PAPER
Electrophilic Chlorination with 2-Chloropyridazin-3(2H)-ones
1139
1
3
Anal. Calcd for C H Cl N O : C, 30.80; H, 2.07; N, 14.37. Found:
C, 30.87; H, 2.13; N, 14.46.
C NMR (CDCl ): d = 13.9, 42.0, 62.9, 69.8, 120.5, 130.4, 166.4.
5
4
2
2
2
3
Anal. Calcd for C H ClO : C, 51.18; H, 6.44. Found: C, 51.16; H,
1
0
15
4
6
.41.
a-Chlorination of Active Methylenes in the Presence of Base;
General Procedure (Table 1)
A mixture of 3 (1.2 mmol), base (1.2 equiv) and anhyd THF (30
mL) was stirred for 20 min at 0 °C. A solution of 2a (1.4 mmol) in
THF (10 mL) was then added slowly with stirring. The mixture was
stirred until the 3 had disappeared at 0 °C (or –78 °C for 3d). After
evaporating the solvent, the residue was poured into a stirred mix-
2
-Acetyl-2-chlorocyclohexanone (4c)
Colorless oil; R 0.63 (EtOAc–n-hexane, 1:4).
f
IR (KBr): 3000, 2900, 1740, 1460, 1440, 1370, 1280, 1200, 1080,
1
–
1
040, 980 cm .
1
H NMR (CDCl ): d = 1.80–1.85 (m, 2 H), 1.94–1.99 (m, 2 H),
3
ture of EtOAc (50 mL) and H O (100 mL). The organic layer was
2
2.09–2.22 (m, 1 H), 2.34–2.37 (m, 4 H, 1 H + CH ), 2.58–2.61 (m,
3
separated and then washed with excess of H O. The organic phase
2
1 H), 2.94–3.00 (m, 1 H).
13
was dried (MgSO ) and co-evaporated with silica gel (1.5 g) under
4
C NMR (CDCl ): d = 21.5, 26.8, 26.9, 37.7, 38.8, 76.8, 201.1,
02.9.
3
reduced pressure. The resulting gel was applied to the top of an
open-bed silica gel column (2.5 × 5 cm). First, the column was elut-
ed with CH Cl . Fractions containing 4 or 5 were combined and
2
Anal. Calcd for C
6.38.
H11ClO : C, 55.02; H, 6.35. Found: C, 55.03; H,
8 2
2
2
evaporated under reduced pressure to give 4 or 5 (Table 1). The col-
umn was then eluted with Et O. Fractions containing compound 1
were combined and evaporated under reduced pressure to give com-
pound 1 in 95–96% yield.
2
a,a-Dichlorobenzylcyanide (5d)
Pale yellow crystals (CH Cl –n-hexane, 1:3); mp 151–152 °C;
R 0.65 (CH Cl –n-hexane, 1:2).
2
2
f
2
2
a-Chlorination of Active Methylenes in the Presence (or Ab-
sence) of Acid; General Procedure (Tables 2 and 3)
IR (KBr): 3010, 2200, 1500, 1440, 1280, 1220, 750 cm–1.
1
H NMR (CDCl ): d = 7.53–7.55 (m, 3 H), 7.83–7.85 (m, 2 H).
CH Cl Method: Acid (30 mol%) was added slowly to a stirring so-
3
2
2
1
3
lution of 3 (1.2 mmol) in CH Cl at r.t. After 10 min, a solution of 2
C NMR (CDCl ): d = 116.6, 125.6, 128.7, 129.3, 131.7, 132.0.
2
2
3
(
1.4 mmol) in anhyd CH Cl (10 mL) was added to the above solu-
2 2
Anal. Calcd for C H Cl N: C, 51.65; H, 2.71; N, 7.53. Found: C,
8
5
2
tion. The resulting mixture was stirred at r.t. until 3 had disappeared.
After co-evaporating with silica gel (1.5 g) under reduced pressure,
the resulting residue was applied to the top of an open-bed silica gel
column (2.5 × 5 cm). The column was eluted with CH Cl . Frac-
5
1.70; H, 2.79; N, 7.61.
2
-Chloroindan-1-one (4e)
2
2
Pale yellow oil; R 0.65 (CH Cl –n-hexane, 1:2).
f
2
2
tions containing 4 or 5 were combined and evaporated under re-
duced pressure to give 4 or 5 (Tables 2 and 3). The column was then
IR (KBr): 3100, 2950, 1740, 1600, 1470, 1440, 1300, 1280, 1200
–
1
eluted with Et O. Fractions containing compound 1 were combined
cm .
2
and evaporated under reduced pressure to give compound 1 in quan-
titative yield.
