stirred at room temperature for 5 min. The precipitate was filtered
9
7
4
3.17; N, 25.17. Found: C, 48.42; H, 2.96; N, 25.14.
off and crystallized from toluene. The yield of 11a was 48%, and the
yield of 11b was 67%.
2
-Chloro-4-(5-methyl-1-oxidopyridin-2-ylamino)pyrimidine
1
(
11b)ꢀYield 37%; mp 272–273°C (dec); H NMR (400 MHz, DMSO-d ):
6
δ 9.28 (br s, 1H), 8.90 (d, 1H, J = 5.8 Hz), 8.38 (s, 1H), 7.90 (d, 1H, J =
Crossover experiment between 9b and 9c
9
.0 Hz), 7.63 (d, 1H, J = 5.8 Hz), 7.38 (d, 1H, J = 9.0 Hz), 2.19 (s, 3H);
1
3
C NMR (100 MHz, DMSO-d ): δ 168.0, 162.5, 158.1, 150.1, 145.2, 133.8,
6
To the solution of pyridinium salts 9b (0.1 mmol) and 9c (0.1 mmol)
in ethanol (2 ml), 25% ammonia (0.1 ml) was added. The mixture
was stirred at room temperature for 5 min. Af er the evaporation
122.5, 115.6, 107.4, 16.3. Anal. Calcd for C H N ClO: C, 50.75; H, 3.83; N,
2
11
9
4
3.67. Found: C, 50.81; H, 3.98; N, 23.58.
1
of solvent, the mixture of products was analyzed by H NMR in
Synthesis
of
2-{[(N,N-dimethylamino)methylene]amino}-
CDCl using nitromethane as internal reference; 11b, yield: 37%;
3
5
-methylpyridine 1-oxide (8b)ꢀA mixture of 2-amino-5-methyl-
1
2, yield: 63%.
pyridine 1-oxide (2b, 2.18 mmol, 0.27 g) and N,N-dimethylformamide
dimethyl acetal (1.9 ml) was stirred at room temperature for 24 h. The
precipitate was filtered off, washed with ethyl ether, and dried in a
vacuum desiccator over phosphorus oxide. Compound 8b was ob- General procedure for the preparation of
-
1 1
tained in 92% yield; mp 110–112°C; IR: 1264, 2922 cm ; H NMR (400
N-(hetero)arylated 2-aminopyridine 1-oxides
MHz, CDCl ): δ 9.07 (s, 1H), 7.96 (s, 1H), 6.95 (d, 1H, J = 8.2 Hz), 6.82
3
1
ꢃ, 1ꢂ, and 16
1
3
(
d, 1H, J = 8.2 Hz), 3.07 (s, 3H), 3.06 (s, 3H), 2.20 (s, 3H); C NMR (100
MHz, CDCl ): δ 156.5, 150.7, 139.5, 128.9, 127.3, 120.0, 43.6, 33.9, 17.5.
3
Method AꢀThe mixture of 2-aminopyridine 1-oxide (2a, 0.24 g, 2.2
mmol), appropriate chloro compound (6, 7, or 15, 1.0 mmol), and p-
toluenesulfonic acid (0.17 g, 1.0 mmol) in DMF (20 ml) was stirred at
HRMS: Calcd for C H N : m/z 180.1131. Found: m/z 180.1132.
9
14
3
8
0°C for 24 h and then poured into ice water (100 ml). Af er neutrali-
General procedure for the preparation of
pyridinium salts 9a,b
zation with sodium bicarbonate, the precipitate was filtered and pu-
rified by column chromatography using dichloromethane/methanol
(
10:1) as an eluent.
To formamidine protected 2-aminopyridine 1-oxide 8a (Wolińska and
Pucko, 2012) or 8b (1 mmol) and 2,4-dichloropyrimidine (6, 0.15 g,
Method BꢀThe solution of Pd dba (0.06 g, 0.06 mmol) and Xant-
2
3
phos (0.084 g, 0.14 mmol) in dry dioxane was stirred for 10 min
under argon. The mixture was added to a flask containing 2-chloro-
pyridine (15, 0.15 g, 1.3 mmol), 2-aminopyridine 1-oxide (2a, 0.17 g,
1
mmol) was added dry DMF (2 ml). The mixture of compounds 8a
and 6 was stirred at room temperature and the mixture of 8b and 6
at 0°C for 24 h. Af er that time, the products were filtered off, washed
with diethyl ether, and dried in vacuo.
1
.6 mmol), Cs CO (1.7 g, 5.3 mmol), and dioxane (4 ml). The mixture
2 3
was stirred for 42 h at 110°C. The solid material was filtered off, and
the filtrate concentrated. The residue of 13, 14, or 16 was purified by
column chromatography using dichloromethane/methanol (50:1)
as an eluent.
