Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring

Article abstract of DOI:10.1016/j.bmcl.2017.12.042

Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution and pattern hopping in the phenyl moiety revealed structure–activity relationships in good agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site properties, the N-methoxy functionality effectively acts as a bioisostere of the ether group in the seven-membered hydrazine ring.

Full text of DOI:10.1016/j.bmcl.2017.12.042

Accepted Manuscript
Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring
Tomas Smejkal, Shuji Hachisu, James N. Scutt, Nigel J. Willetts, Danielle
Sayer, Laura Wildsmith, Sophie Oliver, Caroline Thompson, Michel
Muehlebach
PII:
S0960-894X(17)31216-7
https://doi.org/10.1016/j.bmcl.2017.12.042
BMCL 25498
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 October 2017
17 December 2017
19 December 2017
Please cite this article as: Smejkal, T., Hachisu, S., Scutt, J.N., Willetts, N.J., Sayer, D., Wildsmith, L., Oliver, S.,
Thompson, C., Muehlebach, M., Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring,
Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/10.1016/j.bmcl.2017.12.042
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1
Bioorganic & Medicinal Chemistry Letters
Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring
Tomas Smejkala, Shuji Hachisub, James N. Scuttb, Nigel J. Willettsb, Danielle Sayerb, Laura Wildsmithb,
Sophie Oliverb, Caroline Thompsonb and Michel Muehlebacha, 
aSyngenta Crop Protection AG, Schaffhauserstrasse, CH-4332 Stein, Switzerland
bSyngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored
towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease
of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution
and pattern hopping in the phenyl moiety revealed structure-activity relationships in good
agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA
carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site
properties, the N-methoxy functionality effectively acts as a bioisostere of the ether group in the
seven-membered hydrazine ring.
Keywords:
Cyclic hydrazine
Seven-membered heterocycle
5-Methoxy-[1,2,5]triazepane
Herbicide
2009 Elsevier Ltd. All rights reserved.
Grass weed control
Bioisosteric replacement
Diverse 2-aryl-cyclic-1,3-dione derivatives (ADs) reported in
recent years have demonstrated weed control effects against
monocotyledonous plant species.1,2 They interfere with lipid
biosynthesis in sensitive grass weeds by inhibiting the carboxyl
transferase (CT) domain of homomeric acetyl-coenzyme A
carboxylase (ACCase) located in the chloroplasts. Research work
in the particular 4-aryl-pyrazolidine-3,5-dione subclass that
features 5- to 7-membered cyclic hydrazines, optionally
interrupted by heteroatoms such as oxygen or sulfur, led to the
discovery3 and commercialization of the cereal herbicide
pinoxaden 1 (PXD, Fig. 1). The pivaloyl functionality G acts as a
cleavable group in planta resulting in release of the active
principle PXD-dione 2, which is responsible for the ACCase
target site activity.4
O
O
HN
HN
N
N
N
O
[A]
R
Cyclic
5-methoxy-
[1,2,5]triazepane
2-aryl-1,3-diones
hydrazines
O
N
N
O
O
G
1
2
G=C(O)t-Bu pinoxaden
G=H PXD-dione
We intend herein to describe chemistry and biology of aza-
PXD analogs (pinazadens), more specifically ADs incorporating
a 5-methoxy-[1,2,5]triazepane ring ([A]= -CH2-N(OCH3)-CH2-).
Their preparation relies on the use of corresponding 7-membered
heterocyclic [1,2,5]triazepane building blocks unprecedented in
the chemical literature.
Figure 1. The class of herbicidal ADs containing cyclic hydrazines
illustrated with pinoxaden (PXD) 1 and its active principle AD 2.
bisanion of 1,2-bis-BOC protected hydrazine 5 with 4, followed
by BOC-deprotection of 6 using hydrochloric acid delivered the
5-methoxy-[1,2,5]triazepane hydrochloride salt 7 smoothly.
