An enantioselective synthesis of insecticidal 4-alkynyloxazolines

Article abstract of DOI:10.1016/S0968-0896(01)00153-5

2-(2,6-Difluorophenyl)-4-phenylalkynyl oxazolines are potent insect growth regulators. An efficient and enantioselective synthesis to these compounds has been developed which relies on a (-)-sparteine mediated hydroxymethylation of the lithium dianion of propargylic amides.

Full text of DOI:10.1016/S0968-0896(01)00153-5

Bioorganic & Medicinal Chemistry 9 (2001) 2857–2862
An Enantioselective Synthesis of Insecticidal 4-Alkynyloxazolines
David Clark* and D. Andrew Travis
DuPont Crop Protection, Stine/Haskell Research Center, PO Box 30, Bldg 300, Newark, DE19714, USA
Received 28 February 2001; accepted 2 May 2001
Abstract—2-(2,6-Difluorophenyl)-4-phenylalkynyl oxazolines are potent insect growth regulators. An efficient and enantioselective
synthesis to these compounds has been developed which relies on a (ꢀ)-sparteine mediated hydroxymethylation of the lithium
dianion of propargylic amides. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
2,4-Diaryl oxazolines such as 1 (Fig. 1) were recently
found to be very potent growth regulators on species of
acari and lepidoptera.1 These compounds act by inhi-
biting the synthesis of chitin which is required for the
development of the insect or aracnid exoskeleton. As
compounds that inhibit a molecular pathway that is
specific to arthropods, they represent a selective method
of insect control.
We therefore desired a more efficient approach and
became interested in the work of Metcalf et al. who had
described a bis-metalation of N-Boc protected pro-
pargylamines3 (Scheme 2).
We suspected that this could be extended to the meta-
lation of N-propargyl 2,6-difluorobenzamide systems
such as 8, thus obviating the need for protection of the
amine function, followed by oxazoline formation and
finally a divergent introduction of aryl groups via a
Sonogashira coupling reaction.4
The acetylene spaced analogues such as 5 (Scheme 1)
were discovered at DuPont and found to possess excel-
lent activity on the above species.2 The compounds were
originally synthesized through an electrochemical oxi-
dation of urethane 2 to give 3 followed by reaction with
an alkynyl aluminum to give the urethane 4. Hydrolysis,
acylation and then cyclization with Burgess’ reagent
yielded the desired oxazoline 5. In addition to the gen-
erally low overall yield obtained in this synthesis, the
route is not amenable to efficient analogueing around
the aryl alkyne group since this is introduced early in
the synthesis with an aluminum species that requires
synthesis.
Scheme 1. Prior synthesis of acetylenic oxazolines 5:2 (a) MeOH,
HOAc, n-Bu4NBF4, e-, 80%; (b) Al(CCPh-X)3, toluene, 22 ꢁC, 31%
for R=H; (c) KOH, EtOH, H2O, 78 ꢁC, 70%; (d) 2,6-difluorobenzoyl
chloride, NEt3, CH2Cl2; (e) LiBH4, THF, 66 ꢁC, 62% for two steps; (f)
MeO2CNꢀSO2NEt+3 , THF, 66 C, 70%.
Scheme 2. Metalation of N-Boc propargylamines according to Metcalf
et al.3
Figure 1. Arthropodicidal oxazolines.
*Corresponding author. Fax: +1-302-366-5738; e-mail: david.a.clark@usa.dupont.com
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00153-5

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D. Clark, D. A. Travis / Bioorg. Med. Chem. 9 (2001) 2857–2862
The TIPS protected alkyne 9a was readily available in
two steps from propargyl amine and 2,6-difluoro-
benzoyl chloride. Treatment of this alkyne with LDA in
the presence of TMEDA in THF at ꢀ78 ꢁC followed by
the introduction of formaldehyde gas gave the desired
hydroxymethyl compound 10a along with the allene 11a
in a 4:3 ratio. It was thought that by increasing the size of
the alkyne protecting group it might be possible to
increase the amount of 10 relative to 11. Thus, applying
the same procedure to 9b gave alkyne 10b which was
contaminated with only trace (ca. 5%) amounts of
allene 11b (Scheme 3).
