8930 J . Org. Chem., Vol. 61, No. 25, 1996
South et al.
) 6.0 Hz, 1-H), 4.3-4.2 (m, 2-H), 2.60-2.50 (m, 2-H), 2.40-
2.30 (m, 1-H), 1.78-1.70 (m, 1-H), 1.75-1.65 (m, 1-H), 1.60-
1.40 (m, 6-H), 1.32 (t, J ) 8.0 Hz, 3-H), 1.40-1.20 (m, 2-H),
1.08 (t, J ) 8.0 Hz, 3-H). Anal. Calcd for C20H28N3O2Cl: C,
63.56; H, 7.47; N, 11.12. Found: C, 63.69; H, 7.58; N, 10.97.
5-Eth yl-3-p h en ylp yr id a zin e (16e a n d 7). This compound
was prepared according to the general procedure given for
Table 1 above and was isolated as a yellow solid (1.1 g, 34%
yield) by Prep-500 chromatography after treatment of the
corresponding tetrahydropyridazines with 5 equiv of t-BuOK
in t-BuOH for 4 h at rt. See 7 above for analytical data.
Eth yl 4-Ch lor o-5-eth yl-5,6-d ih yd r o-6-(1-p ip er id in yl)-3-
[3-(t r iflu or om et h yl)p h en yl]-1(4H )-p yr id a zin eca r b oxy-
la te (14f a n d 15f). These compounds were prepared accord-
ing to the general procedure given for Table 1 above and were
isolated as a yellow oil (6.67 g, 52% yield, RI 1.5256). After
chromatography on the Prep-500, the oil was found to be a
2:1 mixture of diastereomers.
(d, J ) 2.5, 1-H), 7.60-7.50 (m, 3-H), 2.45 (s, 3-H); 13C NMR
(75 MHz, CDCl3) δ 158.5, 151.4, 137.6, 136.2, 129.6, 128.7,
126.9, 124.0, 18.3. Anal. Calcd for C11H10N2: C, 77.62; H, 5.92;
N, 16.46. Found: C, 77.57; H, 5.93; N, 16.40.
Eth yl 4-Ch lor o-6-eth oxy-5,6-d ih yd r o-5-m eth yl-3-[3-(tr i-
flu or om eth yl)ph en yl]-1(4H)-pyr idazin ecar boxylates (14h
a n d 15h ). These compounds were prepared according to the
general procedure given for Table 1 above and were separated
from the crude mixture by chromatography on the Prep-500.
Compound 14h was obtained as a white solid (4.53 g, 40%
yield), and 15h was obtained as a clear oil (1.56 g, 14% yield).
1
Data for 14h : mp 61-63 °C; H NMR (400 MHz, CDCl3) δ
8.15 (s, 1-H), 8.05 (d, J ) 8.0 Hz, 1-H), 7.62 (d, J ) 8.0 Hz,
1-H), 7.51 (t, J ) 8.0 Hz, 1-H), 5.51 (s, 1-H), 4.50 (s, 1-H), 4.43-
4.30 (m, 2-H), 3.66 (q, J ) 7.0 Hz, 2-H), 2.88 (bq, J ) 8.0 Hz,
1-H), 1.40 (t, J ) 7.0 Hz, 3-H), 1.20 (t, J ) 7.0 Hz, 3-H), 0.98
(d, J ) 8.0 Hz, 3-H); 13C NMR (100 MHz, CDCl3) δ 155.0, 142.2,
136.0, 130.8 (q, J ) 33.2 hz), 129.5, 128.8, 125.9 (q, J ) 2.3
Hz), 124.0 (q, 269.5 Hz), 123.2 (q, J ) 3.8 Hz), 80.8, 64.0, 63.2,
45.8, 36.2, 16.4, 14.9, 14.3. Anal. Calcd for C17H20N2O3ClF3:
C, 51.98; H, 5.13; N, 7.13. Found: C, 52.13; H, 5.18; N, 7.06.
