Synthesis of the insecticide prothrin and its analogues from biomass-derived 5-(chloromethyl)furfural

Article abstract of DOI:10.1021/jf4045843

Prothrin, a synthetic pyrethroid insecticide, was synthesized from the biomass-derived platform chemical 5-(chloromethyl)furfural in six steps and overall 65% yield. Two structural analogues of prothrin were also prepared following the same synthetic approach. Preliminary testing of these furan-based pyrethroids against the yellow fever mosquito Aedes aegypti indicates promising insecticidal activities.

Full text of DOI:10.1021/jf4045843

Article
pubs.acs.org/JAFC
Synthesis of the Insecticide Prothrin and Its Analogues from
Biomass-Derived 5‑(Chloromethyl)furfural
Fei Chang,† Saikat Dutta,† James J. Becnel,‡ Alden S. Estep,§ and Mark Mascal*,†
†Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
‡Center for Medical, Agricultural, and Veterinary Entomology (CMAVE), Agricultural Research Service (ARS), United States
Department of Agriculture (USDA), 1600 Southwest 23rd Drive, Gainesville, Florida 32608, United States
§Navy Entomology Center of Excellence, Box 43, Naval Air Station, Jacksonville, Florida 32212, United States
S
* Supporting Information
ABSTRACT: Prothrin, a synthetic pyrethroid insecticide, was synthesized from the biomass-derived platform chemical 5-
(chloromethyl)furfural in six steps and overall 65% yield. Two structural analogues of prothrin were also prepared following the
same synthetic approach. Preliminary testing of these furan-based pyrethroids against the yellow fever mosquito Aedes aegypti
indicates promising insecticidal activities.
KEYWORDS: biomass, furans, pyrethroids, synthesis, 5-(chloromethyl)furfural
INTRODUCTION
■
Previously, we have described the synthesis of the natural
herbicide δ-aminolevulinic acid (2)1 and the anti-ulcer drug
ranitidine (Zantac) (3)2 from the renewable platform chemical
5-(chloromethyl)furfural (CMF) (1), which can be derived in a
Pyrethroids are generally well-suited for agricultural and
household uses because of their biodegradability and low
mammalian toxicity, and demand for these products has
single step from either sugars, cellulose, or raw biomass in
isolated yields between 80 and 90%.3 In a continuing effort to
increased in the past decade with the declining use of
organophosphates. However, all United States Environmental
Protection Agency (U.S. EPA)-registered pesticides are
regularly submitted to a process by which they are systemati-
cally reviewed to establish that they can still perform their
intended function without unreasonable adverse effects on
human health or the environment, and this process applies
constant pressure on the development of new generations of
products that are even more selective in their mode of action.
The synthesis of prothrin (4) was first reported in 1969 and
is always completed by esterification of 5-propargylfurfuryl
alcohol (10) with chrysanthemic acid chloride.6 Because
chrysanthemic acid is commercially available as a synthetic
version of the natural product,8 the actual target of prothrin
syntheses becomes compound 10, and most approaches to this
molecule have centered around either the reaction of a
metalated derivative of furfuryl alcohol (9) with a propargyl
electrophile9 or a metalated acetylene with a 5-methyl-
substituted furfuryl alcohol derivative incorporating a leaving
group (11) (Scheme 1).10,11 Looking to the structures of both
compound 10 and CMF (1), it becomes apparent that a
concise route connecting them should be achievable, and we
expand the derivative markets of CMF (1), we now report a
simple, six-step approach to the furan-based pyrethroid
insecticide prothrin (4) alongside five-step routes to analogues
5 and 6.
