2
024
M. Angiolini et al./Bioorg. Med. Chem. 6 (1998) 2013±2027
(
4
m, 4H, aromatic H), 5.50 (t, J=1.25 Hz, 1H, C=CH),
.15 (q, J=7.5 Hz, 2H, OCH CH ), 3.45 (d, J=1.25 Hz,
2 3
J=17, 8 Hz, 1H, N=NHCH), 4.65 (dd, J=17, 10 Hz,
1H, N=NHCH), 4.15 (q, J=6.5 Hz, 2H, OCH CH ),
2
3
2
H, ArCH
2
), 2.45 (t, J=8 Hz, 2H, CH
CH , CH CH CH ), 0.85 (t, J=6.5 Hz,
H, CH CH CH ). C H N O (660.8): calcd C 78.16,
2
CO), 1.65±1.20
3.75 (d, J=15 Hz, 1H, ArHCH), 3.45 (dd, J=10, 8 Hz,
1H, CHCOOEt), 3.15 (d, J=15 Hz, 1H, ArHCH), 2.60
(m, 2H, CH CO), 1.60±1.10 (m, 7H, OCH CH , CH CH
(
m, 7H, OCH
2
3
3
2
2
3
3
2
2
43 40
4
3
2
2
3
3
2
H 6.10, N 8.48; found C 78.22, H 6.19, N 8.59.
CH
(
2
), 0.90 (t, J=6.5 Hz, 3H, CH
3
CH
2
CH
2
). 13C NMR
3
CDCl ) d 205.40, 170.86, 154.46, 142.34, 141.82, 141.20,
0
0
trans-4-Oxo-3-[[2 -(1H-tetrazol-5-yl)[1,1 -biphenyl]-4-yl]-
methyl]-oct-2-enoic-acid ethyl ester (1b). A solution of
trans isomer 11 (0.15 g, 0.227 mmol) in MeOH (3 mL)
was re¯uxed for 4 h. The reaction was then concentrated
and the crude product was puri®ed by ¯ash column
138.19, 130.56, 130.05, 129.74, 128.95, 128.13, 127.52,
126.45, 106.3, 79.97, 62.12, 41.53, 40.13, 37.97, 25.21,
28 6 3
22.16, 14.0, 13.67. C25H N O (460.5): calcd C 65.2, H
6.13, N 18.25; found C 65.23, H 6.15, N 18.21.
0
chromatography (hexane/AcOEt, 8/2 and CHCl
1
3
/
()-trans-2-[[2 -[1-(Triphenylmethyl)-1H-tetrazol-5-yl]-
0
MeOH, 9/1) to aord 1b (0.085 g, yield 90%). H NMR
CDCl ) d 8.34±8.20 (m, 1H, aromatic H), 7.64±7.15 (m,
[1,1 -biphenyl]-4-yl]methyl]-2-valeryl-cyclopropan-1-carb-
(
oxylic acid ethyl ester (14). To a solution of 13
(0.65 g, 0.926 mmol) in acetone (2 mL) 300 mL of hexane
were added and the mixture was loaded into the photo-
reactor provided with a quartz sun-lamp (500 W). After
2 h of irradiation the solvent was removed under
reduced pressure. The residue was puri®ed by ¯ash col-
umn chromatography (hexane/AcOEt, 8/2) to aord 14
3
7
H, aromatic H), 6.73 (s, 1H, C=CH), 4.30 (q,
J=7.5 Hz, 2H, OCH CH ), 3.65 (s, 2H, ArCH ), 2.62
t, J=7.5 Hz, 2H, CH CO), 1.65±1.15 (m, 7H,
2
3
2
(
2
OCH
CH
2
CH
CH CH
3
, CH ), 0.89 (t, J=6.5 Hz, 3H,
26 4 3
). C24H N O (418.5): calcd C 68.88, H
3
CH
2
CH
2
3
2
2
6
.26, N 13.39; found C 68.71, H 6.19, N 13.47.
(
0.34 g, yield 53%) in 9/1 ratio trans/cis. 1H NMR
0
(
)-trans-3-[[2 -[1-(Triphenylmethyl)-1H-tetrazol-5-yl]-
0
(CDCl ) d 8.0±7.80 (m, 1H, aromatic H), 7.62±7.20 (m,
3
[1,1 -biphenyl]-4-yl]methyl]-3-valeryl-4-carbethoxy-1-pyr-
azoline (13). Alkenes 11/12 (1.55 g, 2.35 mmol) were
18H, aromatic H), 7.15±6.90 (m, 4H, aromatic H), 4.20±
4.0 (m, 2H, OCH CH ), 3.29 (s, 2H, ArCH ), 2.44 (dd,
2
3
2
ꢀ
dissolved in 15 mL of Et
tion of CH
low colour permanently appeared in the solution. The
2
O at � 10 C and then a solu-
J=6.5, 3 Hz, 1H, CHCOOEt), 2.35 (t, J=7 Hz, 2H,
CH CO), 1.76±1.20 (m, 9H, OCH CH , CH CH CH
2
N
2
in diethyl ether was added until the yel-
2
2
3
3
2
2
,
CH CHCOOEt), 0.81 (t, J=7.5 Hz, 3H, CH CH CH ).
