Agrochemistry: Insecticides
Baran Group Meeting
What does "Organic" really mean?
The government created the Organic Foods Production Act in 1990 which
contains two lists: "National list of allowed synthetic substances" and
"National list of prohibited non-synthetic stubstances." If a SYNTHETIC
substance is not on the first list, it cannot be used and if a NON-SYNTHETIC
substance is not on the second list, it can be used. The following is a
summary of the substances for crop production only (not livestock).
Allowed synthetic substances:
(NH4)2CO3
B(OH)3
S (elemental) K2O3Si (aqueous)
CuSO4
Calcium Polysulfide (CaSn)
Sucrose Octanoate Esters:
O
HO
OR
OR'
O
OH
O
OH
HO
OH
Me
Me
R= CO(CH2)7CH3
R'= H or CO(CH2)7CH3
N+
H
H
SO42-
Me
O
Me
Me
Me
Me O
O
OH
NH
ryanodine
(See: Shenvi 2004 GM "Ryanodol")
Me
AcO
MeO2C
HO
O
O
O
O
H
MeO
OH
O
AcO
HO
Me
OH
H
H
Me
CO2H
gibberellic acid
(See: Cherney 2009 GM "L. N. Mander")
HO
O
Me
rotenone
O
Me
OAc
Me
O
O
Me
Me
H
AcO
Me
volkensin
O
OH
H
H
Me
HO
9
annonin I
O
Me
OH
O
Me
O
O
OC
HO
O
azadiractin
(See: Renata 2011 GM "Limonoids")
cevadine
O
O
spinosyn A (R= H)
spinosyn D (R= Me)
Me
O
O
OH
OH
H
O
toosendanin
O
HO
O
H
O
R
OMe
O
MeO2C OH
O O
O
Me
HO
O
H
OMe
Me
H
Me
OH
OH
OH
N
MeO
O
Approved Pesticides: Natural Products
OHMe
Me
O
Me
O
H
OMe
O
NH+
O
HO
HO
HO
HO
Me
O
H
N H
N Me
O
Dormant, Suffocating, and Summer oils:
Me
Petroleium Oil, Synthetic Sesame Oil, etc.
Prohibited non-synthetic substances:
As, CaCl2, Lead Salts, KCl, Na3AlF6, NaNO3
Styrchnine:
Nicotine Sulfate:
N
H
Approved Pesticides: Natural Products Me
O
Soap (sodium lauryl sulfate)
OH
Emily Cherney
H
Me
Me
strigol
OH
O H
O
O
O
O
C6H13
H O H
OH
OH
Me
Agrochemistry: Insecticides
Baran Group Meeting
Approved Pesticides: Natural Products Cont'd
HO
MeO HO
Me
O
Me
tetranactin
O
H
O
H
Me
O
N
O
Me
O
H
Me
NH2
N
HO
Me
H CO2H
N
O H
nikkomycin X
H
HO
Me
O
O
H
O
Me
O
HO
O
O
H
MeO
O
Me
H
Me
OH
milbemectin
(and other milbelmycins/
avermectins)
OMe HO
O
O
O
O
OMe
O
N
H
pyrrolnitrin
OH
Me
Me
citronellal
NO2
Cl
Me
Me
thymol
O
Me
H
N
O
O
S
O
terthienyl
NH4+ -O
O
O H
H
O
O
Me
Me
tebufenozide Me
Me Me
Me
O
Me
O
O
Me
O
Pyrethrin I
P OMe
HO
OMe
glyphosate
O
Me
N
O
Me
Me
capsaicin
O
P OMe
OMe
NH2
DL-phosphinothricin
MeO
O
H
N
NH2
methylanthranilate Me
eugenol
HO
S
O
Me
OMe
Me
H
OH
O
diabroticin A
Me
MeO
S
quassin
H
O
HO
Me
H
H
Me
thiangazole
OMe
O
Me
Me
Me
menthol
N
HN
Me
Me
HN
Cl
OH
Me
Me
OH
O
N
OMe
N
NH
OH
NH2
Me
S
N
NH
NH2
OH
Me
N
OHC
OH
OH
N
rocaglamide
Me
S
H Me
O
Me
O
MeO
S
O
Me
O
H O H
O
Me
Me
N
H
O
Me
H O H
O
Emily Cherney
H
N
CO2Me
O
MeO
Me
haedoxan
codelmone
OH
Me O
Me
strobilurin A
Agrochemistry: Insecticides
Baran Group Meeting
Section 1: Total Syntheses of Natural Product Pesticides
1-spinosyn A
Spinosyn A and D are the active ingredients in Spinosad (an insectiside
produced by Dow). These two natural products were isolated from soil
samples collected from an abandoned rum still by an employee vacationing
in the Caribbean in 1982.