The naturally occurring insecticide pyrethrum, isolated from
flowers of Chrysanthemum sp., has been in commercial use for
over 100 years.4 Elucidation of the chemical structure of its
active constituents [i.e., pyrethrins (7)] in 1924 ultimately led
to the production of several synthetic pyrethroids.5 As a result
of extensive structure−activity studies, the insecticidal and
toxicological properties of these compounds typically surpass
those of the natural products. Prothrin (4) is a member of the
synthetic furan-based pyrethroids,6 which class also includes
resmethrin (8), a high-volume commercial insecticide.7
Received: October 14, 2013
Revised: December 18, 2013
Accepted: December 19, 2013
Published: December 19, 2013
© 2013 American Chemical Society
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a
Scheme 1. Approaches to the Synthesis of 5-Propargylfurfuryl Alcohol (10)
a
LG, leaving group; PG, protecting group.
a
Scheme 2.
a
Reagents: a, 1-butanol, concentrated HCl (catalyst), 98%; b, TMS−acetylene, CuI, K2CO3, CH3CN, 55 °C, 88%; c, 1 M aqueous HCl, 97%; d,
NaBH4, MeOH, 0 °C, 98%; e, chrysanthemic acid chloride, benzene, reflux, 95%; and f, Bu4NF, THF, −20 °C, 84%.
were naturally attracted to published methods that involved
CMF (1) as a precursor to structure 1110 but considered the
use of organometallics a serious drawback to any industrial
application of this synthetic approach. We proposed that the
installation of the propargyl group could instead be achieved by
copper(I)-mediated coupling of the chloromethyl functionality
to an acetylene derivative.12 The synthesis is shown in Scheme
2.
compound 1 with either phenol or cyanide were unsuccessful.
From substituted acetals 16 and 17, the syntheses proceeded as
for compound 4 but are one step shorter, because no
deprotection is required at the end (Scheme 3). The overall
yields of analogues 5 and 6 from CMF (1) were 51 and 70%,
respectively.
a
Scheme 3.
Attempts to couple compound 1 and trimethylsilyl (TMS)
acetylene in the presence of the aldehyde group were
unsuccessful; thus, CMF (1) was protected as the dibutyl
acetal (12). Coupling of the alkyne to compound 12 proceeded
to give compound 13 in good yield, which was hydrolyzed to
the furfural derivative (14). Reduction of compound 14 with
sodium borohydride gave alcohol 15. Compound 15 is
essentially a protected form of compound 10, but to complete
the synthesis of prothrin (4), we esterified compound 15 with
chrysanthemic acid chloride and, finally, desilylated with
tetrabutylammonium fluoride. It was necessary to retain the
TMS protecting group until the end of the synthesis, because
any attempt to remove it at an earlier stage resulted in gradual
isomerization of the triple bond to the allene.
The above-described route to prothrin (4) does not
necessitate the synthesis of a 5-methylfurfuryl precursor to
compound 10 but rather derives it directly from biomass. It also
involves no organometallic reagents, requires no chromato-
graphic separations until the final step, and proceeds in an
overall 65% yield. The efficiency of this approach and the ready
availability of CMF (1) presented an attractive opportunity to
carry out analoging studies on the prothrin framework.
A highly apparent analogue to prothrin (4) is the
cyanomethylfuran derivative (5), and this was targeted for
synthesis along with the known resmethrin-like aryloxymethyl
analogue (6).13 Thus, in the approach to analogues 5 and 6, the
acetylene nucleophile is exchanged for cyanide and phenoxide,
respectively. We had initially supposed that conversion of CMF
(1) into acetal 12 would not be necessary in these cases,
because compound 1 is known to be effectively substituted with
nucleophiles, such as alcohols3a and azide anion.1 However,
attempts to directly substitute the chloromethyl group in
a
Reagents: a, for compound 16, NaCN, DMSO, 85 °C, 78%; for
compound 17, phenol, K2CO3, DMSO, 50 °C, 87%; b, 1 M aqueous
HCl; c, NaBH4, MeOH/CH2Cl2, 0 °C; and d, chrysanthemic acid
chloride, benzene, reflux.