2
2
3
2
¯
ask was wrapped with aluminum foil and the mixture
C
found C 78.35, H 6.23, N 8.23.
44
H
42 4 3
N O (674.8): calcd C 78.31, H 6.27, N 8.30;
ꢀ
stirred for 2 h at � 10 C and then warmed to room
temperature. Only the E-isomer reacts (by TLC analy-
sis). The mixture was concentrated under reduced pres-
sure and the residue puri®ed by ¯ash column
0
0
()-trans-2-[[2 -(1H-Tetrazol-5-yl)[1,1 -biphenyl]-4-yl]
methyl]-2-valeryl-cyclopropan-1-carboxylic acid ethyl ester
(4b). A solution of trans isomer 14 (0.28 g, 0.415 mmol)
in MeOH (20 mL) was re¯uxed for 4 h. The reaction was
then concentrated and the crude product was puri®ed by
¯ash column chromatography (hexane/AcOEt, 8/2 and
chromatography (hexane/AcOEt, 8/2) to aord 13
1
(
913 mg, yield 55%) and 12 (440 mg). H NMR (CDCl )
3
d 8.0±7.80 (m, 1H, aromatic H), 7.62±7.20 (m, 18H,
aromatic H), 7.15±6.90 (m, 4H, aromatic H), 4.88 (dd,
J=17, 6 Hz, 1H, N=NHCH), 4.45 (dd, J=17, 8 Hz,
CHCl /MeOH, 9/1) to aord 4b (0.16 g, yield 90%).
3
1
H, N=NHCH), 4.15 (q, 2H, OCH
2
CH
3
), 3.25 (dd,
Successful ¯ash column chromatography with CH
2
Cl
allowed the isolation of the product. H NMR (CDCl
d 8.0±6.90 (m, 8H, aromatic H), 4.15 (q, J=7 Hz, 2H,
OCH CH ), 3.29 (dd, J=15 Hz, 2H, ArCH ), 2.44 (dd,
J=6, 3 Hz, 1H, CHCOOEt), 2.35 (m, 2H, CH CO),
2
1
J=8, 6 Hz, 1H, CHCOOEt), 3.21 (d, J=14 Hz, 1H,
ArHCH), 3.06 (d, J=14 Hz, 1H, ArHCH), 2.25 (t,
J=7 Hz, 2H, CH
3
)
2
CO), 1.68±1.10 (m, 7H, OCH
CH
2
CH
CH
3
,
).
2
3
2
CH CH CH ), 0.75 (t, J=6.5 Hz, 3H, CH
2
3
2
3
2
2
2
13
C NMR (CDCl ) d 207.10, 170.15, 164.27, 142.22,
1.70±1.35 (m, 6H, CH CH CH , CH CHCOOEt), 1.22
2
3
3
2
2
1
1
7
41.82, 141.22, 138.18, 130.60, 130.15, 129.74, 128.93,
(t, J=7 Hz, 3H, OCH
H
28
2
CH
3
), 0.75 (t, J=7.5 Hz, 3H,
(432.5): calcd C 69.42, H
28.15, 127.52, 127.11. C44
5.19, H 6.02, N 11.96; found C 75.08, H 6.17, N 11.94.
H
42
N
6
O
3
(702.8): calcd C
CH
3
CH
2
CH
2
). C25
6.53, N 12.95; found C 69.45, H 6.59, N 12.88.
4
N O
3
0
0
(
methyl]-3-valeryl-4-carbethoxy-1-pyrazoline (3b).
)-trans-3-[[2 -(1H-Tetrazol-5-yl)[1,1 -biphenyl]-4-yl]-
A
() 2-(2-Hydroxyhexyl)pyridine (15). To a stirred solu-
tion of 2-picoline (10 g, 0.107 mol) in dry THF (70 mL)
solution of 13 (0.25 g, 0.356 mmol) dissolved in 40 mL of
MeOH was re¯uxed for 4 h and then the reaction was
concentrated. The residue was then recrystallized from
ethyl acetate to provide 0.16 g of 3b (yield 97%), mp
BuLi 2.5 M in hexane (43 mL, 0.107 mol) was dropped
ꢀ
under N
stirred at 0 C for 30 min, then a solution of valer-
aldehyde (11.4 mL, 0.107 mol) in dry THF (30 mL) was
2
atmosphere at � 10 C. The red solution was
ꢀ
ꢀ
1
ꢀ
1
51.4±152.7 C. H NMR (CDCl
aromatic H), 7.62±7.20 (m, 7H, aromatic H), 4.85 (dd,
3
) d 8.20±8.10 (m, 1H,
added dropwise at 0 C. The cooling bath was removed.
The mixture reached room temperature in 1 h and was