Data for 15h : RI 1.4947; 1H NMR (400 MHz, CDCl3) δ 7.90
(s, 1-H), 7.80 (d, J ) 8.0 Hz, 1-H), 7.61 (d, J ) 8.0 Hz, 1-H),
7.50 (t, J ) 8.0 Hz, 1-H), 5.55 (d, J ) 3.0 Hz, 1-H), 5.35 (d, J
) 6.0 Hz, 1-H), 4.41-4.27 (m, 2-H), 3.65 (q, J ) 8.0 Hz, 2-H),
2.62 (qdd, J ) 7.0, 6.0, 3.0 Hz, 10 lines, 1-H), 1.38 (t, J ) 8.0
Hz, 3-H), 1.18 (t, J ) 8.0 Hz, 3-H), 1.05 (d, J ) 7.0 Hz, 3-H);
13C NMR (100 MHz, CDCl3) δ 154.7, 146.3, 136.8, 130.9, 130.4
(q, J ) 32.4 Hz), 128.3, 125.5 (q, J ) 3.8 Hz), 124.5 (q, J ) 3.0
Hz), 124.0 (q, J ) 269.5 Hz), 83.9, 64.3, 63.2, 51.7, 34.7, 15.0,
14.3, 12.4. Anal. Calcd for C17H20N2O3ClF3: C, 51.98; H, 5.13;
N, 7.13. Found: C, 52.06; H, 5.16; N, 7.03.
Data for 14f: 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1-H),
8.05 (d, J ) 8.0 Hz, 1-H), 7.62 (d, J ) 8.0 Hz, 1-H), 7.51 (t, J
) 8.0 Hz, 1-H), 4.72 (bs, 1-H), 4.51 (s, 1-H), 4.40-4.30 (m, 2-H),
2.77 (bt, J ) 8.0 Hz, 1-H), 2.63-2.55 (m, 2-H), 2.48-2.40 (m,
2-H), 1.60-1.40 (m, 6-H), 1.38 (t, J ) 8.0 Hz, 3-H), 1.30-1.20
(m, 2-H), 1.05 (t, J ) 8.0 Hz, 3-H).
Data for 15f: 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1-H),
7.89 (d, J ) 8.0 Hz, 1-H), 7.63 (d, J ) 8.0 Hz, 1-H), 7.52 (t, J
) 8.0 Hz, 1-H), 5.09 (d, J ) 4.0 Hz, 1-H), 4.79 (d, J ) 6.0 Hz,
1-H), 4.40-4.30 (m, 2-H), 2.65-2.55 (m, 1-H), 2.45-2.40 (m,
2-H), 2.25-2.17 (m, 1-H), 1.90-1.80 (m, 1-H), 1.60-1.40 (m,
6-H), 1.38 (t, J ) 8.0 Hz, 1-H), 1.30-1.20 (m, 2-H), 1.03 (t, J
) 8.0 Hz, 3-H). Anal. Calcd for C21H27N3O2ClF3: C, 56.57;
H, 6.10; N, 9.42. Found: C, 56.65; H, 6.13; N, 9.37.
5-Meth yl-3-[3-(tr iflu or om eth yl)ph en yl]pyr idazin e (16h ).
This compound was prepared according to the general proce-
dure given for Table 1 above. The corresponding tetrahydro-
pyridazines were treated with 5 equiv of 2.5 N NaOH in DMSO
at 100 °C for 15 min. After workup, the residue was recrystal-
lized from EtOAc/cyclohexane to give the product as an off-
white solid (1.4 g, 76% yield): mp 110-112 °C; 1H NMR (400
MHz, CDCl3) δ 9.05 (d, J ) 2.5 Hz, 1-H), 8.32 (s, 1-H), 8.22 (d,
J ) 8.0 Hz, 1-H), 7.70 (d, J ) 8.0 Hz, 1-H), 7.68 (d, J ) 2.5
Hz, 1-H), 7.60 (t, J ) 8.0 Hz, 1-H), 2.42 (s, 3-H). 13C NMR
(100 MHz, CDCl3) δ 157.4, 152.1, 138.2, 137.3, 131.3 (q, J )
32.4 Hz), 130.3, 129.4, 126.4 (q, J ) 3.8 Hz), 124.1, 124.0 (q,
J ) 268.0 Hz), 123.9 (q, J ) 3.8 Hz), 18.4. Anal. Calcd for
C12H9N2F3: C, 60.51; H, 3.81; N, 11.76. Found: C, 60.42; H,
3.82; N, 11.72.