MATERIALS AND METHODS
■
2-(Chloromethyl)-5-(dibutoxymethyl)furan (12).14 CMF (1)
(2.00 g, 13.8 mmol) was dissolved in 1-butanol (40 mL), and
concentrated HCl (0.1 mL) was added. The solvent was then removed
using a rotary evaporator under high vacuum (0.1 mmHg) while
cooling the evaporating flask in an ice−water bath. The product 12
1
was obtained as a yellow oil (3.721 g, 98%). H NMR (300 MHz,
CDCl3) δ: 6.32 (s, 1H), 6.29 (s, 1H), 5.47 (s, 1H), 4.53 (s, 2H), 3.51
(m, 4H), 1.52 (m, 4H), 1.35 (m, 4H), 0.88 (t, 7.3 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ: 153.1, 150.1, 110.4, 109.4, 96.5, 65.7, 37.7, 31.9,
19.5, 14.0. HRMS: (M − OBu)+, C10H14O2Cl calculated, 201.0682;
found, 201.0678.
2-(Dibutoxymethyl)-5-[3-(trimethylsilyl)prop-2-yn-1-yl]furan
(13). Copper(I) iodide (0.269 g, 1.41 mmol), potassium carbonate
(0.328 g, 2.37 mmol), and (trimethylsilyl)acetylene (0.21 mL, 0.15 g,
1.5 mmol) were added to a solution of compound 12 (0.328 g, 1.19
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mmol) in anhydrous acetonitrile (10 mL) under argon. The
suspension was heated to 55 °C and stirred overnight. Saturated
aqueous NaHCO3 (50 mL) was added and the layers were separated.
The aqueous layer was extracted with dichloromethane, the organic
layers were combined and dried over sodium sulfate, and the solvent
was evaporated to give compound 13 as a yellow oil (0.353 g, 88%).
1H NMR (300 MHz, CDCl3) δ: 6.31 (d, 3.1 Hz, 1H), 6.17 (d, 3.1 Hz,
1H), 5.45 (s, 1H), 3.61 (s, 2H), 3.56−3.44 (m, 4H), 1.59−1.52 (m,
4H), 1.40−1.32 (m, 4H), 0.90 (t, 7.5 Hz, 6H), 0.16 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ: 151.0, 150.1, 109.0, 106.7, 101.0, 96.5, 86.5, 65.4,
31.8, 20.1, 19.4, 13.9, 0.0. HRMS: (M − OBu)+, C15H23O2Si
calculated, 263.1462; found, 263.1469.
3.0 Hz, 1H, Hc and Hc′), 5.35 (d, 8.4 Hz, 0.4H, Hj), 5.04−4.90 (m, 2H,
He and He′), 4.85 (d, 7.9 Hz, 0.6H, Hj′), 3.56 (d, 2.4 Hz, 2H, Hb and
Hb′), 2.13 (t, 2.4 Hz, 1H, Ha and Ha′), 2.05 (dd, 7.9 Hz, 5.4 Hz, 0.6H,
Hi′), 1.87 (t, 8.4 Hz, 0.4H, Hi), 1.72−1.65 (m, 6H, Hk, Hk′, Hl, and
Hl′), 1.40 (d, 5.4 Hz, 0.6H, Hf′), 1.24−1.09 (m, 6H, Hg, Hg′, Hh, and
Hh′). 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.5, 150.5, 150.4, 149.2,
149.1, 135.4, 134.6, 121.1, 118.1, 111.4, 111.3, 107.3, 78.6, 70.3, 57.9,
57.5, 34.5, 32.9, 32.4, 30.9, 28.8, 28.7, 26.6, 25.9, 25.5, 22.1, 20.3, 18.5,
18.4, 18.2, 14.7. HRMS: (M + H)+, C18H23O3 calculated, 287.1642;
found, 287.1639.