Alternatively the triazepane ring formation could also be
achieved under phase transfer catalysis conditions.6 Bis-
alkylation of the orthogonally protected hydrazine 86b with
mesylate 4 similarly afforded the 5-methoxy-[1,2,5]triazepane
The 7-membered cyclic hydrazine building blocks 7 and 10
were prepared in multigram quantities from readily available
starting materials (Scheme 1). Thus, oxirane was condensed
twice with O-methyl-hydroxylamine and the resulting bis-
hydroxyethylamine 35 further converted into the corresponding
bis-mesylate 4 under standard conditions. N,N’-alkylation of the
———
 Corresponding author. Tel.: +41-62-866-0252; fax: +41-62-866-0860; e-mail: michel.muehlebach@syngenta.com

2
monoester 10 after deprotection, isolated either as a free base or
analogs at best. In contrast, a 2,4,6-trimethyl substitution (15c)
returned decent potency against grasses. That phenyl pattern
further tolerated a number of bulkier substituents in the ortho-
position, such as bromo, ethyl, ethynyl or methoxy (15d, 15j,
15m, 15n), usually associated with an improved herbicidal
activity impact. However, phenyl in this ortho-position was
detrimental (15p). Combining chloro and ethyl in the 2,6-
positions unveiled an interestingly active compound (15o), but
as a hydrochloride salt.7
Aryl-pyrazolidine-3,5-diones 14 were mainly prepared by
base-mediated cyclization3 of intermediates 13, themselves
available by coupling activated aryl acetic acid derivatives 11
with the novel cyclic hydrazine monoester 10 (Scheme 2, route
[a]). When handling substrates 13 with bulky substitution in the
BOC
NH
NH
O
5
RO
BOC
BOC
(d)
(a)
N
N
HN
HN
N
O
N
O
N O
+
(c)
H2NOCH3 . HCl
40% in H2O
BOC
3HCl
RO
3 R=H
4 R=Ms
6
7
(b)
(e)
BOC
(f)
N
N
HN
N
N
O
N
O
BOC
EtOOC
EtOOC
NH
NH
2HCl
8
EtOOC
9
10
Scheme 1. Preparation of the 5-methoxy-[1,2,5]triazepane building blocks 7 and 10.
Reagents and conditions: (a) Oxirane, O-methyl-hydroxylamine hydrochloride (40% w/w in H2O), NaOH, 0°C; (b) CH3SO2Cl, NEt3, THF, 0°C-RT; (c)
BOCNHNHBOC 5, NaH, DMF, 0 to 65°C; or alternatively 5, bis-mesylate 4, 30% NaOH w/w in H2O, Bu4NBr cat., toluene, reflux; (d) 2M HCl in Et2O, Et2O,
0°C-RT, isolate precipitate; then 4M HCl in dioxane, EtOAc, 90°C; (e) BOCNHNHCOOEt 8, NaH, DMF, 0 to 65°C; (f) 2M HCl in Et2O, Et2O, RT; optional
aqueous basic workup.
ortho-position of the phenyl ring, the ring closure reaction had to
be performed at elevated temperature. Conversely, thermal
condensation reactions between appropriately substituted aryl
malonic acid esters 12 and the methoxy-triazepane building block
7 were also possible, albeit delivering 14 in low yields (route
[b]). Nearly all dione active principles 14 were derivatized as
enol ethyl carbonate pro-herbicides8 15.9
the extent of crop damage was too severe. Conversely, the para-
position (R2) was found sensitive to the substituent type,
halogens or ethynyl (15e, 15f, 15g, 15l) led to weakened control
of the monocotyledonous species. A 4-methyl substituent (15d,
15j, 15k, 16, 15o) appeared satisfactory, if not optimal, with
respect to performance against the targeted grassy weeds, but
even bulkier groups were tolerated (4-F-Ph, 15r). The latest
however exhibited a gap on LOLPE, whilst also showing
borderline cereal selectivity. Owing to observations that
substituted phenyl rings at R4 were indulged1, we also explored
2-methyl-5-halophenyl derivatives (15q, 15s). The 2,5-
disubstituted analog 15q displayed acceptable levels of grass
control, but phytotoxicity to wheat may be of some concern.
