Synthesis and herbicidal activity of phenylpyridines - A new lead

Article abstract of DOI:10.2533/000942903777678650

Novel phenylpyridines were synthesized based on molecular modeling oriented design by super-position of herbicidal phenyl-uracils, -indazoles, and diphenylethers. Their preparation follows Suzuki-type coupling conditions of reactive 2-chloro-pyridines with appropriate 2,5-substituted 4-chloro-phenyl boronic acids. Depending on the nature of substituents in the pyridine, and in particular the phenyl group, a large number of derivatives are readily accessible. Besides open-chain phenylpyridines also anellated compounds, such as pyridine-substituted 2H-1,4-benzothiazin-3(4H)-one or 3,4-dihydro-1H- quinolin-2-one, were prepared. Phenylpyridines act by inhibition of protoporphyrinogen-IX-oxidase. Their synthesis will be described in conjunction with structure-activity relationships. Phenylpyridines are highly active against many important broadleaf and grass weed species under pre- and - in particular - post-emergent conditions.

Full text of DOI:10.2533/000942903777678650

CROP PROTECTION RESEARCH
715
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 715–719
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Synthesis and Herbicidal Activity
of Phenylpyridines – A New Lead
Peter Schäfer, Gerhard Hamprecht*, Michael Puhl, Karl-Otto Westphalen, and Cyrill Zagar
Abstract: Novel phenylpyridines were synthesized based on molecular modeling oriented design by super-
position of herbicidal phenyl-uracils, -indazoles, and diphenylethers. Their preparation follows Suzuki-type
coupling conditions of reactive 2-chloro-pyridines with appropriate 2,5-substituted 4-chloro-phenyl boronic
acids. Depending on the nature of substituents in the pyridine, and in particular the phenyl group, a large
number of derivatives are readily accessible. Besides open-chain phenylpyridines also anellated compounds,
such as pyridine-substituted 2H-1,4-benzothiazin-3(4H)-one or 3,4-dihydro-1H-quinolin-2-one, were
prepared. Phenylpyridines act by inhibition of protoporphyrinogen-IX-oxidase. Their synthesis will be
described in conjunction with structure–activity relationships. Phenylpyridines are highly active against many
important broadleaf and grass weed species under pre- and – in particular – post-emergent conditions.
Keywords: Phenylpyridines · Protoporphyrinogen-IX-oxidase inhibitors · SAR · Suzuki-coupling
1. Introduction
the enzyme protoporphyrinogenoxidase ethers, that lead to biphenyls as a first step
(Protox) of the porphyrin pathway, a key (Scheme 1). The latter showed good PPO
Over the past 30 years, the number of enzyme of chlorophyll biosynthesis. By in- enzyme- but only poor green-house activi-
herbicides that inhibit the enzyme pro- hibiting Protox (‘PPO-inhibitors’), these ty. Introduction of a pyridine nitrogen
toporhyrinogen-IX-oxidase (Protox) has herbicides induce protoporphyrinogen IX strongly increased control of undesired
grown from a few experimental compounds accumulation – the desired enzyme inter- plants. As shown in Fig. 1, molecular mod-
to one of the largest classes of patented her- mediate. They do so, however, at the wrong eling is very helpful for visualizing and un-
bicides; see overview [1]. The reasons for place – being exported from the plastid en- derstanding the degree of superposition of
industrial engagement were
• low application rates,
• fast activity,
• broad spectrum against grasses
• and weeds, and
velop into the cytoplasma, where it is oxi- uracils and phenylpyridines, with one car-
dized by autoxidation [3] and herbicide-re- bonyl oxygen being imitated by a chlorine
sistant extraorganellar oxidases [6] into atom and the other by the pyridine nitrogen
protoporphyrin IX, a very efficient photo- with its free electron pair.
sensitiser, generating singlett oxygen when
• residual activity.
