Synthesis of an Analogue of the Insecticide Pirate
231
128.2 (C3ꢀ,5ꢀ), 125.6 (C2ꢀ,6ꢀ), 123.4 (C5), 122.9 (C2), 114.7 (C3), 109.3
(C4), 20.9 (CH3). m/z (ESI+) 288 (MNa+, 20%).
reduced pressure. Water (1 mL) was added dropwise, followed by aque-
ous ammonia until the solution became basic.The solution was extracted
with DCM (2 × 10 mL) and worked up as described above. The crude
product was recrystallized (DCM/hexane) and dried to yield the title
compound 18 as a white solid (0.758 g, 55%), mp 112–112.5◦C (Found:
364.0883. M+ requires 364.0882). vmax (KBr)/cm−1 3154, 1601, 1357,
1176. δH (400 MHz, CDCl3) 7.79 (2 H, d, J 8.5, o-SO2C6H4), 7.63 (2
H, d, J 7.1, H2ꢀꢀ, 6ꢀꢀ), 7.58 (1 H, dd, J 1.7, 3.4, H5ꢀ), 7.43 (2 H, m,
H3ꢀꢀ, 5ꢀꢀ), 7.39 (1 H, s, H4), 7.35 (1 H, m, H4ꢀꢀ), 7.26 (2 H, d, J 8.5,
m-SO2C6H4), 6.90 (1 H, dd, J 1.7, 3.4, H3ꢀ), 6.40 (1 H, dd, J 3.4, 3.4,
H4ꢀ), 2.39 (3 H, s, CH3). δC (100 MHz, CDCl3) 153.2 (C1ꢀꢀ), 151.5 (C5),
145.2 (p-SO2C6H4), 135.6 (i-SO2C6H4), 129.7 (m-SO2C6H4), 128.9
(C3ꢀꢀ, 5ꢀꢀ), 128.6 (C4ꢀꢀ), 127.7 (o-SO2C6H4), 126.3 (C5ꢀ), 124.4 (C2ꢀꢀ,
6ꢀꢀ), 122.9 (C4), 121.9 (C2ꢀ), 119.5 (C3ꢀ), 111.7 (C4ꢀ), 21.6 (CH3), C2
not observed. m/z (ESI+) 397 (MNa+, 84%).
Bis(1-tosyl-1H-pyrrol-2-yl) Ketone 15: Example Isolation
Oxalyl chloride (2.63 g, 1.8 mL, 20.7 mmol) and aluminium chloride
(5.5 g, 41.5 mmol) in 1,2-DCE (1,2-dichloroethane; 50 mL) were
reacted as above at 0◦C for 30 min. 1-Tosyl-1H-pyrrole (4.515 g,
20.4 mmol) in 1,2-DCE (3 mL) was added, and the resulting mix-
ture stirred at room temperature for 1.5 h. Quenching and workup as
described above gave a slurry which was kept in the freezer overnight.
The solid that formed was isolated by filtration, dried under vacuum,
and recrystallized (diethyl ether) to give the title compound 15 as a
white solid (0.85 g, 18% from N-tosylpyrrole), mp 180–182◦C (Found:
468.0819. [M]+ requires 468.0814). vmax (KBr)/cm−1 1645, 1361,
1171. δH (200 MHz, CDCl3) 7.85 (2 H, d, J 8, H2ꢀ, 6ꢀ), 7.65–7.73
(1 H, m, H5), 7.35 (2 H, d, J 8, H3ꢀ, 5ꢀ), 6.82 (1 H, dd, J 1.4, 3.6, H3),
6.30 (1 H, dd, J 3.8, 3.8, H4), 2.49 (3 H, s, CH3). δC (50 MHz, CDCl3)
172.2 (C=O), 145.0 (C1ꢀ), 136.3 (C4ꢀ), 133.4 (C2), 129.4 (C5), 129.3
(C3ꢀ,5ꢀ), 128.9 (C2ꢀ,C6ꢀ), 124.5 (C3), 110.7 (C4), 22.0 (CH3). m/z (EI)
468 (3%, M+), 313 (34), 249 (46), 155 (51).
5-Phenyl-2-(1H-pyrrol-2-yl)oxazole 5
The tosylpyrrole oxazole 18 (0.500 g, 1.37 mmol), sodium hydroxide
(2.75 mL, 5 M), and methanol (8 mL) were heated at reflux for 3.5 h.