Adding a further methyl group in the ortho-position (2,5,6-
trisubstituted 15s) surprisingly resulted in significant diminished
herbicidal activity at the rate tested.
Phenyl substitution impact of pinazaden compounds 15 on
weed control efficacy (four key grasses: Alopecurus
myosuroides, Avena fatua, Echinochloa crus-galli, Lolium
perenne) and on crop tolerance (wheat and rice) is presented in
Table 1 for post-emergence applications at a use rate of 62.5 g ai
ha-1 under standard screening conditions (see Supporting
Information). Tolerance data on winter wheat shoots grown from
seeds treated with the safener cloquintocet-mexyl (TRZAW-
CQC), when compared to the unsafened control (TRZAW),
permitted to estimate the potential for crop injury reduction
(safener10 action). The herbicidal potency/selectivity data of
pinoxaden 1 is included for comparison.
Interesting herbicidal activity of the 4-halophenyl derivative
15r prompted to further explore para-substituted analogs (Table
2, activity/selectivity data of dione active principles 14). A 4-
propynyl substituent (14t) already demonstrated improved
graminicidal activity over its ethynyl equivalent 14l. Noticeably
Probing a 2,5-dimethyl (15a) or 2,4,5-trimethyl (15b)
substitution on the phenyl ring resulted in very weak active
R2
R4
R1
O
(a)
(b)
N
N
N
O
R1
R3
R1
R3
O
O
O
R1
R3
R3
(from 11)
EtOOC
Ra
Rb
route [a]
(d)
HN
N
N
N
N
N
R2
R2
N O
R2
N
O
N
O
+
13
Rc
R4
R4
O
R4
xHCl
(c)
O
11 Ra=C(O)Cl; Rb=H
12 Ra=Rb=COORd
7 Rc=H
10 Rc=COOEt
15
14
EtO
(from 12)
route [b]
Scheme 2. Preparation of 5-methoxy-[1,2,5]triazepane containing ADs 14 and their corresponding enol ethyl carbonate pro-herbicides 15.
Reagents and conditions: (a) Aryl-acetyl chloride 11, methoxy-triazepane 10, NEt3, DMAP cat., THF, 0°C-RT; (b) NaOMe, DMF, 10°C-RT (and up to 80°C,
depending on bulkiness of ortho-aryl substitution); (c) Aryl malonate 12 (Rd = Me or Et), methoxy-triazepane 7, NEt3, xylene, reflux; (d) EtOC(O)Cl, NEt3,
DMAP cat., THF, 0-5°C.

3
Table 1
Influence of the phenyl substitution of carbonic acid ethyl ester 3-methoxy-9-oxo-8-phenyl-2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl esters
on crop selectivity and herbicidal grass activitya
R1
O
2
4
N
R2
N O
N
6
R4
R3
O
O
EtO
15
TRZAW-
CQC
Compound
R1
R2
R3
R4
TRZAW ORYSA ALOMY AVEFA ECHCG LOLPE
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Cl
H
CH3
CH3
CH3
Br
H
H
CH3
CH3
H
0
0
0
0
0
30
80
90
10
40
10
20
0
0
20
70
90
60
60
40
70
20
100
90
100
30
80
70
90
10
50
50
0
15a
15b
15c
15d
15e
15f
0
0
0
0
0
10
70
100
30
10
40
70
0
CH3
20
60
40
30
20
30
0
60
100
50
60
40
60
50
100
90
100
10
90
70
100
30
70
80
0
80
90
10
30
20
50
10
100
100
100
10
90
70
90
10
90
80
0
0
Br
H
0
CH3
H
10
0
Cl
CH3
H
Cl
Br
H
15g
15h
15i
0
CH3
CH3
CH3
CH3
CH3
-C≡CH
CH3
CH3
CH3
CH3
H
Br
H
0
CH3
CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
Cl
-CH=CH2
CH2CH3
CH2CH3
CH2CH3
CH3
H
0
H
40
0
90
70
60
0
100
100
100
20
80
70
100
30
20
100
0
15j
100
100
100
30
90
80
100
0
H
15k
16b
H
0
H
15l
0
-C≡CH
OCH3
OCH3
Ph
H
20
60
50
0
80
70
90
20
80
50
0
15m
15n
15o
15p
15q
15r
15s
H
H
CH3
CH3
CH3
CH3
H
H
4-Cl-Ph
H
40
10
0
80
100
0
4-F-Ph
H
CH3
CH3
4-F-Ph
H
PXD 1c CH2CH3
CH3
CH2CH3
40
90
5
90
100
100
100
a Post-emergence crop damage and grass control (%) at 62.5 g ai ha-1 on whole plants of formulated compounds 15 with 0.5% adjuvant Tween 20 (v/v).