exposed to light [2]. The latter destroys cell
The mode of action, which ultimately led to membranes, the pigments bleach out and 2. Materials and Methods
the use of the term ‘peroxidizing herbi- the plant becomes brown and necrotic: the
cides’[2], was, however, not discovered un- plant burns up [7]. Therefore, the light-re-
Phenylpyridine synthesis was achieved
til 1987 [3–5]. Their molecular target site is quiring step – the generation of singlett by Suzuki-type coupling of reactive 2-
oxygen – is only a secondary event, result- chloropyridines with appropriate 4-chloro-
ing from the initial formation of protopor- phenyl-boronic acids. Depending on the na-
phyrin IX.
ture of groups R1–R3 and, especially, R4
Among the early PPO-inhibitors are (see Fig. 2), a large number of derivatives
diphenyl ethers like Blazer® (acifluorfen are readily accessible [8][9].
sodium; Rohm and Haas, BASF) which
were followed by N-phenyl-imides, espe- 2.1. Synthesis of 3-Chloro-2-
cially phenyl uracils and tetrahydrochlo- (phenyl)-5-(trifluormethyl)-pyridines
rindazoles like S 275 (Sumitomo) [1].
2,3-Dichloro-5-trifluormethylpyridine
(1a) (Scheme 2) is converted by a sequence
of Suzuki-coupling with 4-chloro-phenyl-
1.1. Molecular Modeling
*Correspondence: Dr. G. Hamprecht
BASF Aktiengesellschaft
D-67056 Ludwigshafen, Germany
Tel.: + 49 6201 41612
Fax: + 49 6201 20440
E-Mail: gerhard.hamprecht@basf-ag.de
We became interested in new deriva- boronic acid (2a), nitration and Pt/C-cat-
tives based on molecular modeling-orient- alyzed hydrogenation in N-ethylmorpho-
ed design by superposition of herbicidal line to the pyridyl substituted phenylhy-
phenyl uracils, -indazoles and diphenyl- droxylamine 4 with 75% overall yield. The

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CHIMIA 2003, 57, No.11
chromatography the propanoic ester 11 in
31% yield.
Cl
O
N
X
X
Cl
CO2Na
For the synthesis of the sulfonamide 13,
2,3-dichloro-5-trifluormethylpyridine (1a)
is coupled under Suzuki conditions with 4-
chloro-2-fluoro-phenylboronic acid (2c) to
the phenylpyridine 3c, which is submitted
to chlorosulfonylation at 130 °C, followed
by reaction with sarcosin-methyl ester hy-
drochloride in 72% and 68% yield, respec-
tively.
CF3
N
Y
Y
CF3
O
NO2
N
N
H3C
O
Z
Z
uracils
diphenylethers
(Blazer)
tetrahydrochlorindazoles
Cl
The first step for the synthesis of the
2H-1,4-benzothiazin-3-(4H)-one 17 is nu-
cleophilic displacement of the fluorine
atom in 14 with thioglycolic acid to afford
the thioether 15 which by reductive cy-
clization yields the 6-(2-pyridinyl)-2H-1,4-
benzothiazin-3(4H)-one 16 in an overall
yield of 50%. The latter is alkylated with
propargyl bromide in the presence of sodi-
um hydride in DMF, resulting in a yield of
80%.
CF3
Cl
PPO l50= 4 . 10-8 mol/l
biphenyls
weak herbicidal activity
OCH3
Cl
phenylpyridines
PPO l50 = 4 . 10-8 mol/l
CF3
Cl
N
good herbicidal activity
OCH3
Scheme 1. Phenylpyridines generated by superposition of phenyluracils, indazoles and
diphenylethers
2.2. Biological Tests
2.2.1. Greenhouse Experiments
All the data were taken from screening-
type trials in the greenhouse. For post-
emergence tests, plants were cultivated in
plastic pots of 8.6 cm diameter containing
loamy sand with about 1.2% humus as the
substrate. The test plants were sown, grown
in the test pots to a height of 4–12 cm and
then treated with the test compound in a
spray chamber at a rate of 31.25 g/ha a.i.,
formulated as emulsion concentrates. The
number of replicates was one and, for com-
parison, four untreated control pots were
included in each test. After the application,
the test plants were kept for 18–20 days at
18–27 °C, during which period the plants
were maintained and their reaction to the
individual treatments was assessed and
recorded.