HH
(77%)
OTBS
O
(86%)
TBDPSO
PMBO
no yield
given for
step 4
H
O
13 steps
TBDPSO
H
Br
HH
1) KHMDS, Comin's
O
HH
H
PMBO
H
HH
O
Et
OTBS
PMBO
OPiv
Pd2(dba)3•CHCl3
(iPr)2NEt, PhH
H 8 steps including:
Yamaguchi lactonization
2x glycosylation
Et
OTBS
OPMB
Me
(iPr)
O
SugO
LiCl,
CH3CN, rt, 19h
O
O
O
2NEt,
(75%)
Tandem HWE-DA
H
Et
Br
Et
O O P
OEt
EtO
Cl
O
H
(88%) Me3P (8 eq)
t-amyl alcohol
(0.005 M)
OPMB
Me
7 steps
O
O
SugO
spinosyn A
H
H
spinosyn A
Et
Me
OTBDPS
Me
O
(83%)
H
H
PMBO
OTBDPS
Me
Me
TESO
O
Br
H
O
OPMB
Et
OPMB
OPiv
Me3SnSnMe3
(48%)
P
2) Parikh-Doering [O]
(82%)
Me3Sn
MeO
O
Br
1) Pd(PPh3)4, Tl2CO3,
(HO)2B
OH
SugO
OPiv 2) (Ph3P)4Pd, LiCl
Br
1) Ba(OH)2, THF, H2O
2) THF/AcOH/H2O
O
O
3)
OPMB
EtO P
OH MeO
EtO EDCI
O
P
OEt
EtO
OTBS
H
PMBO
O
Br
Br
(91%)
O
H
1) PivCl, pyr.
2) TBAF
3) PCC, Al2O3
4) K2CO3, MeOH
HH
O
Me
O
(54%)
H
Br
SugO
OTBS
1) DIBAL-H
2) Martin
sulfurane;
OH AcOH, H O, THF
2
HH
MeO
MeO H
CHO
(73%)
(73%)
OTBS
OH
OMe
Roush et al: PNAS (2004) v. 101, pp. 11955-11959.
1) O3
SugO
1) TBAF
SugO
2) PPh3=CHCO2Me
2) Dess-Martin
SugO
3) DIBAL-H
3) CBr4, Ph3P
4) Parikh-Doering [O]
OTBDPS
Paquette et al, JACS (1998) v. 120, pp. 2543-2562.
tBuLi;
MeO OMe
Br
NaH, THF;
CeCl3;
MeOH, H2O
MeO
Emily Cherney
Br
O
Et
Agrochemistry: Insecticides
Baran Group Meeting
2-rocaglamide
Frontier et al, JACS (2009) v. 131, pp. 7560-7561
O
HCl (1M)
2) OsO4, NMO;
3) NaIO4
O
PMBO
1) DDQ
2) KHMDS,
PhNTf2
O
OTf
O
(exo)
CO2Me
OMe
O
1) NaOMe,
MeO HO
MeOH;
2) Me4NBH(OAc)3
MeO
61%, 82% ee
2 steps
CO2Me
O
(!)-rocaglamide
OMe
MeO HO
1) Pd(PPh3)4, CO,
MeOH, (iPr)2NEt,
2)PtO2, H2, EtOH
(51%)
MeO
OMe
MeO
O
OMe
O
HO
MeO HO
MeO
Ph
O
MeO
MeO
OMe
(59%)
MeO HO
MeO
HO
MeO HO
MeO
O
OMe
OMe
1) tBuLi, Bu3SnCl,
PMBO
Et2O, !40 °C
MeO
2) mCPBA, DMF, rt
(50%)
h" , TADDOL
O
O
O
MeO
MeO
OMe OH
CO2Me
PhMe/DCM, !70 °C
OH
MeO
1) nBuLi,
45%
over
H
Ph
5 steps 2) KH, NaI, PMBCl
Ph
MeO
Ph
OMe O
MeO
O
MeO
OMe
H
NMe2
O
O
O
O
3-thiangazole
Heathcock
et al, JOC (1994) v. 59, pp. 4733-4734
CO2Me
Bn
BnS
O Me
H
H
N
N
CO2Me
S
N
CBZ
N
H
Me
Me
O
Me
SBn
SBn
1) Na, NH3,
S
N
THF, !78 °C
OMe
2) TiCl4, DCM
Me
4 steps (50%)
(68%)
S
N
1) NaHB(OAc)3
2) LiOH, THF/H2O
3) Me2NH, DCC, DMAP
(28%)
H
N
Bn
O
(±)-rocaglamide
OMe
BnS
O Me
N
Me H
SBn
H
N
O
Me
O
N
Me H
SBn
O
(38%)
Me
OBn
NHMe
1) DMP
2) TsOH,
4Å sieves
3) DDQ
O
HO
Me
NH
O
HN Me
thiangazole
O
O
Porco et al, JACS (2006) v. 128, pp. 7754-7755
OMe 1) vinylMgBr, CeCl3;
MeO
Emily Cherney
Agrochemistry: Insecticides
Baran Group Meeting
4-deguelin
Sames et al, Org. Lett. (2003) v. 5, pp. 4053-4055
O
MeO
MeO
OH
acetone, pyr.