Crops: TRZAW-CQC = wheat with a cloquintocet-mexyl seed treatment applied at a rate of 0.5g ai kg-1 seeds, TRZAW = wheat, ORYSA = rice;
Grass weeds: ALOMY = Alopecurus myosuroides, AVEFA = Avena fatua, ECHCG = Echinochloa crus-galli, LOLPE = Lolium perenne.
b Enol pivaloyl pro-herbicide of active principle 14k, which was prepared in analogy to published procedures.3
c Results for PXD are representative of several independent experiments (project standard) and show arithmetic means (n=65).
haloheteroaryl derivatives 14u-x revealed good to excellent post-
emergence grass weed control, wherein pyridyl (14w) and
pyrimidinyl (14x) analogs overcame the LOLPE gap observed
amongst other halo(het)aryl variants (14r, 14u). Remarkably the
binding site appears able to accommodate such bulky groups at
the 4-position located deepest in the ACCase dimer interface (see
discussion Fig. 2 below). As a major drawback however, those
attractive compounds clearly lacked crop selectivity.
phenyl moiety expressed excellent activity levels over the cereal
weed spectrum and particularly noteworthy demonstrated a clear
trend to reduce wheat crop injury in combination with a safener
exertion. Their common active principle N-methoxy triazepane
dione 14k moreover exhibits a very similar biological profile in
comparison to the PXD-dione 2 (Table 3). Indeed, an essentially
equipotent performance (both activity levels and wheat crop
selectivity) was obtained at 15.6 g ai ha-1 to achieve roughly 80-
90% grass weed control with low wheat damage which can be
fully cleared through the cloquintocet safener treatment. In
contrast, the mesityl active principle analog 14c is biologically
much less attractive.
Potent pinazaden compounds 15 on the cereal grass weed
spectrum (Alopecurus myosuroides, Avena fatua, Lolium
perenne) were also controlling the rice weed Echinochloa crus-
galli efficiently. Noticeably though the degree of rice damage
was almost consistently higher than phytotoxicity on wheat. Lack
of intrinsic rice tolerance as an insufficient attribute of this AD
class represents therefore a serious challenge for a post-
emergence application in rice.
The observed herbicidal activity similarity between
derivatives incorporating either a 5-methoxy-[1,2,5]triazepane
(14c, 14k) or a [1,4,5]oxadiazepane (17, 2) ring may be in part
rationally explained when looking at basic molecular properties
(Table 4). Weak acid character of the cyclic-1,3-dione unit, water
solubility and lipophilicity are all in close range within pairs.
Proherbicides 15k and 16 incorporating a 5-methoxy-
[1,2,5]triazepane ring and featuring a 2,6-diethyl-4-methyl-

4
Those physicochemical properties importantly drive translocation
properties in planta, movement which was demonstrated to
happen bi-directionally (two-way systemicity or ambimobility).4
Of further particular note, the maize chloroplastic ACCase
activity also turned out to be of the same order of magnitude
when measuring matched pairs indicating similar receptor
affinities.