2-(Cyanomethyl)-5-(dibutoxymethyl)furan (16). Sodium cya-
nide (0.174 g, 3.55 mmol) was added to a solution of compound 12
(0.811 g, 2.95 mmol) in dimethyl sulfoxide (DMSO) (6 mL) and the
mixture was stirred at 90 °C under argon for 3 h. Saturated aqueous
NaHCO3 (50 mL) was added and the mixture was extracted with
hexanes. The combined organic layers were washed with saturated
aqueous NaHCO3, dried over sodium sulfate, and decolorized with
charcoal. The solvent was evaporated to give compound 16 as a light
5-[3-(Trimethylsilyl)prop-2-yn-1-yl]furfural (14). A mixture of
compound 13 (0.210 g, 0.624 mmol) and 1 M HCl (10 mL) was
stirred for 2 h and then extracted with dichloromethane. The
combined organic layers were dried over sodium sulfate and the
solvent was evaporated to give compound 14 as a yellow solid (0.125
1
g, 97%) with a melting point (mp) of 46 °C. H NMR (300 MHz,
1
yellow oil (0.608 g, 78%). H NMR (300 MHz, CDCl3) δ: 6.34 (s,
CDCl3) δ: 9.55 (s, 1H), 7.19 (d, 3.6 Hz, 1H), 6.49 (d, 3.6 Hz, 1H),
3.72 (s, 2H), 0.18 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 177.2,
157.5, 152.5, 123.1, 109.9, 98.9, 88.1, 20.5, −0.1. HRMS: (M + H)+,
C11H15O2Si calculated, 207.0835; found, 207.0833.
1H), 6.28 (s, 1H), 5.44 (s, 2H), 3.60−3.42 (m, 4H), 1.65−1.47 (m,
4H), 1.45−1.27 (m, 4H), 0.90 (t, 7.5 Hz, 6H). 13C NMR (75 MHz,
CDCl3) δ: 152.8, 143.1, 115.6, 109.4, 109.2, 96.5, 65.9, 31.9, 19.5, 17.8,
14.1. HRMS: (M − OBu)+, C11H14NO2 calculated, 192.1019; found,
192.1019.
2-(Hydroxymethyl)-5-[3-(trimethylsilyl)prop-2-yn-1-yl]furan
(15). Sodium borohydride (0.0720 g, 1.90 mmol) was added to a
solution of compound 14 (0.391 g, 1.90 mmol) in methanol (10 mL)
at 0 °C. The mixture was allowed to come to room temperature over 2
h with stirring. The solvent was evaporated and the residue was taken
up in dichloromethane (25 mL), which was washed with saturated
aqueous NH4Cl solution. The aqueous layer was back-extracted with
dichloromethane, the organic layers were combined and dried over
sodium sulfate, and the solvent was evaporated to give compound 15
5-(Cyanomethyl)furfural (18). A mixture of compound 16 (0.224
g, 0.844 mmol) and 1 M HCl (10 mL) was stirred for 2 h and then
extracted with dichloromethane. The organic layers were combined
and dried over sodium sulfate, and the solvent was evaporated to give
1
compound 18 as a brown oil (0.109 g, 95%). H NMR (300 MHz,
CDCl3) δ: 9.55 (s, 1H), 7.20 (d, 3.0 Hz, 1H), 6.56 (d, 3.0 Hz, 1H),
3.88 (s, 2H). 13C NMR (75 MHz, CDCl3) δ: 177.6, 153.2, 149.9,
122.7, 114.6, 111.7, 18.2. HRMS: (M + H)+, C7H6NO2 calculated,
136.0393; found, 136.0389.
1
as a pale yellow oil (0.388 g, 98%). H NMR (300 MHz, CDCl3) δ:
6.21 (d, 3.0 Hz, 1H), 6.16 (d, 3.0 Hz, 1H), 4.56 (s, 2H), 3.62 (s, 2H),
1.73 (s, 1H), 0.17 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 153.4,
150.2, 108.8, 107.1, 101.1, 86.6, 57.3, 20.0, 0.0. HRMS: (M + H)+,
C11H17O2Si calculated, 209.0992; found, 209.0987.