Injury to the plants was assessed on a
scale from 0 to 100 in comparison to the un-
treated controls, with 0 denoting no damage
and 100 denoting complete destruction of at
least the visible plant parts. Fig. 3 denotes
the average injury across three grass
species (grey bars) or seven broadleaf
species (black bars).
Fig. 1. Superposition of uracils and phenylpyridines
2
3
R
R
R1
Cl
Substituent constants
N
R4
Pyridine nucleus
R1: CF3 > F2CH ∼ F2CHO > CH3SO2 > Cl
R1 CF3 F2CH F2CHO CH3SO2
Cl
MR 5.02
5.20
0.32
0.44
7.90
0.18
0.31
13.49
0.72
6.03
0.23
0.71
R2: Cl ∼ F > CF3 > CH3, OCH3, SCH3
ı-p 0.54
ʌ
0.88
-1.63
Phenyl moiety and side chain
R3: F > H > Cl
R4: highly variable
Fig. 2. Structure–activity relationship of the pyridine and phenyl moieties
key step is the following Bamberger re- with sulfuric acid. The acid 9 is obtained in 2.2.2. Test Species
arrangement for the introduction of the flu- high yield by sodium chlorite oxidation fol-
orine atom into the 2-phenyl position of 5 in lowed by standard esterification (10).
The following plant species were used:
Grasses: Alexander grass (Bracharia plan-
86% yield. The latter is diazotized to the
phenol and alkylated to the propargyl ether yl)propanoate 11, 2-chloro-5-[3-chloro-5- crus galli), and giant foxtail (Setaria faberi)
7 in 64% yield over both steps. (trifluormethyl)-2-pyridinyl]-4-fluoroani- Broadleaf weeds: velvet leaf (Abuthilon
To obtain the methyl 2-chloro-3-(phen- taginea), barnyard grass, (Echinochloa
NBS bromination of another Suzuki line 5 is diazotized in a t-butyl nitrite solu- theophrasti), redroot pigweed (Amaranthus
coupling product 3b yields a dibromo- tion in acetonitrile in the presence of methyl retroflexus), hairy beggarticks (Bidens pi-
methyl derivative, which is transferred to acrylate and cupric chloride during 4 h at losa), common lambs-quarters (Cheno-
the corresponding aldehyde 8 by treatment 0 °C and 12 h at 22 °C to produce after podium album), cleavers (Galium ap-

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CHIMIA 2003, 57, No.11
Phenylpyridine ethers
Cl
[Pd(PPh3)4]
Na2CO3
Cl
Cl
HNO3
H2, Pt/C
NMM
H2SO4
+
CF3
Cl
(HO)2B
Cl
CF3
Cl
CF3
Cl
98%
95%
81%
N
N
N
NHOH
1a
2a
4
3a
Cl
F
Cl
F
Cl F
1. NaNO2/H2SO4
2. CuSO4
HF
Br
CF3
Cl
CF3
Cl
CF3
Cl
86%
74%
86%
N
N
N
NH2
OH
O
5
6
7
Phenylpyridine carboxylic acid derivatives
NBS
hν
Cl
F
F
[Pd(PPh3)4]
Na2CO3
Cl
CCl4
H2SO4
74%
+
CF3
Cl
(HO)2B
Cl
CF3
Cl
95%
73%
N
N
CH3
CH3
1a
2b
3b
Cl
F
Cl
F
Cl
F
NaClO2, H2O2
NaH2PO4
SOCl2/ROH
90%
CF
Cl
CF
Cl
CF
Cl
3
3
3
86%
N
N
N
CO2R
CO2H
CHO
10
8
9
Phenylpyridine propanoic esters
Cl
F
F
Cl
ON = O
H C CH CO CH
2
2
3
CF3
Cl
Cl
CF3
Cl
CuCl
31%
2
N
N
NH2
5
CO2CH3
11
Phenylpyridine sulfonamides
Cl
F
F
.