π stacking on planar
protein amide fragments
solvent
exposed
located deepest
in the binding site
Equally important are facts taken from the binding mode of
those inhibitors in the ACCase active site. By analogy to PXD-
dione 2, AD 14k is likely bound to the carboxyl transferase (CT)
domain at its dimer interface. Figure 2 summarizes key anchoring
points of interaction,11 such as the enolate hydrogen-bonding to
the main chain amides of Ala1627 and Ile1735 (oxyanion site),
the hydrogen bond between the other oxygen of the central
pyrazoline ring and the amide of Gly1998’, one of the ethyl
substituents that points in the direction of a hydrophobic pocket
that containing residue Leu1705 or pi-stacking of the phenyl ring
to flat amide fragments. Importantly, the 5-methoxy-
ethyl group points in the
direction of a hydrophobic
pocket containing Leu1705
Oxyanion site
Figure 2. Schematic drawing of the anchoring points of interaction between
AD 14k and the yeast CT domain active site (adapted from Tong et al. [11]).
[1,2,5]triazepane ring is largely solvent exposed without relevant
Table 2
Influence of selected alkynyl and halo(het)aryl substitution in the 4-position of 8-(2,6-dimethylphenyl)-3-methoxy-1,2,4,5-tetrahydropyrazolo[1,2-
a][1,2,5]triazepine-7,9-dione on crop selectivity and herbicidal grass activitya
CH3
CH3
O
O
N
N
R2
N O
4
14
TRZAW-
CQC
Compound
R2
TRZAW ORYSA ALOMY AVEFA ECHCG LOLPE
-C≡CH
-C≡CCH3
14l
14t
30
NTb
90
20
70
80
80
70
90
80
10
60
80
70
70
90
90
40
80
40
60
30
30
70
90
80
0
0
30
10
20
60
60
70
60
70
70
70
80
70
4-F-Ph
14r
14u
14v
14w
14x
100
90
4-chloropyrazol-1-yl
5-chloro-2-pyridyl
5-chloro-3-fluoro-2-pyridyl
5-chloropyrimidin-2-yl
80
70
70
100
90
100
90
a Post-emergence crop damage and grass control (%) at 62.5 g ai ha-1 on whole plants of formulated compounds 14 with 0.5% adjuvant Tween 20 (v/v).
Crops: TRZAW-CQC = wheat with a cloquintocet-mexyl seed treatment applied at a rate of 0.5g ai kg-1 seeds, TRZAW = wheat, ORYSA = rice;
Grass weeds: ALOMY = Alopecurus myosuroides, AVEFA = Avena fatua, ECHCG = Echinochloa crus-galli, LOLPE = Lolium perenne.
b NT = not tested.
Table 3
Crop selectivity and herbicidal grass activitya of N-methoxy triazepane derivative 14k in comparison to PXD-dione 2.
R1
O
N
R2
N O
N
R4
R3
O
14
TRZAW-
CQC
Compound
R1
R2
R3
R4
TRZAW ORYSA ALOMY AVEFA ECHCG LOLPE
CH3
CH3
CH3
CH3
CH3
H
H
H
30
80
80
50
80
90
20
90
80
40
90
90
50
90
70
14c
14k
0
0
0
0
CH2CH3
CH2CH3
CH2CH3
20
10
PXD-dione 2 CH2CH3
a Post-emergence crop damage and grass control (%) at 15.6 g ai ha-1 on whole plants of formulated compounds 14 and 2 with 0.5% adjuvant Tween 20 (v/v).
Crops: TRZAW-CQC = wheat with a cloquintocet-mexyl seed treatment applied at a rate of 0.5g ai kg-1 seeds, TRZAW = wheat, ORYSA = rice; Grass weeds:
ALOMY = Alopecurus myosuroides, AVEFA = Avena fatua, ECHCG = Echinochloa crus-galli, LOLPE = Lolium perenne.