Alcohol 10b could now be cyclized to the desired oxa-
zoline 14b using Tf2O in pyridine6 and the TIPS group
was readily removed using TBAF/HOAc to give the
terminal alkyne 15. This compound was stable for 1–2
days at ambient temperature if kept in solution but it
appears to polymerize when stored neat. The overall
yield of the sequence was around 30% and multigram
amounts are readily obtainable. Finally, as anticipated,
alkyne 15 was readily coupled to aryl iodides at ambient
temperature and, albeit in lower yield, to aryl bromides
at elevated temperature (80–90 ꢁC) (Scheme 5).
The 4-t-butylphenyl analogue 16 was a representative
example. This compound completely controlled larval
two spotted spider mites (Tetranychus urticae) on kid-
ney bean at 0.1 ppm and larval Fall Army Worm (Spo-
doptera frugiperda) on lima bean at 1.0 ppm. Smaller
substituents on the alkynyl phenyl group resulted in a
sharp loss in lepidopteran activity. Naphthalene alkynes
were somewhat more active but the most potent com-
pounds were substituted biphenyl alkynes such as 21.
Methyl substitution around the oxazoline ring had a
detrimental effect on activity (Tables 1 and 2).
The use of formaldehyde in this reaction presented a
few technical difficulties due to its rapid repolymeriza-
tion at ꢀ78 ꢁC. It was best introduced through a thick
cannula well above the surface of the liquid and rely on
vigorous vortexing of the mixture for its absorption (see
Experimental). The moderate yield obtained in this
reaction was suspected to be due to the formation of
formic acid via a Cannizzaro reaction of formaldehyde.
This led to the recovery of a mixture of starting material
and allene 12 in a 1:1 ratio and was later addressed by
the controlled heating of paraformaldehyde at 130 ꢁC.
Dimethylformamide and methyl chloroformate were
also examined as alternative electrophiles that might
provide a more convenient access to the desired alcohol
10 and might also be of utility in preparing analogues of
the antibiotic ethynyl glycine.5 However, upon quench-
ing the dianion of 9 with either of the above, com-
pounds 13a and 13b were isolated, apparently resulting
from a 1,4-addition of the amide oxygen into an a,b,g
unsaturated carbonyl group followed by tautomerisation
(Scheme 4).
Scheme 4. Reagents and conditions: (a) 2.1 equiv n-BuLi, 2.2 equiv
diisopropylamine, THF, ꢀ78 ꢁC, then 1.1 equiv HCO2Et or
ClC(O)OMe, 2 h, 50%.
Scheme 3. Reagents and conditions: (a) 1.05 equiv propargylamine,
1.25 equiv NEt3, 0.01 equiv DMAP, CH2Cl2, 0–20 ꢁC, 6 h, 97%: (b)
2.1 equiv n-BuLi, 2.2 equiv diisopropylamine, THF, ꢀ78 ꢁC, then 1.1
equiv R3SiCl, ꢀ78 to 20 ꢁC, 14 h, 85% for 9b; (c) 2.05 equiv n-BuLi,
2.1 equiv diisopropylamine, 2.1 equiv TMEDA, THF, ꢀ78 ꢁC, then
excess CH2O(g), 0.5 h, 45% of 10b.
Scheme 5. Reagents and conditions: (a) 1.05 equiv Tf2O, pyridine, 15–
20 ꢁC, 0.5 h, 64%; (b) 1.2 equiv TBAF, 1.2 equiv HOAc, THF, 20 ꢁC,
3 h, 88%; (c) 0.05 equiv Pd(PPh3)4, 0.1 equiv CuI, 3.5 equiv NEt3, 2
equiv 4-t-butyliodobenzene, DMF, 20 ꢁC, 14 h, 98%.

D. Clark, D. A. Travis / Bioorg. Med. Chem. 9 (2001) 2857–2862
2859
Given the successful preparation of the target com-
pounds, we now examined a modification of the route
to provide an enantiomeric synthesis. To the best of our
Conclusion
In conclusion, an efficient route to 2-aryl-4-alkynyl
oxazolines has been developed which enables the diver-
gent synthesis of compounds such as 16. This route is
also amenable to the synthesis of enantioenriched ana-
logues via an enantioselective lithiation/alkylation
mediated by (ꢀ)-sparteine.
knowledge,
a
sparteine mediated enantioselective
deprotonation/alkylation7 of proparglic amide systems
has not been reported. Treatment of propargyl amide 9b
with LDA in ethyl ether in the presence of one equiva-
lent of (ꢀ)-sparteine followed by introduction of gas-
eous formaldehyde gave optically active alcohol 10b.