2) MeI, K2CO3
O
O
1)
THF, - 78 °C
2) MnO2, DCM
O
O
Me
Me
OH
Me
O
OMe
MeO
1) BCl3, DCM,
(86%)
- 78 °C
2) KOAc, EtOH, !
H
O
MeO
MeO
O
H
O
O
(±)-deguelin
O
O
O
OH
OH
Wittig
Me
O
Me
(97%)
O
Me
O
MeO
Me
Me
1) PPh3,
DEAD, Et3N
2) Grubbs II
Me 1) ADmix- #
Me 2) IBX
3) Zn, AcOH, µ"
O
O
MeO
($)-deguelin
MeO
O
H
O
Section 2: From Natural Products to Synthetic Pesticides
Natural Product
O
Commericial Insectiside
Me Me
Me Me
OMe
Indigenous tribes in French Guiana smashed
jicama roots containing rotenone to use while
fishing. The rotenone poisoned the fish
causing them to rise to the surface of the
water.
The fish were still edible since
rotenone is poorly absorbed by the GI tract in
humans. Today it is also used in aquatic
research to collect cryptic fish.
Me
Me
(16%)
O
H
1- Pyrethrin
H
MeO
O
H
O
H
O
A story brought to you by:
rotenone
Me
Me
MeO
Me
MeO
O
OH
(49%)
O
MeO
OMe
MeO
K2CO3, KI, CuI
2) µ" , m-xylene,
180 °C
(91%)
MeO
(49%)
O
OH (90%)
(87%)
O
Me 5 mol% PtCl2,
Me PhH, 55 °C
O
MeO
1) Cl
O
OMe
(36%)
OH
1) NIS, TFA
OH 2) Pd(OAc) MeO
2
nBuLi,
O
1)
OH
NaH, µ" MeO
80 °C
(70%)
(quant.)
OH
MeO
MeO
Br
MeO
O
Winssinger et al, Chem. Eur. J. (2010) v. 16, pp. 9767-9771
K2CO3, DMF
MeO
Emily Cherney
Me
Me
Me
Cl
O
O
Cl
O
O
O
CN
O
pyrmethrin I
cypermethrin
Agrochemistry: Insecticides
Baran Group Meeting
2-nicotine
1-pyrethrin (cont'd.)
A Synthesis of cyhalothrin: US Patent No. 7,468,453 B2
Syngenta process route to cyhalothrin: formulated in and marketed
under the names "Karate" "Kung-fu" and "Matador"
Me Me
F3C
Cl
SOCl2,
PhH
OH
F3C
O
cyhalothrin
O
Ar
O
N
O
N
N
H
N
NO2
Imidacloprid
1) MeNH2, NaOH,
H2O, EtOH
2) Aq. CH2O, 80 °C, O
pH 8-9
recrystallization Cl
Cl
Cl
Me
A Synthesis of Thiamethoxam: US!Patent No: 6861522 !(B2)
Me Me
Cl
N
nicotine
NaCN, Hexane,
w/ or w/o H2O,
w/ or w/o Et3N
O
Commericial Insectiside
N
H
Cl
Cl
O
Natural Product
Me Me
Me Me
Cl
Emily Cherney
O
O
CN
O
CN
Sorry for the vague procedures here, but to quote the patent: "The reaction can be
carried out in a solvent or in a mixture of a water immiscible solvent or an aqueous
solution of the source of cyanide or in the absence of a solvent"
additionally... "the acid chloride and 3-phenoxybenzaldehyde can be added sequentially
or simultaneously to the source of cyanide in the presence of the solvent or the solvent
mixture, optionally in the presence of an organic base or an onium salt."