5-Eth yl-3-[3-(tr iflu or om eth yl)p h en yl]p yr id a zin e (16f).
This compound was prepared according to the general proce-
dure given for Table 1 above from the corresponding tetrahy-
dropyridazines by treatment with 5 equiv of NaOH in DMSO/
water at 100 °C for 1 h. After workup, chromatography on a
Prep-500 and recrystallization from cyclohexane afforded the
compound as a white solid (1.0 g, 33% yield): mp 71-73 °C;
1H NMR (400 MHz, CDCl3) δ 9.03 (bs, 1-H), 8.34 (s, 1-H), 8.22
(d, J ) 8.0 Hz, 1-H), 7.70 (d, J ) 8.0 Hz, 1-H), 7.68 (bs, 1-H),
7.60 (t, J ) 8.0 Hz, 1-H), 2.75 (q, J ) 8.0 Hz, 3-H), 1.35 (t, J
) 8.0 Hz, 3-H); 13C NMR (100 MHz, CDCl3) δ 157.5, 151.4,
143.8, 137.4, 131.4 (q, J ) 32.4 Hz), 130.3, 129.4, 126.4 (q, J
) 3.8 Hz), 124.0 (q, J ) 3.8 Hz), 124.0 (q, J ) 271.0 Hz), 122.8,
25.8, 13.7. Anal. Calcd for C13H11N2F3: C, 61.90; H, 4.40; N,
11.11. Found: C, 61.84; H, 4.39; N, 11.09.
Eth yl 4-Ch lor o-5,6-d ih yd r o-6-(4-m or p h olin yl)-5-p h en -
yl-3-[3-(t r iflu or om et h yl)p h en yl]-1(4H )-p yr id a zin eca r -
boxyla tes (14i a n d 15i). These compounds were prepared
according to the general procedure given for Table 1 above and
were separated from the crude reaction by chromatography
on a Prep-500. Compound 14i was obtained as a white solid
(6.67 g, 46% yield), and 15i was obtained as a white solid (5.70
g, 39% yield).
Eth yl 4-Ch lor o-6-eth oxy-5,6-d ih yd r o-5-m eth yl-3-p h en -
yl-1(4H)-p yr id a zin eca r boxyla tes (14g a n d 15g). These
compounds were prepared according to the general procedure
given for Table 1 above and were isolated by separation of the
crude reaction mixture on a Prep-500 to give 14g as a yellow
oil (5.35 g, 66% yield) and 15g as a white solid (2.08 g, 26%
yield).
Data for 14g: RI 1.5558; 1H NMR (300 MHz, CDCl3) δ 7.70-
7.60 (m, 2-H), 7.20-7.10 (m, 3-H), 5.28 (s, 1-H), 4.31 (s, 1-H),
4.22-4.05 (m, 2-H), 3.44 (q, J ) 7.0 Hz, 2-H), 2.65 (q, J ) 7.4
Hz, 1-H), 1.18 (t, J ) 7.0 Hz, 3-H), 0.99 (t, J ) 7.0 Hz, 3-H),
0.75 (d, J ) 7.4 Hz, 3-H); 13C NMR (75 MHz, CDCl3) δ 155.0,
143.4, 134.9, 129.3, 128.1, 126.1, 80.5, 63.6, 62.8, 45.7, 36.0,
16.2, 14.7, 14.2. Anal. Calcd for C16H21N2O3Cl: C, 59.17; H,
6.52; N, 8.62. Found: C, 58.87; H, 6.56; N, 8.48.