Mosher ester analysis of this material showed a 5:2 ratio
of diastereomers. This ratio was not affected by the use
of 2 equivalents of (ꢀ)-sparteine. The reaction did not
proceed well in toluene. Conversion of this optically
active alcohol to the 4-bromobiphenyl analogue 21 gave
a solid with aD +2.5ꢁ. This could be crystallized from
chlorobutane to give material with aD of +7.8ꢁ.
Recrystallization did not increase the optical rotation of
the material. The absolute configuration was deter-
mined by X-ray crystallographic analysis (Fig. 2).
Unfortunately, this enantiomer proved not to be the
biologically relevant material.
Experimental
General
Reactions were carried out under an atmosphere of dry
nitrogen using anhydrous solvents purchased from the
Aldrich Chemical Company Inc. where appropriate.
Amine bases were dried and stored over potassium
hydroxide. Glassware was oven dried before use. Reac-
tions were monitored by TLC on E. Merck silica gel
plates (0.25 mm) and visualized under UV light (254
nm) and/or heating with phosphomolybdic acid ethanol
solution. Reaction temperatures were measured intern-
ally. Solvents used for work up and chromatography
were reagent grade from E. Merck or VWR Scientific.
Flash chromatography was performed on E. Merck
silica gel (60, particle size 0.040–0.063 mm). Yields refer
to chromatographically and spectroscopically (1H
NMR) pure materials.
Table 1. Insecticidal and acaricidal activity of substituted phenyl
alkynes
Compd
X
Y
Z
R
Fall army Two spotted
worm spider mite
(LC80, ppm) (LC80, ppm)
16
17
18
19
20
21
22
23
24
25
26
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
t-Bu
O-t-Bu
H
0.1
10
>10
>10
0.01
NMR spectra were recorded on a Varian 300 MHz
instrument at 25 ꢁC. Chemical shifts are reported rela-
tive to the residual solvent peak. Multiplicities are
designated singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m) or broad singlet/multiplet (bs/bm). IR
samples were prepared by evaporation of a solution of
the compound from CDCl3 onto a NaCl plate under
a stream of nitrogen. IR spectra were recorded on a
Perkin–Elmer 1600 series spectrometer. Mass spectra
were recorded on a Micromass spectrometer under FAB
conditions. Melting points were recorded on a Thomas
Hoover Unimelt apparatus and are uncorrected.
Microanalyses were performed at Quantitative
Technologies Inc., Whitehouse, NJ, USA.
CF3
4-OTf-Ph
4-Br-Ph
4-F-Ph
Ph
4-t-Bu
4-t-Bu
4-t-Bu
<0.1
<0.1
<0.1
<0.1
0.3
0.5
10
0.01
0.01
IC50’s are accurate to approximatelyꢂ50%.
Table 2. Insecticidal and acaricidal activity of substituted naphthyl
alkynes
Compd
R=
Fall army worm
(LC80, ppm)
27
28
29
OTf
OCH2CF3
Br
0.2
1
5
N-Propargyl 2,6-difluorobenzamide (8). To a solution of
propargylamine (17.67 g, 321 mmol), 4-dimethylamino-
pyridine (391 mg, 3.2 mmol) and triethylamine (54 mL,
388 mmol) in methylene chloride (320 mL) at 0 ꢁC was
added 2,6-difluorobenzoyl chloride (38.3 mL, 305
mmol) in a dropwise fashion. Upon complete addition,
the cooling bath was removed and the mixture was stir-
red at ambient temperature for a further 6 h. The reac-
tion mixture was then washed with normal HCl, dried
(magnesium sulfate), concentrated and crystallized from
toluene to give amide 8 (57.6 g, 97%) as a white solid.
White solid, mp 89–90 ꢁC. Rf 0.32 (silica gel, 3:2 ethyl
1
ether/hexanes); H NMR (300 MHz, CDCl3) d 7.4 (m,
1H), 6.96 (t, 2H), 6.2 (bs, 1H), 4.27 (m, 2H), 2.29 (d,
1H); 13C NMR (75 MHz, CDCl3) d 158.5, 158.5 (dt,
J=253, 6.9 Hz), 130.5 (t, J=10.4 Hz), 111.9 (t, J=19.5
Hz), 110.4 (m), 77.17, 70.6, 28.1; IR (film) nmax 3296,
3072, 1650, 1536, 1463, 1235, 1004 cmꢀ1; MS (M+H+)
Figure 2. ORTEP representation of the X-ray crystal structure of
compound 21.