NC
H
N
CN
Cl
NH
N
N
N CN
steps
Me
1) NaSCN
2) Cl2
Cl
S
Cl
S
N
N
Cl
N
O
NNO2
Me
Cl
more vagueness continues on like this for about a dozen more paragraphs...
A Synthesis of Thiacloprid: US Patent No:!1987-17641"A5
Analogs based on pyrethrin:
CN
ACS Symposium Series v. 504 (1992): "Synthesis and Chemistry of Agrochemicals III"
CN H2N
HN
K+
pp. 258-282
N
SH
BnCl
NCl
1) (COCl)2
O
1) Wittig
NC
CS2- K+
S
N
2)
BnS
SBn - 2x BnSH
H
2) BH3•THF
OH
N
Cl
N
OH
O 3) [O]
O
R
R
R
3)
KOH, DMF
MgBr
Other Commericial Products:
NaH,
N CN
NNO2
Cl
Me
Cl
N
N
N
O
S
O
N
N
H
H
O
Me
S
R
N
Cl
N
NO2
Me
F
clothianidine
Cl
thiacloprid
N CN
Me Me
Me
acetamiprid
N
N
simplified:
H
O
EtO
MTI-800
Cl
N
Me nitenpyram
Agrochemistry: Insecticides
Baran Group Meeting
3-organophosphates
Natural Product
HO
H
N
glyphosate
3-organophosphates (cont'd.)
A Synthesis of Azinophos-Methyl: Tetrahed. (1991) 8917; J. Het. Chem.
(2007) 951; Bioconj. Chem. (1997) 256
Commericial Insectiside
O
O
O
O
O
MeO P N
MeS H
P OH
OH
NH2
S
P2S5, MeOH, PhH
P
MeO
OMe
SH
(Nongyao (2001) 13)
MeO
P
Cl
OMe, NH4OH, DCM
MeO
OMe
NH2
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
MeO
P
OMe, SO4Me2
NH2
MeS
R
P
OMe
NH2
MeS
OMe
NHR
(R= E+)
S
P
P
Cl
R
R
P
Cl
O
POCl3, 1 eq EtOH, Et3N
then 1 eq ArOH
(Tetrahedron (1995) 7981)
EtO
P
Cl
OAr
EtO
R
S
H2N
MeO
P
OMe
SH
N
NHR
OAr
fenamiphos
S
HN
OMe
OMe
N
N
OMe
N
S
CH2O
MeO
Methidathon
A Synthesis of Pyrimiphos-Methyl: (Huaxue Shiji (2010) 845)
O
Me
NEt2
H2N C N
H2N
Me
Me
NH
P
OMe
SH
NEt2
O
N
OMe
NH
Me
O
NEt2
S
SnPr
SnPr
P
O
phosgene
S
P S
P
ethoprop
O
EtO
OMe
OMe
SH
O
Cl
S
Base
O
H
N
R'
(R'= Nu-)
O
(Huazhong Nongye Daxue Zuebqo (2000) 339)
1) MeOH
2) H2NNH2
MeO OMe
S
EtO
S C S
OMe
NHR
(R= E+)
P
N
N
P
Cl
A Synthesis of Methidathon: (Nongyao (2001) 13)
P
MeO
O
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
POCl3, 1 eq EtOH, Et3N
N
OMe
SR
(R= E+)
O
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
PSCl3, 2 eq RMgBr
N
N
N
Azinophos-Methyl
P
MeO
S
S
P
S
OMe
R
(R= Nu-)
S
CH2O,
SOCl2
S
O
N
P
MeO
NH
N
target
S
S
S
O
NaNO2, HCl
NH2
Making various Phosphates:
(Phosphorous, Sulfur, Silicon and Related Elements (2010) 347)
O
Me
acephate
reagents
product
- PSCl3, MeOH, NaOH, PhMe
S
- PCl3, MeOH, NaOH, Et3N, S
P
- P2S5, MeOH then Cl2
MeO
OMe
- P(O)(OMe)2, Lawsesson's then SO2Cl2
Cl
Emily Cherney
S
MeO
N
N
P
O
OMe
Pyrimiphos-Methyl
MeO
Me
P
Cl
OMe
Agrochemistry: Insecticides
Baran Group Meeting
Kepone and Mirex:
4- Carbamates
Cl
Natural Product
Me
O
MeN
Commericial Insectiside
H
N
N
Me
physostigmine
Me
N
H
N
O
S
Me
Me
N
H
Me
N
H
O
Me
N
H
Me
O
O
N
H
N
O
S
Cl
Me
Cl
Cl Cl
Cl
Cl
Cl
Cl
Me
Cl
Cl
Cl
Cl
Mirex
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
MeO
DDT was discovered by a Paul Müller in 1940. It was first
brought to market in 1944 and was used during the second
half of WWII to prevent the spread of malaria and typhus.