Data for 14i: mp 116-117 °C from EtOAc/cyclohexane; 1H
NMR (400 MHz, CDCl3) δ 8.30 (s, 1-H), 8.15 (d, J ) 8.0 Hz,
1-H), 7.78 (d, J ) 8.0 Hz, 1-H), 7.65 (t, J ) 8.0 Hz, 1-H), 7.40-
7.30 (m, 3-H), 7.15-7.05 (m, 2-H), 5.02 (s, 1-H), 4.93 (s, 1-H),
4.35 (q, J ) 8.0 Hz, 2-H), 3.90-3.75 (m, 4-H), 3.00-2.70 (m,
4-H), 1.38 (t, J ) 8.0 Hz, 3-H). Anal. Calcd for C24H25N3O3-
ClF3: C, 58.13; H, 5.08; N, 8.47. Found: C, 58.20; H, 5.10; N,
8.45.
Data for 15i: mp 134-135 °C from EtOAc/cyclohexane; 1H
NMR (400 MHz, CDCl3) δ 8.15 (s, 1-H), 8.05 (d, J ) 8.0 Hz,
1-H), 7.75 (d, J ) 8.0 Hz, 1-H), 7.63 (t, J ) 8.0 Hz, 1-H), 7.50-
7.40 (m, 3-H), 7.40-7.30 (m, 2-H), 5.42 (d, J ) 6.0 Hz, 1-H),
5.15, (d, J ) 5.2 ha, 1-H), 4.40-4.30 (m, 2-H), 3.90 (apparent
bt, J ) 6.0 Hz, 1-H), 3.80-3.70 (m, 4-H), 2.85-2.75 (m, 4-H),
1.40 (t, J ) 8.0 Hz, 3-H); 13C NMR (100 MHz, CDCl3) δ 155.0,
149.9, 137.0, 136.3, 131.5 (q, J ) 32.6), 129.5, 129.5, 129.3,
128.7, 126.8 (q, J ) 3.7 Hz), 124.5 (q, J ) 4.0 Hz), 124.5 (q, J
) 272.46 Hz), 75.6, 67.4, 63.4, 50.0, 49.5, 44.5, 14.4. Anal.
Calcd for C24H25N3O3ClF3: C, 58.13; H, 5.08; N, 8.47. Found:
C, 58.22; H, 5.09; N, 8.44.
Data for 15g: mp 84-86 °C from EtOAc/cyclohexane; 1H
NMR (300 MHz, CDCl3) δ 7.42-7.35 (m, 2-H), 7.20-7.08 (m,
3-H), 5.33 (d, J ) 3.2 Hz, 1-H), 5.14 (d, J ) 6.3 Hz, 1-H), 4.21-
4.05 (m, 2-H), 3.44 (q, J ) 7.2 Hz, 2-H), 2.39 (qdd, J ) 6.9,
6.3, 3.2 Hz, 1-H), 1.18 (t, J ) 7.2 Hz, 3-H), 0.98 (t, J ) 7.2 Hz,
3-H), 0.85 (d, J ) 6.9 Hz, 3-H). 13C NMR (75 MHz, CDCl3) δ
154.7, 147.9, 135.9, 128.8, 127.7, 127.4, 83.7, 64.0, 62.8, 51.8,
34.7, 14.9, 14.2, 12.4. Anal. Calcd for C16H21N2O3Cl: C, 59.17;
H, 6.52; N, 8.62. Found: C, 59.41; H, 6.57; N, 8.68.
5-Meth yl-3-p h en ylp yr id a zin e (16g). This compound was
prepared according to the general procedure given for Table 1
above and was isolated by separation on the Prep-500.
Compound 16g was obtained as an off-white solid (2.08 g, 68%
1
yield): mp 89-91 °C from EtOAc/cyclohexane; H NMR (400
5-P h en yl-3-[3-(tr iflu or om eth yl)ph en yl]pyr idazin e (16i).
This compound was prepared according to the general proce-
MHz, CDCl3) δ 9.02 (d, 2.5 Hz, 1-H), 8.15-8.05 (m, 2-H), 7.68