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D. Clark, D. A. Travis / Bioorg. Med. Chem. 9 (2001) 2857–2862
196.06. Anal. calcd for C10H7NOF2: C, 61.54; H, 3.62;
N, 7.18. Found: C, 61.40; H, 3.75; N, 7.09.
and purified by flash column chromatography (silica
gel, 2:3 ethyl ether/hexanes) to give the alcohol 10b
(13.5g, 45%) as a white solid. White solid. Mp 100–
N-3-(Triisopropylsilyl)-2-propargyl 2,6-difluorobenzamide
(9b). To a solution of diisopropylamine (36.2 mL, 258
mmol) in tetrahydrofuran (240 mL) at ꢀ10 ꢁC was
added, dropwise with stirring, n-BuLi (99 mL, 2.5 M
solution in hexane, 248 mmol). After 0.25 h at this
temperature the mixture was added to a cooled solution
of terminal alkyne 8 (22.93 g, 118 mmol) in tetra-
hydrofuran (240 mL) such that the temperature was
maintained below ꢀ65 ꢁC. After complete addition, the
mixture was stirred for an additional 0.25 h before the
addition of chlorotriisopropylsilane (26.4 mL, 123
mmol). The mixture was then stirred at ꢀ78 ꢁC for an
additional 3.5 h and at ambient temperature overnight.
The reaction was quenched with a saturated solution of
ammonium chloride and the mixture was twice extrac-
ted with ethyl ether. The ether extract was dried (mag-
nesium sulfate), concentrated and crystallized from
hexanes to give an off white solid. The solid was dis-
solved in methylene chloride and filtered through a pad
of silica gel to give alkynyl silane 9b (35.2 g, 85%) as a
white solid upon concentration. White solid, mp 94–
101 ꢁC. Rf 0.32 (silica gel, 7:3 ethyl ether/hexanes); H
1
NMR (300 MHz, CDCl3) d 7.44–7.33 (m, 1H), 6.96 (t,
2H), 6.43 (bd, 1H), 5.17–5.09, (m, 1H), 3.88–3.80 (m,
2H), 2.22 (t, 1H), 1.07 (m, 21H); 13C NMR (75 MHz,
CDCl3) d 158.6 (dt), 158.4, 130.6 (t, J=10.6 Hz), 110.6
(m), 101.3, 85.2, 64.2, 43.9, 17.0, 9.5; IR (film) nmax
3420, 3280, 2943, 2865, 2176, 1658, 1626, 1468, 1010
cmꢀ1
;
MS (M+H+) 381.96. Anal. calcd for
C20H29NO2F2Si: C, 62.96; H, 7.66; N, 3.67; Si, 7.36.
Found: C, 63.05; H, 7.83; N, 3.57; Si, 7.34.
Enantioselective alkylation of 9b. To a solution of diiso-
propylamine (8.0 mL, 57.1 mmol) in ethyl ether (150
mL) at ꢀ10 ꢁC was added, dropwise with stirring,
n-BuLi (21.8 mL, 2.5 M solution in hexane, 54.5 mmol).
After 0.5 h at this temperature the mixture was cooled
in a dry ice/acetone bath and (ꢀ)-sparteine (11.9 mL,
51.8 mmol) was added. Amide 9b (9.1 g, 25.9 mmol) in
ethyl ether (50 mL) was added in dropwise fashion
keeping the temperature below ꢀ60 ꢁC. After an addi-
tional 2 h, formaldehyde was introduced as described
above with the exception that the paraformaldehyde
was held at 130 ꢁC by means of an oil bath and not
decomposed with a heat gun. After the purple color was
quenched, a saturated solution of ammonium chloride
was added and the mixture was warmed to ambient
temperature. The mixture was extracted with ethyl ether
and the ether extract was twice washed with normal
HCl, dried (magnesium sulfate), concentrated and puri-
fied by flash column chromatography (silica gel, 2:3
ethyl ether/hexanes) to give the non-racemic alcohol 10b
(1.0 g, 10%) as a white solid. This material (ca. 40% ee
by Mosher ester analysis) had an aD of ꢀ0.7ꢁ.