Paul Müller won the Nobel Prive in Physiology and
Medicine for the discovery in 1948. It was later used as an
insecticide, however it was found to be harmful to wildlife,
particularly birds including the bald eagle, and was banned
from use in the US in 1972.
Section 3: Totally Synthetic Pesticides
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
dichlorodiphenyl
dichloroethane
Cl
Cl
OM
e
Methoxychlor
dichlorodiphenyl
trichloroethane (DDT)
methomyl
fenobucarb
Cl
Cl
Cl
Cl Cl
Cl
H
O
O
Me
Cl
Cl
bendiocarb
Me
carbaryl
N
H
O
bendiocarb
O
O
Me
O
aldicarb
O
Cl
Cl
O
O
Cl
H2SO4
(cat.)
O
O
Cl
Cl
chlorodecone
(Kepone)
DDT etc.:
xylylcarb
Other Commerical Carbamates:
Me
Cl
Cl
O
Me
Me Me
Cl
Cl Cl
Cl
Me
Cl
Cl
Cl
Cl
O
H
N
O
Me
O
O
Emily Cherney
OH
Cl
Cl
Cl
Cl
Cl
1-organochlorides*
Cl
Cl
Cl
Diels
!Alder
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Chlorodane
Cl
Cl
hexachlorobenzene
Cl
Cl
Lindane
Cl
Cl
pentachlorophenol
2-fun transformations from the agrochemistry literature!
Yamamoto et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 34-42.
Aldrin
similarly:
Cl
Cl
* Almost all organochlorides have been banned globally.
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
Endrin
Cl
Cl
Cl
O
S
Cl
Cl
O
RO2C
Cl
RO2C
O
Cl
Endosulfan
Cl
RO2C
S
C
S
1) NaOH
2) ClCO2Me
S
RO2C
CO2R
S
CO2R
HO
CO2R
MeNHNH2
N
N
Me
SH
Agrochemistry: Insecticides
Baran Group Meeting
2-fun transformations from the agrochemistry literature! (cont'd)
Emily Cherney
McCann et al. Synthesis and Chemistry of Agrochemicals VI (2002) p. 166-177.
Meier et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 313-326.
R
O
R
NH2(Me)2, CH2O,
HCl, EtOH
O
O
NH
R
R
H2NNH2
Ar
HN
(Me)2N
Me
1) NaNO2
2)
MeO2C
R
Me
N
HN
MeO2C
N
N N
N
Cl
Cl
Cl
OR
N
CO2H
N
O
OH
Me
N
O
O
CO2R
Me
Me
DBU
Me
1) NaBH4
CO2R 2) DBU
RO2C
RO2C
F3C
N
H
CF3
F3C
N
CO2R
CO2Me
HO
O
CF2H
F3C
N
CFH2
1) NaBH4
2) DBU
Me
Me
Me
RO2C
F3C
N
O
RO2C
NH
Wepplo et al. Synthesis and Chemistry of Agrochemicals IV (1995) p. 149-160.
HO
Me
Via:
Me
Me
2) (PhO)2PON3, Et3N
1) NH2OH•HCl,
NaOMe, MeOH
2) HCl, MeOH
Ar
NH
O
Me
O
iPr Me
Me
Theodoridis et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 134-146.
iPr
OH
N NH
N
HN
1) O
Ar
NH
Lee et al. Synthesis and Chemistry of Agrochemicals II (1991) p. 195-208.
Guaciaro et al. Synthesis and Chemistry of Agrochemicals III (1992) p. 56-74.
Et3N,
R
R
iPr
R
Me
N
CO2Me
O NaH
NOH H2N
NHNH2
NH2
O
Ar
CH3CHO;
KNCO, AcOH;
NaOCl
O
Ar
CH2(OEt)2, H+
NH
R
Ar
Cl
NH2
O
Ar
R
MeO2C
H
N
Me
O
H2N
Cl
NH3+Cl-
O
Me
Cl
Cl
, base; HCl
N
Ar
Ar
H
N
N
H H
Me
CO2R
RO2C
CF2H
F3C
CO2R
N
CH3