5
Table 4
Key physicochemical properties and maize chloroplastic ACCase inhibition of N-methoxy triazepanes 14c and 14k in comparison to PXD-dione analogs 17
and 2.
R1
O
N
R2
X
N
R3
O
log P
log D
pH 6a
Solubilityb (ppm)
ACCasec
Compound
R1
R2
R3
X
pKa
neutral
neutral
pH 6a
IC50 (M)
CH3
CH3
CH3
CH3
NOCH3
3.98
3.78
1.6
2.2
-0.5
-0.1
499
121
52702
20277
4.78 ± 1.21
0.10 ± 0.02
14c
14k
CH2CH3
CH2CH3 NOCH3
17d
CH3
CH3
CH3
CH3
O
O
3.91
3.84
1.2
1.8
-0.9
-0.3
435
248
53975
36057
5.44 ± 0.96
0.34 ± 0.10
PXD-dione 2 CH2CH3
CH2CH3
a LogD and solubility at pH 6 are calculated.
b Water solubility expressed as parts per million (ppm).
c Inhibition of the maize chloroplastic isoform of ACCase (colourimetric assay): arithmetic mean and standard deviation based on 4 replicates.
d Preparation of compound 17 was disclosed previously.3
interactions with the enzyme. Hence, the N-methoxy surface
region of the 7-membered ring derivative 14k is likely to
predominantly impact participation in polar interactions with
water, as is the oxygen functionality of its ether counterpart 2.
Hereby, the basicity of the N-methoxy nitrogen plays a minor
role as hydroxylamines are known to be considerably less basic
than amines.12
[1,4,5]oxadiazepane and 5-methoxy-[1,2,5]triazepane containing
graminicides to similarities of the physicochemical properties,
the receptor affinities and the key interactions at the binding site
suggest a bioisosteric relation wherein oxygen can be replaced by
N-methoxy in the seven-membered hydrazine ring.
Acknowledgments
Above molecular properties and target site binding data
highlight the N-methoxy group within the [1,2,5]triazepane as a
surrogate for the in-ring oxygen of the [1,4,5]oxadiazepane
moiety. Owing the low nitrogen basicity (the aqueous basicity of
Me2NOMe [3.65] is more than 6 pK units weaker12a than NMe3
[9.80]), and hence the unlikely role of the hydroxylamine
nitrogen to act as a hydrogen bond acceptor, this in-ring ether is
formally isosterically substituted with an on-ring methoxy
functionality. Overall, this effective bioisosteric replacement13
elicits very similar herbicidal effects, as both grass weed control
and wheat tolerance of ADs 15k/16 and 14k are on par with their
pinoxaden analogues 1 and 2.14 Other ring ether isosteric
replacements explored thus far, such as classical bivalent
methylene, sulfur (in all oxidation states) or N-methyl groups,3
indeed also resulted in bioactive inhibitors, though with (much)
diminished graminicide potency levels. By contrast, a simple
alcohol group on the seven-membered carbocyclic hydrazine ring
investigated previously4 was identified as a potent on-ring
oxygenated isostere variant, albeit with a too severe extent of
crop damage.
The authors are grateful to Simonetta Masala, Domenico
Bloise, Markus Walti, Rebecca Fox, Adam Burriss, Chantal Belie
and Ben Robinson for skillful experimentation.
References and notes
1. Wenger J, Niderman T, Mathews C. Acetyl-CoA Carboxylase
Inhibitors. In: Krämer W, Schirmer U, Jeschke P, Witschel M, eds.
Modern Crop Protection Compounds. Weinheim, Germany: Wiley-
VCH; 2012:447-477.