Methanol was removed under vacuum and the residue extracted (ethyl
acetate, 3 × 5 mL). Upon workup, as described above, the crude product
obtained was recrystallized (DCM/hexane) and dried to yield the title
compound 5 as a brown solid (0.150 g, 52%), mp 158–159◦C (Found:
210.0796. M+ requires 210.0793). vmax (KBr)/cm−1 3195, 1607, 1514.
δH (400 MHz, CDCl3) 10.29 (1 H, br, NH), 7.70 (2 H, d, J 8.4, H2ꢀꢀ, 6ꢀꢀ),
7.45 (2H, m, H3ꢀꢀ, 5ꢀꢀ), 7.36 (1H, s, H4), 7.34 (1H, m, H4ꢀꢀ), 6.98 (1H, m,
H5ꢀ), 6.95 (1H, m, H3ꢀ), 6.35 (1H, m, H4ꢀ). δC (100 MHz, CDCl3) 156.6
(C2), 149.9 (C5), 128.9 (C3ꢀꢀ, 5ꢀꢀ), 128.2 (C4ꢀꢀ), 127.9 (C1ꢀꢀ), 123.9 (C2ꢀꢀ,
6ꢀꢀ), 122.2 (C4), 121.5 (C5ꢀ), 120.4 (C2ꢀ), 110.6 (C3ꢀ), 110.2 (C4ꢀ). m/z
(ESI+) (MH+, 100%).
N-Phenacyl-p-toluenesulfonamide 16
1-Tosyl-1H-pyrrole-2-carboxylic acid 12 (0.485 g, 1.83 mmol) was
refluxed in thionyl chloride (15 mL) overnight. Excess thionyl chloride
was removed by rigorous drying under high vacuum, and the residue
was dissolved in DCM (15 mL). Triethylamine (0.508 g, 5.02 mmol,
0.7 mL) and DMAP (0.006 g, 0.05 mmol) were added followed by the
bromide 11 (0.436 g, 1.88 mmol), and the reaction mixture was stirred
for 48 h. The solvent was removed under vacuum and the residue puri-
fied by column chromatography on silica gel (DCM/methanol, 99 : 1
v/v) to yield the title compound 16 as orange/brown crystals (0.139 g,
26%), mp 115–117◦C (lit.[20] 118.5–120◦C, lit.[26] 195–197◦C). vmax
(KBr)/cm−1 3277, 1685, 1345, 1165. δH (400 MHz, CDCl3)7.81(2H, d,
J 7.7, o-C6H5), 7.75 (2 H, d, J 8.1, o-SO2C6H4), 7.56 (1 H, m, p-C6H5),
7.42 (2 H, dd, J 7.7, 7.7, m-C6H5), 7.24 (2 H, d, J 8.1, m-SO2C6H4),
5.70 (1 H, br t, NH), 4.40 (2 H, d, J 5.4, CH2), 2.35 (3 H, s, CH3).
δC (100 MHz, CDCl3) 192.5 (C(O)NH), 143.7 (p-SO2C6H4), 136.0
(i-SO2C6H4), 134.3 (p-C6H5), 133.7, (i-C6H5), 129.7 (m-SO2C6H4),
128.9 (m-C6H5), 127.8 (o-C6H5), 127.1 (o-SO2C6H4), 48.6 (CH2),
21.4 (CH3). m/z (ESI−) 290 ([M − H]−, 100%).
2-[1-Ethoxymethyl-1H-pyrrol-2-yl]-5-phenyl-1,3-oxazole 4
The pyrrole oxazole 5 (0.190 g, 0.9 mmol) was added to a solution of
dry THF and hexane (1 : 1, 16 mL) at 0◦C. n-Butyllithium (0.82 mL,
0.9 mmol, 1.09 M as a solution in hexanes) was added dropwise while
the temperature was maintained between 0 and 5◦C. The solution was
stirred for 15 min at 0◦C, and then warmed to room temperature. DMSO
(20 mL) was added and the solution heated to 65◦C. The reaction mix-
ture was treated portionwise with chloromethyl ethyl ether (0.095 mL,
0.102 g, 1.08 mmol) over 1 h and stirred for 12 h at 65◦C. The solution
was cooled and a diethyl ether/water (1 : 1; 20 mL) mixture was added.