CO CH HCl
Cl
Cl F
HN
2
3
ClSO H
3
NEt
3
CF
Cl
CF
Cl
CF
Cl
3
3
3
72 %
68%
N
N
N
SO N
SO Cl
CO CH
2
2
2
3
3c
12
13
Anellated phenylpyridines
Cl
Cl
HS–CH2–CO2H
E t 3 N
CH2CO2H
CF3
S
CF
F
3
N
N
NO2
NO2
14
15
NaH/DMF
Br
Cl
Cl
Fe/AcOH
50%
CF3
S
CF3
S
80%
N
N
based on 14
N
N
16
17
H
O
O
Scheme 2. Synthesis of phenylpyridines

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CHIMIA 2003, 57, No.11
SAR of the phenyl side chain
Cl
CF
CF3
Cl
F
CF3
CF3
Cl
CF3
Cl
Cl
CF3
Cl
3
F
F
F
F
F
N
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
O
S
N
O
O
O
O
N
O
O
O
O
O
O
O
19
100
20
O
23
18
22
21
100
100 100
100
100
100
95
90
87
77
70
O
Cl
F
S
O
N
Cl
O
24
100
33
SAR of anellation in comparison
CF3
Cl
CF3
Cl
CF3
Cl
CF3
Cl
Cl
CF3
F
N
N
N
N
N
Cl
O
S
O
N
N
N
N
N
O
O
O
O
28
26
29
27
25
99
100
91
89
88
70
52
37
30
23
m,p- versus o,m-anellation
F
F
F
F
Pyr
O
Pyr
Cl
Pyr
Cl
Pyr
Cl
>
>
>
N
O
N
O
N
O
N
O
O
CO2CH3
Cl
33
30
31
32
Fig. 3. Structure–activity relationship of the side chain and type of anellation. Grey bars: injury to grass species, black bars: injury to broadleaf
species.

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CHIMIA 2003, 57, No.11
[9] P. Schäfer, G. Hamprecht, E. Heistracher,
H. König, R. Klintz, P. Münster, H. Rang,
K.-O. Westphalen, M. Gerber, H. Walter,
‘Substituted 2-fused Phenylpyridines with
Herbicidal Activity’ (BASF AG), WO
95/02590, 1995.
[10] Y.C. Martin, ‘Quantitative Drug Design:
A Critical Introduction’ in ‘Medicinal
Research’, Ed. G.L. Grunewald, Marcel
Dekker, Inc., New York, 1978.
[11] C. Hansch, A. Leo, D. Hoekman, ‘Explor-
ing QSAR. Hydrophobic, Electronic, and
Steric Constants’, American Chemical
Society, Washington, 1995.
parine), tall morning glory (Pharbitis pur- tion – apparently decrease herbicidal activ-
purea), and ladysthumb (Polygonum persi- ity. The (1,4-benzoxazin-3-one-6-yl)-pyri-
caria)
dine m,p-anellation 30 is herbicidally more
active than the (benzoxazole-7-yl)-pyridine
derivative 31 with o,m-anellation.
3. Results and Discussion
3.1. Structure–Activity
Relationships (SAR)
3.1.1. Pyridine Moiety
4. Conclusion
Novel phenylpyridines were conceived
Electron-withdrawing substituents in based on molecular modeling-oriented
the pyridine moiety (Fig. 2) change the her- design – superposition of herbicidal N-
bicidal activity of the phenylpyridines in phenylimides and diarylethers. Their syn-
question. In position R1 trifluoromethyl thesis via Suzuki-coupling is the method of
roughly has the same steric requirement choice for obtaining high yields.