2-(Cyanomethyl)-5-(hydroxymethyl)furan (20). Sodium bor-
ohydride (0.0560 g, 1.47 mmol) was added to a solution of compound
18 (0.155 g, 1.15 mmol) in methanol (10 mL) at 0 °C. The reaction
was allowed to stir for 2 h at 0 °C. Saturated aqueous NH4Cl (25 mL)
was added and the mixture was extracted with dichloromethane. The
organic layers were combined and dried over sodium sulfate, and the
solvent was evaporated to give compound 20 as a brown liquid (0.142
Mixture of ( )-cis- and ( )-trans-{5-[3-(Trimethylsilyl)prop-
2-yn-1-yl]furan-2-yl}methyl-2,2-dimethyl-3-(2-methylprop-1-
en-1-yl)cyclopropane-1-carboxylate. Compound 15 (0.157 g,
0.754 mmol) was dissolved in dry benzene (25 mL) under argon. A
mixture of ( )-cis- and ( )-trans-chrysanthemic acid chloride (0.156
g, 0.836 mmol) was added and the solution was heated at reflux for 5
h. The reaction was allowed to cool to room temperature and the
solvent was evaporated. Excess chrysanthemic acid chloride was
removed under high vacuum (0.1 mmHg) to give the product as a
1
g, 90%). H NMR (300 MHz, CDCl3) δ: 6.22 (d, 3.0 Hz, 1H), 6.20
(d, 3.0 Hz, 1H), 4.48 (s, 2H), 3.72 (s, 2H), 3.16 (br, 1H, OH). 13C
NMR (75 MHz, CDCl3) δ: 154.9, 142.8, 115.7, 109.3, 108.9, 56.9,
17.5. HRMS: (M − OH)+, C7H6NO calculated, 120.0444; found,
120.0435.
1
brown oil (0.257 g, 95%). H NMR (300 MHz, CDCl3) δ: 6.32 (m,
Mixture of ( )-cis- and ( )-trans-[5-(Cyanomethyl)furan-2-
yl]methyl-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)-
cyclopropane-1-carboxylate (5). Compound 20 (0.152 g, 1.11
mmol) was dissolved in dry benzene (25 mL) under argon. A mixture
of ( )-cis- and ( )-trans-chrysanthemic acid chloride (0.247 g, 1.32
mmol) was added and the solution was heated at reflux for 2 h. The
reaction was allowed to cool to room temperature and the solvent was
evaporated. The residue was taken up in dichloromethane (20 mL),
which was then washed with brine. The aqueous layer was back-
extracted with dichloromethane. The organic layers were combined
and dried over sodium sulfate, and the solvent was evaporated. The
crude product was purified by flash column chromatography on silica
gel (10:1 hexanes/ethyl acetate) to give compound 5 as a light yellow
1H, Hd and Hd′), 6.19 (m, 1H, Hc and Hc′), 5.38 (d, 8.5 Hz, 0.4H, Hj),
5.09−4.90 (m, 2H, He and He′), 4.88 (d, 7.7 Hz, 0.6H, Hj′), 3.62 (s,
2H, Hb and Hb′), 2.06 (dd, 7.7 Hz, 5.5 Hz, 0.6H, Hi′), 1.88 (t, 8.5 Hz,
0.4H, Hi), 1.75−1.65 (m, 6H, Hk, Hk′, Hl, and Hl′), 1.41 (d, 5.5 Hz, 0.6
H, Hf′), 1.25−1.11 (m, 6H, Hg, Hg′, Hh, and Hh′), 0.18 (s, 9H). 13C
NMR (75 MHz, CDCl3) δ: 172.2, 170.7, 151.1, 151.0, 149.2, 149.1,
135.6, 134.9, 121.2, 118.1, 111.6, 111.4, 107.4, 100.8, 86.7, 58.1, 57.7,
34.7, 33.1, 32.6, 31.1, 29.0, 28.9, 26.8, 26.0, 25.7, 22.2, 20.5, 20.1, 18.6,
18.4, 14.8, 0.1. HRMS: (M + H)+, C21H31O3Si calculated, 359.2037;
found, 359.1999.