Theaqueouslayerwasextracted(diethylether, 3 × 5 mL). Uponworkup,
as described above, micro-flash chromatography (hexane flush followed
by a DCM flush) was performed on the crude product to yield the
title compound 4 (207 mg, 89%), mp 70–73◦C (Found: 268.1212. M+
requires 268.1212). vmax (KBr)/cm−1 2925, 1600, 1100. δH (400 MHz,
CDCl3) 7.69 (2 H, d, J 8.14, H2ꢀꢀ, 6ꢀꢀ), 7.44 (2 H, m, H3ꢀꢀ, 5ꢀꢀ), 7.38
(1 H, s, H4), 7.32 (1 H, m, H4ꢀꢀ), 7.01 (1 H, dd, J 1.83, 2.75, H5ꢀ), 6.98
(1 H, dd, J 1.83, 3.85, H3ꢀ), 6.30 (1 H, dd, J 2.75, 3.85, H4ꢀ), 5.89
(2 H, s, NCH2O), 3.54 (2 H, q, J 7.05, OCH2CH3), 1.18 (3 H, t,
J 7.05, OCH2CH3). δC (100 MHz, CDCl3) 155.8 (C2), 149.4 (C5),
128.9 (C3ꢀꢀ, 5ꢀꢀ), 128.1 (C1ꢀꢀ, 4ꢀꢀ), 126.2 (C3ꢀ), 124.0 (C2ꢀꢀ, 6ꢀꢀ), 122.7
(C4), 121.1 (C2ꢀ), 113.6 (C4ꢀ), 109.4 (C5ꢀ), 77.1 (NCH2O), 64.0
(OCH2CH3), 14.9 (OCH2CH3). m/z (ESI+) (MLi+, 100%).
N-(2-Oxoethylphenyl)-1-tosyl-1H-pyrrole-2-carboxamide 17
Triethylamine (4.90 mL, 3.557 g, 35 mmol) and DMAP (0.047 g,
0.4 mmol) were added to N-tosylpyrrole-2-carbonyl chloride 14
(4.044 g, 14 mmol) in DCM (75 mL) and then the bromide 11 (3.249 g,
14 mmol) was added. The reaction mixture was stirred at room tem-
perature for 48 h. Water (15 mL) was added and the solution extracted
(DCM, 3 × 15 mL). The organic layers were washed (saturated, aque-
ous Na2CO3, 2 × 20 mL) and then worked up as described above. The
crude product was recrystallized (DCM/hexane) and dried to yield the
title compound 17 as a brown solid (1.930 g, 36%), mp 178.6–180.0◦C
(Found: 382.0983. M+ requires 382.0987). vmax (KBr)/cm−1 3358,
1642, 1367, 1158. δH (400 MHz, CDCl3) 8.00 (2 H, d, J 7.3, H2ꢀꢀ,
6ꢀꢀ), 7.93 (2 H, d, J 7.3, o-SO2C6H4), 7.64 (1 H, m, H4ꢀꢀ), 7.55 (1 H, dd,
J 1.8, 3.4, H5), 7.52 (2 H, m, H3ꢀꢀ, 5ꢀꢀ), 7.32 (2 H, d, J 7.3, m-SO2C6
H4), 7.30 (1 H, br, NH), 6.82 (1 H, dd, J 1.8, 3.4, H3), 6.30 (1 H, dd,
J 3.4, 3.4, H4), 4.89(2H, d, J 4.4, H1ꢀ), 2.41(3H, s, CH3). δC (100 MHz,
CDCl3) 193.7 (C2ꢀ), 160.0 (C(O)NH), 145.1 (p-SO2C6H4), 135.9
(i-SO2C6H4), 134.3 (C1ꢀꢀ), 134.2 (C4ꢀꢀ), 129.6 (m-SO2C6H4), 129.1
(C2), 128.9 (C3ꢀꢀ, 5ꢀꢀ), 127.9 (C2ꢀꢀ, 6ꢀꢀ, o-SO2C6H4), 126.9 (C5), 118.7
(C3), 110.8 (C4), 46.8 (C1ꢀ), 21.7 (CH3). m/z (ESI+) 383 (MLi+, 68%).
Brine Shrimp Assay
A. salina eggs were kept for 24 h in artificial seawater as described
previously,[23] and the nauplii (n ≈ 15) were brought into a 24-well
micro-titre plate with brine (980 µL). Compounds 4 and 5 were added
in various concentrations (0.1, 1.0, 10, and 100 µg dissolved in 20 µL
of DMSO). Assays were carried out in quadruplicate for each con-
centration. DMSO was required to improve compound solubility. The
maximum concentration tested was 100 µg mL−1. After incubation at
26◦C for 24 h, the surviving larvae were counted and compared to the
DMSO controls. The total brine shrimp per well was counted upon
addition of formaldehyde (200 µL). The control deaths were <2%.
5-Phenyl-2-(1-tosyl-1H-pyrrol-2-yl)oxazole 18
The pyrrole-2-carboxamide 17 (1.500 g, 3.7 mmol) was dissolved in
phosphorus oxychloride (40 mL), and the resulting solution was heated
at reflux for 2 h, and then stirred at room temperature for an addi-
tional 2 h. Excess phosphorus oxychloride was removed by distillation at