95 ꢁC. Rf 0.24 (silica gel, 3:7 ethyl ether/hexanes); H
1
NMR (300 MHz, CDCl3) d 7.5–7.3 (m, 1H), 6.96 (t,
2H), 6.1 (bs, 1H), 4.31 (d, 2H), 1.07 (m, 21H); 13C NMR
(75 MHz, CDCl3) d 158.6 (dt, J=253, 6.8 Hz), 158.2,
130.4 (t, J=10.4 Hz), 110.5 (m), 100.4, 83.9, 29.3, 17.0,
9.6; IR (film) nmax 3251, 3069, 2942, 2866, 2183, 1643,
1468, 1007 cmꢀ1; MS (M + H+) 352.14. Anal. calcd for
C19H27NOF2Si: C, 64.92; H, 7.74; N, 3.98; Si, 7.99.
Found: C, 64.78; H, 7.81; N, 3.92; Si, 8.16.
N-(1-Hydroxy-4-triisopropylsilyl-3-butyn-2-yl) 2,6-difluoro-
benzamide (10b). To a solution of diisopropylamine
(24.0 mL, 171 mmol) in tetrahydrofuran (200 mL) at
0 ꢁC was added, dropwise with stirring, n-BuLi (65.5
mL, 2.5 M solution in hexane, 164 mmol). After 0.5 h at
this temperature the mixture was cooled in a dry ice/
acetone bath and TMEDA (25.9 mL, 172 mmol) was
added. Amide 9b (27.35 g, 77.9 mmol) was added in
dropwise fashion keeping the temperature below
ꢀ65 ꢁC. After an additional 1 h, with very rapid
mechanical stirring, formaldehyde (generated by ther-
mal decomposition of paraformaldehyde with a heat
gun) was introduced near the top of the flask via a 15
cm long 12 gauge cannula. A stream of nitrogen is
introduced into the flask containing paraformaldehyde
to aid the transfer and is outlet from the reaction flask via a
bubbler so that the system can be monitored for blockage.
It is important to keep the cannula end as far from the cold
solution as possible and employ an extremely vigorous
mechanical stirring for efficient absorption of the gas.
2-(2,6-Difluorophenyl)-4-(2-triisopropylethynyl)-1,3-oxa-
zoline (14b). To a solution of hydroxy amide 10b (9.3 g,
24.4 mmol) in pyridine (50 mL) was added tri-
fluoromethanesulfonic anhydride (4.5 mL, 25.2 mmol)
such that the internal temperature was maintained
below ꢀ15 ꢁC. On complete addition, the mixture was
allowed to warm to ambient temperature and stirred for
an additional 0.3 h. The mixture was then diluted with
ethyl ether and washed with a saturated solution of
sodium bicarbonate, dried (magnesium sulfate), con-
centrated and purified by flash column chromatography
(silica gel, 1:9 ethyl ether/hexanes) to give the oxazoline
14b (5.65 g, 64%) as a colorless oil. Rf 0.33 (silica gel,
1
1:4 ethyl ether/hexanes); H NMR (300 MHz, CDCl3) d
7.46–7.35 (m, 1H), 6.96 (t, 2H), 5.09, (t, 1H), 4.64 (dd,
1H), 4.40 (t, 1H), 1.08 (m, 21H); 13C NMR (75 MHz,
CDCl3) 159.7 (dt, J=256, 5.8 Hz), 156.6, 131.0 (t,
J=10.6 Hz), 110.3 (m), 105.3 (t, J=16.6 Hz), 103.9,
84.2, 71.9, 56.8, 17.0, 9.6; IR (film) nmax 2944, 2866,
2183, 1666, 1622, 1470, 133, 1291, 1240, 1084, 1014
cmꢀ1; MS (M + H+) 364.13. Anal. calcd for
C20H27NOF2Si: C, 66.08; H, 7.49; N, 3.85; Si, 7.73.
Found: C, 66.07; H, 7.56; N, 3.80; Si, 7.55.