1
-(2-Chloropyrimidin-4-yloxy)-2-{[(N,N-dimethylamino)meth-
ylene]amino}pyridin-1-ium chloride (9a)ꢀYield 80%; mp 139°C
-
1 1
(dec); IR: 3609 cm ; H NMR (400 MHz, DMSO-d ): δ 8.91 (d, 1H, J = 5.6
6
Hz), 8.88–8.86 (m, 2H), 8.30–8.26 (m, 1H), 8.10 (dd, 1H, J = 1.6 Hz, 8.8
Hz), 7.70 (d, 1H, J = 5.6 Hz), 7.39 (dt, 1H, J = 1.6 Hz, 7.2 Hz), 3.24 (s, 3H),
2
,4-Bis(1-oxidopyridin-2-ylamino)pyrimidine (13) ꢀYield 50%
-1 1
13
(Method A); mp 237–238°C; IR: 3136, 3304, 1203 cm ; H NMR (400
MHz, DMSO-d ): δ 10.46 (br s, 1H), 9.79 (br s, 1H), 8.66 (dd, 1H, J =
2
.82 (s, 3H); C NMR (100 MHz, DMSO-d ): δ 168.9, 163.1, 159.5, 158.5,
6
1
55.0, 144.2, 139.0, 117.8, 116.2, 105.5, 41.5, 35.0. Anal. Calcd for C H
6
1
2
13
1
.6 Hz, 8.4 Hz), 8.55 (dd, 1H, J = 1.6 Hz, 8.4 Hz), 8.39–8.35 (m, 3H),
N OCl : C, 45.88; H, 4.17; N, 22.29. Found: C, 45.68; H, 4.26; N, 22.11.
5
2
1
3
7
.50–7.41 (m, 2H), 7.15 (d, 1H, J = 6.0 Hz), 7.11–7.02 (m, 2H); C NMR
(100 MHz, DMSO-d ): δ 159.6, 157.2, 156.8, 144.3, 144.0, 137.4, 137.0,
1
1
-(2-Chloropyrimidin-4-yloxy)-2-{[(N,N-dimethylamino)methyl-
6
ene]amino}-5-methylpyridin-1-ium chloride (9b)ꢀYield 47%; mp
27.2, 126.9, 118.0, 117.0, 115.2, 113.2, 103.8. Anal. Calcd for C14H12
1
N O ·0.5H O: C, 55.08; H, 4.29; N, 27.53. Found: C, 54.79; H, 4.34;
1
47°C (dec); H NMR (400 MHz, DMSO-d ): δ 8.91 (d, 1H, J = 5.6 Hz),
6 2 2
6
N, 27.69.
-(1-Oxidopyridin-2-ylamino)pyrimidine (14)ꢀYield 67% (Meth-
8
.84–8.78 (m, 2H); 8.19 (dd, 1H, J = 2.0 Hz, 9.2 Hz), 7.97–7.95 (m, 1H),
1
3
7
.69 (d, 1H, J = 5.6 Hz), 3.22 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H); C NMR
2
(
1
100 MHz, DMSO-d ): δ 168.8, 163.2, 159.3, 158.5, 153.2, 146.1, 136.6,
6
-1 1
od A); mp 152–153°C; IR: 3245 cm ; H NMR (400 MHz, CDCl ): δ
26.7, 116.9, 105.4, 41.3, 34.8, 16.6. HRMS: Calcd m/z for C H N OCl:
3
13
15
5
1
0.08 (br s, 1H), 8.72 (dd, 1H, J = 2.0 Hz, 8.8 Hz), 8.56 (d, 2H, J = 4.8
2
92.0959. Found: m/z 292.0964.
Hz), 8.28 (d, 1H, J = 4.0 Hz), 7.33 (dt, 1H, J = 1.2 Hz, 8.8 Hz), 6.92 (t,
1
3
1
H, J = 5.2 Hz), 6.88 (dt, 1H, J = 1.6 Hz, 7.6 Hz); C NMR (100 MHz,
CDCl ): δ 158.3, 158.1, 144.7, 137.1, 127.7, 116.2, 114.7, 113.4. Anal. Calcd
3
General procedure for the rearrangement
of pyridinium salts 9a,b into N-(hetero)
arylated products 11a,b
To the solution of pyridinium salt 9a or 9b (1 mmol) in anhydrous and 66% (Method B); mp 165–166°C (lit. mp 165–166°C; Rykowski and
ethanol (6 ml), 25% ammonia (0.3 ml) was added. The mixture was Pucko, 1998).
for C H N O: C, 57.44; H, 4.28; N, 29.77. Found: C, 57.35; H, 4.32; N,
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8
4
29.79.
2-(Pyridin-2-ylamino)pyridine 1-oxide (16)ꢀYield 19% (Method A)
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