1
H NMR (CDCl ): d = 3.30 (dd, 1 H, J = 4.0, 17.6 Hz), 3.80 (dd, 1
3
H, J = 7.8, 17.6 Hz), 4.56 (dd, 1 H, J = 4.0, 7.8 Hz), 7.40–7.47 (m,
H O Method: A mixture of 3 (2.14 mmol), 2 (2.14 mmol) and H O
2 H), 7.64–7.70 (m, 1 H), 7.80 (d, 1 H, J = 7.7 Hz).
2
2
(
30 mL) was stirred for 1 h at r.t. The product was extracted with
13
C NMR (CDCl ): d = 37.5, 55.7, 124.9, 126.4, 128.3, 133.7,
3
EtOAc (2 × 30 mL). The ester layer was dried (MgSO ) and then
4
136.11, 150.8, 199.3.
co-evaporated with silica gel (1.5 g) under reduced pressure. The re-
sulting residue was applied to the top of an open-bed silica gel col-
umn (2.5 × 5 cm). The column was eluted with CH Cl . Fractions
Anal. Calcd for C H ClO: C, 64.88; H, 4.23. Found: C, 64.90; H,
9
7
4
.28.
2
2
containing 4 or 5 were combined and evaporated under reduced
pressure to give 4 or 5 (Tables 2 and 3). The column was then eluted
with Et O. Fractions containing compound 1 were combined and
2
,2-Dichloroindan-1-one (5e)
Yellow crystals (CH Cl –n-hexane, 1:4); mp 74–75 °C; R 0.73
2
2
f
2
(
CH Cl –n-hexane, 1:2).
evaporated under reduced pressure to give compound 1 in quantita-
2
2
tive yield.
IR (KBr): 3100, 2900, 1730, 1600, 1580, 1460, 1420, 1300, 1260,
–
1
1
200, 1140, 1050, 980, 950, 850, 800 cm .
2
-Benzyl-2-chloromalonic Acid Diethyl Ester (4a)
1
H NMR (CDCl ): d = 4.06 (s, 2 H), 7.42–7.53 (m, 2 H), 7.71–7.77
3
Colorless oil; R 0.70 (CH Cl ).
f
2
2
(
1
m, 1 H), 7.92 (d, 1 H, J = 7.7 Hz).
IR (KBr): 3000, 2950, 1760, 1460, 1400, 1280, 1250, 1200, 1100,
1
3
C NMR (CDCl ): d = 50.1, 81.5, 126.2, 126.6, 129.0, 130.3, 137.0,
–
1
3
040, 1000 cm .
1
47.2, 191.8.
1
H NMR (CDCl ): d = 1.28 (t, 6 H, J = 7.0 Hz), 3.60 (s, 2 H), 4.28
q, 4 H, J = 7.0 Hz), 7.28–7.32 (m, 5 H).
3
Anal. Calcd for C H Cl O: C, 53.77; H, 3.01. Found: C, 57.79; H,
3
9
6
2
(
.11.
1
3
C NMR (CDCl ): d = 14.1, 43.3, 63.3, 71.0, 127.9, 128.5, 130.8,
3
1
16.7, 133.9.
2-Acetyl-2-chloro-3,4-dihydro-2H-naphthalen-1-one (4f)
Pale yellow crystals (EtOAc–n-hexane, 1:9); mp 48–50 °C; R 0.75
Anal. Calcd for C H ClO : C, 59.06; H, 6.02; Cl, 12.45. Found: C,
f
14
17
4
(EtOAc–n-hexane, 1:9).
5
9.08; H, 6.04; Cl, 12.51.
IR (KBr): 3100, 2950, 1720, 1680, 1600, 1460, 1420, 1360, 1300,
1240, 1200, 900, 850, 750, 720 cm .
–
1
2
-Allyl-2-chloromalonic Acid Diethyl Ester (4b)
Colorless oil; R 0.55 (EtOAc–n-hexane, 1:4).
f
1
H NMR (CDCl ): d = 2.42 (s, 3 H), 2.45–2.51 (m, 1 H), 2.90–2.99
3
IR (KBr): 3100, 3000, 1760, 1640, 1480, 1460, 1380, 1300, 1280,
1
(m, 1 H), 3.05–3.08 (m, 1 H), 3.12–3.16 (m, 1 H), 7.41–7.46 (m, 2
–
1
240, 1200, 1120, 1100 cm .
H), 7.63–7.69 (m, 1 H), 7.95 (d, 1 H, J = 7.8 Hz).
1
13
H NMR (CDCl ): d = 1.29 (t, 6 H, J = 7.1 Hz), 2.98–3.00 (m, 2 H),
C NMR (CDCl ): d = 25.0, 26.6, 30.0, 75.9, 127.3, 127.7, 129.2,
3
3
4
.27 (q, 4 H, J = 7.1 Hz), 5.18–5.22 (m, 2 H), 5.77–5.85 (m, 1 H).
129.5, 134.7, 142.9, 189.3, 201.0.
Synthesis 2005, No. 7, 1136–1140 © Thieme Stuttgart · New York