Mixture of ( )-cis- and ( )-trans-Prothrin (4). A mixture of
( )-cis- and ( )-trans-{5-[3-(trimethylsilyl)prop-2-yn-1-yl]furan-2-
yl}methyl-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-
carboxylate (0.143 g, 0.399 mmol) was dissolved in tetrahydrofuran
(THF) (10 mL) and the solution was cooled to −20 °C in a dry-ice/
ethylene glycol bath. A solution of tetrabutylammonium fluoride in
THF (1.0 M, 0.44 mL, 0.44 mmol) was added dropwise with stirring.
After 15 min at −20 °C, saturated ammonium chloride (50 mL) was
added and the aqueous layer was separated and extracted with ethyl
acetate. The organic layers were combined and dried over sodium
sulfate, and the solvent was evaporated. The residue was purified by
flash column chromatography on silica gel (20:1 hexanes/ethyl
1
oil (0.244 g, 77%). H NMR (300 MHz, CDCl3) δ: 6.28 (s, 1H, Hd
and Hd′), 6.22 (s, 1H, Hc and Hc′), 5.28 (d, 8.3 Hz, 0.4H, Hj), 5.01−
4.84 (m, 2H, He and He′), 4.80 (d, 7.0 Hz, Hj′), 3.70 (s, 2H, Hb and
Hb′), 1.99 (t, 7.0 Hz, 0.6H, Hi′), 1.83 (t, 8.3 Hz, 0.4H, Hi), 1.68−1.56
(m, 6H, Hk, Hk′, Hl, and Hl′), 1.33 (d, 5.4 Hz, 0.6H, Hf′), 1.20−1.00
(m, 6H, Hg, Hg′, Hh, and Hh′). 13C NMR (75 MHz, CDCl3) δ: 172.0,
170.6, 150.9, 150.8, 144.0, 144.0, 135.7, 135.0, 121.1, 118.1, 115.6,
111.8, 111.7, 109.6, 57.8, 57.4, 34.6, 33.2, 32.7, 31.0, 29.1, 28.8, 26.9,
26.0, 25.7, 22.2, 20.5, 18.6, 18.5, 17.6, 14.9. HRMS: (M + H)+,
C17H22NO3 calculated, 288.1600; found, 288.1612.
1
acetate) to give compound 4 as a pale yellow oil (0.095 g, 84%). H
2-(Dibutoxymethyl)-5-(phenoxymethyl)furan (17). Phenol
NMR (300 MHz, CDCl3) δ: 6.30 (t, 3.0 Hz, 1H, Hd and Hd′), 6.18 (d,
(0.232 g, 2.47 mmol) and potassium carbonate (0.360 g, 2.61
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mmol) were added to a solution of compound 12 (0.564 g, 2.05
mmol) in DMSO (5 mL), and the mixture was stirred at 50 °C under
argon for 5 h. Saturated aqueous NaHCO3 (50 mL) was added and
the mixture was extracted with hexanes. The organic layers were
combined, washed with saturated aqueous NaHCO3, and dried over
sodium sulfate. The solvent was evaporated to give compound 17 as a
pale yellow oil (0.592 g, 87%). 1H NMR (300 MHz, CDCl3) δ: 7.34−
7.25 (m, 2H), 7.02−6.93 (m, 3H), 6.42 (d, 3.3 Hz, 1H), 6.40 (d, 3.3
Hz, 1H), 5.55 (s, 1H), 4.99 (s, 2H), 3.65−3.49 (m, 4H), 1.70−1.55
(m, 4H), 1.51−1.35 (m, 4H), 0.95 (t, 7.2 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ: 158.3, 152.4, 150.2, 129.4, 121.2, 114.9, 110.3, 109.0,
96.5, 65.5, 62.4, 31.8, 19.4, 13.9. HRMS: (M − OBu)+, C16H19O3
calculated, 259.1329; found, 259.1331.
were reared in an environmental chamber at 28 °C, 80% relative
humidity, and a photoperiod of 14 h/10 h (light/dark). Adults were
held in a screened cage and provided 10% sucrose ad libitum. Female
adults were used for all bioassays.