[12] P. J. Dehlinger, JPTOS 1992, 74, 463.
and lipophilicity as chlorine, but due to its
Phenylpyridines are potent inhibitors of
stronger electron-withdrawing properties is protoporphyrinogen-IX oxidase in plants,
herbicidally much more active. Difluoro- where they constitute a new herbicidal lead.
methylderivatives and methyl sulfonyl are They have strong herbicidal activity against
in between, either because of less electron- a broad range of grasses and broadleaf
withdrawing character and lipophilicity or weed species. Structure-activity relation-
as a result of just too much bulkiness in the ship studies show that the optimum sub-
methyl sulfonyl case [11][12]. Additional- stitution pattern of the pyridine ring is
ly, in position R2 electron-withdrawing 3-chloro-5-trifluormethyl. The phenyl ring
substituents are required. Chlorine and should be 4-chloro-2-fluoro-substituted
fluorine show comparable herbicidal activ- with an additional (high variable) sub-
ity, better than trifluoromethyl and superior stituent in the 5-position.
to methyl and ether substituents, which are
excessively electron-donating.
Most active side chains in the 5-position
of the phenyl ring are the N-methyl-N-
(alkoxy-carbonyl)alkyl sulfonamides, the
alkyl and (alkoxycarbonyl)alkyl carboxy-
3.1.2. Phenyl Moiety
In the phenyl moiety (Fig. 2) herbicidal lates, as well as the propargyl ether. Among
activity decreases in the R3 position on the benzanellated derivatives, the (1,4-ben-
passing from fluorine to hydrogen and zoxazin-3-one-6-yl)-pyridine substitution
chlorine by about a factor of 3 to 4. The R4 shows the strongest herbicidal activity.
position, on the other hand, is highly flexi- Phenylpyridines are also very good pre-
ble.
emergent herbicides (data not shown).
Received: September 15, 2003
3.1.3. SAR of the Phenyl Side Chain
The phenyl side chain in position R4
(Fig. 3) is highly variable and at a rate of
31.25 g/ha a.i. shows the same herbicidal
activity on broadleaf weeds, irrespective of
the electronic and steric character of the
chosen chain. But differences become evi-
dent upon examination of grass activity.
The most active is the sulfonamide side
chain 21, followed by esters like 18 and 19
and the ether 23. With propanoic esters 20
and oximes 22 grass activity falls into the
70% range. The methyl pyridyl sulfon 24
has insufficient grass activity.
[1] ‘Peroxidizing Herbicides’, Eds. P. Böger,
K.Wakabayashi, Springer-Verlag, Berlin,
Heidelberg, 1999.
[2] M. Matringe, R. Scalla, Brit. Crop Prot.
Conf. -Weeds-, 1987, Vol. 3, 981.
[3] M. Matringe, R. Scalla, Plant Physiol.
1988, 86, 619.
[4] S.O. Duke, J. M. Becerril, T. D. Sherman,
J. Lydon, H. Matsumoto, Pestic. Sci. 1990,
30, 367.
[5] R. Scalla, M. Matringe, J.-M. Camadro,
P. Labbe, Z. Naturforsch. 1990, 45c, 503.
[6] J. M. Jacobs, N. J. Jacobs, T. D. Sherman,
S. O. Duke, Plant Physiol. 1991, 97, 197.
[7] P. Böger, K. Wakabayashi, Z. Naturforsch.
1995, 50c, 159.
3.1.4. SAR of Anellation
in Comparison
When anellation in the 3,4-phenyl posi-
tion is investigated, the 1,4-benzoxazin-3-
one heterocycle 26 is about twice as strong
on grasses as the 3,4-dihydro-1H-quinolin-
2-one type 25 or the related 1,4-benzoth-
iazin-3-one 27. Lowest grass activity is
shown by the 1,3-dihydro-indol-2-one type
28. Predetermined breaking points in the
heterocyclic nucleus – prone to metaboliza-
[8] P. Schäfer, G. Hamprecht, E. Heistracher,
H. König, R. Klintz, P. Münster, H. Rang,
K.-O. Westphalen, M. Gerber, H. Walter,
‘Substituted 2-Phenylpyridines with Her-
bicidal Action’ (BASF AG), WO
95/02580, 1995.