After the purple color was quenched, a saturated solu-
tion of ammonium chloride was added and the mixture
was warmed to ambient temperature. The mixture was
extracted with ethyl ether and the ether extract was
washed with normal HCl. The aqueous washings were
re-extracted with ethyl ether and the combined organic
phase was washed with a saturated solution of sodium
bicarbonate, dried (magnesium sulfate), concentrated
2-(2,6-Difluorophenyl)-4-ethynyl)-1,3-oxazoline (15). To
a solution of alkynyl silane 14 (5.65 g, 15.6 mmol) in

D. Clark, D. A. Travis / Bioorg. Med. Chem. 9 (2001) 2857–2862
2861
tetrahydrofuran (65 mL) was added acetic acid (1.08
mL, 18.9 mmol) followed by tetrabutylammonium fluo-
ride (18.8 mL, 1.0 M in tetrahydrofuran). After stirring
at ambient temperature for 3 h, the mixture was diluted
with ethyl ether, washed with a saturated solution of
sodium bicarbonate, dried (magnesium sulfate), con-
centrated and purified by flash column chromatography
(silica gel, 1:4 then 2:3 ethyl ether/hexanes) to give the
terminal alkyne 15 (2.83 g, 88%) as a colorless oil. The
compound appears to polymerize when neat but may be
stored in solution. Rf 0.32 (silica gel, 2:3 ethyl ether/
131.2, 131.0, 130.8, 130.4, 127.0, 125.2, 120.4, 120.3,
110.6, 110.4, 86.9, 82.5, 71.4, 56.6; IR (film) nmax 2906,
1658, 1621, 1588, 1482, 1468, 1355, 1330, 1291, 1239,
1088, 1052, 1012 cmꢀ1; MS (M + H+) 437.85, 440.
Anal. calcd for C23H14NOBrF2: C, 63.03; H, 3.22; N,
3.20; Br, 18.23. Found: C, 62.83; H, 3.25; N, 2.85; Br,
19.96.
Testing on Fall Armyworm (Spodoptera frugiperda)
Test units, each consisting of a HIS (high impact sty-
rene) tray with 16 cells were prepared. Wet filter paper
and approximately 8 cm2 of lima bean leaf was placed
into 12 of the cells. A 0.5-cm layer of wheat germ diet
was placed into the four remaining cells. Fifteen to 20
third-instar larvae of fall armyworm (Spodoptera frugi-
perda) were placed into a 230-mL (8-ounce) plastic cup.
Solutions of each of the test compounds in 75:25 ace-
tone/distilled water solvent were sprayed into the tray
and cup. Spraying was accomplished by passing the tray
and cup on a conveyer belt directly beneath a flat fan
hydraulic nozzle which discharged the spray at a rate of
0.138 kg of active ingredient per hectare (about 0.13
pounds per acre) at 207 kPa (30 psi). The insects were
transferred from the 230-mL cup to the HIS tray (one
insect per cell). The trays were covered and held at 27 ꢁC
and 50% relative humidity for 48 h, after which time
readings were taken on the 12 cells with lima bean
leaves. The four remaining cells were read at 6–8 days
for delayed toxicity.
1
hexanes); H NMR (300 MHz, CDCl3) d 7.48–7.36 (m,
1H), 6.97 (t, 2H), 5.06, (ddd, 1H), 4.65 (dd, 1H), 4.42 (t,
1H), 2.47 (d, 1H); 13C NMR (75 MHz, CDCl3) 159.7
(dt, J=257, 5.7Hz), 157.2 (t, J=2.3Hz), 131.2 (t,
J=10.4Hz), 110.4 (m), 105.0 (t, J=17.3Hz), 80.4, 71.4,
71.2, 55.7; IR (film) nmax 3300, 2907, 1661, 1622, 1591,
1469, 1357, 1292, 1240, 1089, 1053, 1012 cmꢀ1; MS (M
+ H+) 208.11. Anal. calcd for C11H7NOF2: C, 63.77;
H, 3.41; N, 6.76. Found: C, 62.33; H, 3.30; N, 6.67.