Adult Topical Bioassays. To determine the toxicity of each
compound against female A. aegypti, samples were initially diluted to a
10% solution in DMSO. This solution was then serially diluted 1:10 in
acetone and then topically applied to individual mosquitoes. Each
addition of diluent and stock solution was weighed to allow for
accurate concentration calculations and to account for pipetting
variability because of the volatility of acetone. Prior to application, 5−
7-day-old females were cold-anaesthetized and placed on a 4 °C chill
table (BioQuip Products, Rancho Dominguez, CA). A 0.5 μL droplet
of chemical solution was applied to the thorax using a 700 series
gastight syringe and a PB 600 repeating dispenser (Hamilton, Reno,
NV). Control treatments with 0.5 μL of acetone alone gave control
mortality of less than 10%. After treatment, mosquitoes were kept in
plastic cups and supplied with 10% sucrose solution for 24 h before
mortality was recorded. Temperature and relative humidity were
maintained at 26−27 °C and 80%, respectively. Cohorts of 20−30
mosquitoes were treated at each dose. Bioassays were replicated 3
times. Technical-grade permethrin (Chemservice, West Chester, PA),
a combination of 46.1% cis and 53.2% trans isomers, was used as the
positive control in all assays and diluted in the same manner as the test
compounds. This system reliably results in a LD50 for permethrin of
around 0.1 ng per mosquito.
5-(Phenoxymethyl)furfural (19).15 A mixture of compound 17
(0.322 g, 0.970 mmol) and 1 M HCl (10 mL) was stirred for 2 h and
then extracted with dichloromethane (20 mL). The organic layers
were combined and dried over sodium sulfate, and the solvent was
evaporated to give compound 19 as a yellow solid (0.194 g, 99%), with
1
a mp of 84 °C. H NMR (300 MHz, CDCl3) δ: 9.64 (s, 1H), 7.36−
7.20 (m, 3H), 7.05−6.91 (m, 3H), 6.61 (d, 3.3 Hz, 1H), 5.10 (s, 2H).
13C NMR (75 MHz, CDCl3) δ: 178.0, 158.1, 157.0, 152.9, 129.9,
122.4, 122.0, 115.0, 111.9, 62.7. HRMS: (M + H)+, C12H11O3
calculated, 203.0703; found, 203.0706.
2-(Hydoxymethyl)-5-(phenoxymethyl)furan (21).13 Sodium
borohydride (0.269 g, 7.08 mmol) was added to a solution of
compound 19 (1.196 g, 5.915 mmol) in a 1:1 mixture of methanol and
dichloromethane (20 mL) at 0 °C. The reaction was allowed to come
to room temperature over 2 h with stirring. The solvent was
evaporated, and the residue was taken up in dichloromethane (20 mL)
and washed with brine. The aqueous layer was back-extracted with
dichloromethane. The organic layers were combined, dried over
sodium sulfate, and evaporated to give compound 21 as a pale yellow
liquid (1.156 g, 96%). 1H NMR (300 MHz, CDCl3) δ: 7.36−7.25 (m,
2H), 7.04−6.94 (m, 3H), 6.37 (d, 2.7 Hz, 1H), 6.26 (d, 2.7 Hz, 1H),
4.96 (s, 2H), 4.56 (s, 2H), 2.91 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3) δ: 158.5, 155.0, 150.3, 129.8, 121.6, 115.1, 111.1, 108.9, 62.6,
57.6. HRMS: (M + H)+, C12H13O3 calculated, 205.0859; found,
205.0861.
RESULTS AND DISCUSSION
■
Preliminary entomological testing of pyrethroids 5 and 6 was
conducted against prothrin (4) and the commercial insecticide
permethrin as standards using the “Orlando” strain of the
pesticide-susceptible mosquito A. aegypti, as described above.
Mortality was recorded at 24 h post-application, and three
replicates were performed. Averaged mortality counts are
included in Table S1 of the Supporting Information, and the
estimated LD50 values are given in Table 1. The activities of
Mixture of ( )-cis- and ( )-trans-[5-(Phenoxymethyl)furan-
2-yl]methyl-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)-
cyclopropane-1-carboxylate (6).13 Compound 21 (0.331 g, 1.62
mmol) was dissolved in dry benzene (25 mL) under argon. A mixture
of ( )-cis- and ( )-trans-chrysanthemic acid chloride (0.364 g, 1.95
mmol) was added and the solution was heated at reflux for 3 h. The
reaction was allowed to cool to room temperature and the solvent was
evaporated. The residue was taken up in dichloromethane (25 mL),
which was then washed with brine. The aqueous layer was back-
extracted with dichloromethane. The organic layers were combined
and dried over sodium sulfate, and the solvent was evaporated. The
crude product was purified by flash column chromatography on silica
gel (15:1 hexanes/ethyl acetate) to give compound 6 as a colorless oil
Table 1. Estimated LD50 Values (ng/Mosquito) of Analogues
5 and 6 with Prothrin (4) and Permethin Standards against
A. aegypti “Orlando” Strain Mosquitos
toxicant
LD50
permethrin
0.07
0.50
7.0
prothrin (4)
5
6
3.3
analogues 5 and 6 are thus within about a log of that of prothrin
(4), which itself is more active than the natural pyrethrins.17
Further testing will determine whether these derivatives show
any useful selectivity in their action.
In conclusion, CMF (1), a biomass-derived platform
chemical, is an attractive starting material for the high-yield
synthesis of prothrin (4) and analogues 5 and 6. This scalable
synthetic approach could be generalized toward the renewable-
sourced production of a variety of furan-based pyrethroids,
which will enable further structure−activity studies and
potential commercial development of this important family of
insecticides.
1
(0.484 g, 85%). H NMR (300 MHz, CDCl3) δ: 7.35−7.24 (m, 2H),
7.03−6.93 (m, 3H), 6.39 (s, 2H, Hc, Hc′, Hd, and Hd′), 5.37 (d, 8.3 Hz,
0.15H, Hj), 5.13−4.95 (m, 4H, Hb, Hb′, He, and He′), 4.88 (d, 7.5 Hz,
0.85H, Hj′), 2.08 (t, 7.5 Hz, 0.85H, Hi′), 1.90 (t, 8.3 Hz, 0.15H, Hi),
1.81−1.65 (m, 6H, Hk, Hk′, Hl, and Hl′), 1.43 (d, 5.1 Hz, 0.85H, Hf′),
1.30−1.08 (m, 6H, Hg, Hg′, Hh, and Hh′). 13C NMR (75 MHz, CDCl3)
δ: 172.3, 170.9, 158.5, 151.1, 151.1, 150.8, 150.6, 135.8, 135.1, 129.7,
121.5, 121.3, 118.3, 115.1, 111.6, 111.5, 111.1, 62.6, 58.2, 57.9, 34.8,
33.3, 32.8, 31.3, 29.2, 29.0, 27.0, 26.2, 25.8, 22.4, 20.6, 18.8, 18.6, 15.0.
HRMS: (M + H)+, C22H27O4 calculated, 355.1909; found, 355.1925.
Entomological Studies. Mosquitoes. The Orlando strain of Aedes
aegypti (established 1952) was reared in the insectary of the Mosquito
and Fly Research Unit at the Center for Medical, Agricultural, and
Veterinary Entomology (CMAVE), Agricultural Research Service
(ARS), United States Department of Agriculture (USDA), according
to the procedures described by Pridgeon et al.16 Briefly, eggs were
hatched in a flask with deionized water, left overnight, and transferred
to a plastic tray containing distilled water. A powdered diet (2:1 pot
belly pig chow/brewer’s yeast) was added to each tray. Mosquitoes
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of entomological data and 1H and 13C NMR data for all
compounds prepared in this work. This material is available free
of charge via the Internet at http://pubs.acs.org.
479
dx.doi.org/10.1021/jf4045843 | J. Agric. Food Chem. 2014, 62, 476−480

Journal of Agricultural and Food Chemistry
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: mjmascal@ucdavis.edu.
■
Notes
The authors declare no competing financial interest.
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