4-(4-tert-Butylphenyl)ethynyl-2-(2,6-difluorophenyl)-1,3-
oxazoline (16). To a mixture of alkyne 15 (0.285 g, 1.38
mmol), copper(I) iodide (26 mg, 0.14 mmol), triethyl-
amine (670 mL, 4.83 mmol) and 4-t-butyliodobenzene
(716 mg, 2.75 mmol) in dimethylformamide (3 mL) was
added palladium tetrakis(triphenylphosphine) (40 mg,
0.035 mmol). The mixture was stirred at ambient tem-
perature for 14 h before being diluted with ethyl ether,
twice washed with water, dried (magnesium sulfate),
concentrated and purified by flash column chromato-
graphy (silica gel, 1:4 ethyl ether/hexanes) to give com-
pound 16 (0.46 g, 98%) as a colorless oil. The
compound turns brown on standing. Rf 0.40 (silica gel,
Testing of Two-spotted spider mite (Tetranychus urticae)
Pieces of kidney bean leaves, each approximately 6.5
cm2 (1 square inch) in area, that had been infested on
the undersides with 25 to 30 adult mites (T. urticae),
were sprayed with their undersides facing up on a
hydraulic sprayer with a solution of the test compound
in 75:25 acetone-distilled water solvent. Spraying was
accomplished by passing the leaves, on a conveyor belt,
directly beneath a flat fan hydraulic nozzle which dis-
charged the spray at a rate of 0.138 kg of active ingre-
dient per hectare (about 0.13 pounds per acre) at 207
kPa (30 psi). The leaf squares were then placed under-
side-up on a square of wet cotton in a Petri dish and the
perimeter of the leaf square was tamped down onto the
cotton with forceps so that the mites could not escape
onto the untreated leaf surface. The test units were held
at 27 ꢁC and 50% relative humidity for 48 h, after which
time mortality readings were taken.
1
2:3 ethyl ether/hexanes); H NMR (300 MHz, CDCl3) d
7.46–7.28 (m, 5H), 6.97 (t, 2H), 5.30, (t, 1H), 4.71 (dd,
1H), 4.48 (t, 1H), 1.30 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 159.7 (dt, J=258, 5.8 Hz), 156.9 (t, J=2.3
Hz), 150.2, 131.2 (t, J=10.4 Hz), 130.0, 123.7, 117.9,
110.4 (m), 105.2 (t, J=17.3 Hz), 84.8, 83.3, 71.5, 56.7,
29.6; IR (film) nmax 2963, 1659, 1622, 1469, 1354, 1291,
1239, 1087, 1052, 1011 cmꢀ1; MS (M + H+) 340.12.
Anal. calcd for C21H19NOF2: C, 74.32; H, 5.64; N, 4.13.
Found: C, 73.59; H, 5.61; N, 4.16.
4-(40-Bromobiphen-1-yl)ethynyl-2-(2,6-difluorophenyl)-1,3-
oxazoline (21). To a solution of non-racemic alkyne 15
(0.36 g, 1.74 mmol), copper(I) iodide (33 mg, 0.17
mmol), triethylamine (850 mL, 6.09 mmol) and 4,40-
dibromobiphenyl (1.62 g, 5.22 mmol) in dimethylfor-
mamide (15 mL) was added palladium tetra-
kis(triphenylphosphine) (100 mg, 0.087 mmol). The
mixture was heated at 90 ꢁC for 1.3 h before being
cooled, diluted with ethyl ether, twice washed with
water, dried (magnesium sulfate), concentrated and
purified by flash column chromatography (silica gel, 1:4
ethyl ether/hexanes) to give compound non racemic 21
(0.12 g, 16%) as a white solid. The compound was
crystallized from chlorobutane. Rf 0.34 (silica gel, 2:3
ethyl ether/hexanes); aD +7.8ꢁ; mp 132–134 ꢁC; 1H
NMR (300 MHz, CDCl3) d 7.59–7.38 (m, 9H), 6.99 (t,
2H), 5.33, (dd, 1H), 4.74 (dd, 1H), 4.52 (t, 1H); 13C
NMR (75 MHz, CDCl3) 158.0, 138.4, 137.7, 131.3,
The same units were held an additional 5 days and read
for larvicide/ovicide mortality and/or developmental
effects.
Acknowledgements
The authors would like to thank Dave Marsden, Chris
Clark Jim Gilmour and John Nogaj for biological
assays, Bruce Lockett, Mike Kline and John Groce for
NMR support, Gina Blankenship and Jim Doughty for
mass spectral data and Will Marshall for X-ray analysis.

2862
D. Clark, D. A. Travis / Bioorg. Med. Chem. 9 (2001) 2857–2862
We would also like to thank Professor Barry Trost and
Renee Lett for useful discussions.
4. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.
5. Kuroda, Y.; Okuhara, M.; Goto, T.; Iguchi, E.; Kohsaka,
M.; Aoki, H.; Imanaka, H. J. Antibiot. 1980, 33, 125. Kuroda,
Y.; Okuhara, M.; Goto, T.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1980, 33, 132.
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