2. For recent contributions to the field of herbicidal ACCase inhibitors,
see: (a) Scutt JN, Jeanmart SAM, Mathews CJ, Muehlebach M, Smejkal
T, Smith SC, Smits H, Wailes JS, Whittingham WG, Willetts NJ. New
Approaches to the Design and Synthesis of Inhibitors of Acetyl-CoA
Carboxylase. In: Maienfisch P, Stevenson TM, eds. Discovery and
Synthesis of Crop Protection Products. Washington, USA: American
Chemical Society; 2015:291-304.
(b) Stevenson TM, Cenizal TM, Marshall EA, Sun KM, Taggi AE,
Currie MJ, Rardon PL. 4-Azolyl-5-Hydroxy Pyridazinones: Potent
Grass Herbicides. In: Maienfisch P, Stevenson TM, eds. Discovery and
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In summary, we conducted herein a series of chemical and
biological investigations in the 4-aryl-pyrazolidine-3,5-dione
class of compounds incorporating a 5-methoxy-[1,2,5]triazepane
ring. Such 7-membered heterocyclic AD derivatives were easily
prepared in few steps and through the key involvement of
versatile cyclic hydrazine [1,2,5]triazepane building blocks 7 and
10. Modulation of the aryl substitution (both pattern and
substituent type) revealed derivatives with significant post-
emergence herbicidal action against grass weeds and attractive
tolerance to wheat, particularly in combination with a
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relationship observations follow earlier described trends3,4 in the
PXD 1 class and unveil here the pinazaden family 14/15 of
ACCase inhibitors. Linking this SAR parallelism between
4. Muehlebach M, Cederbaum F, Cornes D, Friedmann AA, Glock J, Hall
G, Indolese AF, Kloer DP, Le Goupil G, Maetzke T, Meier H,

6
Schneider R, Stoller A, Szczepanski H, Wendeborn S, Widmer H.
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(q, J = 7.6 Hz, 2H), 2.29 (s, 3H), 2.68 (q, J = 7.6 Hz, 2H), 3.07-3.13 (m,
2H), 3.36-3.41 (m, 2H), 3.55 (s, 3H), 3.92-4.05 (m, 2H), 4.20-4.31 (m,
2H), 4.67 (s, 1H), 6.90 (s, 1H), 6.92 (s, 1H) ppm; LC/MS (ES+): 346
(M+H)+ and (ES-): 344 (M-H)-, Rt = 1.40 min.
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14. The development of resistance to ACCase inhibitors in several
agronomically important grass weeds1,14a and involved resistance
mechanisms11a,14b were extensively documented over the past several
years, see in particular:
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The potent and wheat safe AD 15k/16-safener combination reported
herein does not provide breakthrough solutions for the control of
resistant biotypes.
9. Detailed experimental and analytical data for compounds 3, 4, 6, 7, 9
and 10, as well as representative procedures for the preparation of
aryldiones 14 and their corresponding enol ethyl carbonate pro-
herbicides 15 incorporating a 5-methoxy-[1,2,5]triazepane ring can be
found in the Supplementary Material. Data for key compounds:
Carbonic acid 8-(2,6-diethyl-4-methyl-phenyl)-3-methoxy-9-oxo-
2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl ester
ethyl ester (15k): 1H NMR (400 MHz, CDCl3):  1.13 (t, J = 7.6 Hz,
6H), 1.21 (t, J = 7.1 Hz, 3H), 2.31 (s, 3H), 2.39-2.60 (m, 4H), 3.20 (m,
2H), 3.25 (m, 2H), 3.54 (s, 3H), 3.96 (br s, 2H), 4.15 (q, J = 7.1 Hz,
2H), 4.25 (br s, 2H), 6.92 (s, 2H) ppm; LC/MS (ES+): 418 (M+H)+, Rt =
1.57 min.
Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.xxx.
8-(2,6-Diethyl-4-methyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-
a][1,2,5]triazepine-7,9-dione (14k): mp 240 °C (dec); 1H NMR (400
MHz, CDCl3): 1.17 (t, J = 7.6 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H), 2.22
Graphical abstract
R1
O
O
HN
HN
HN
HN
N
R2
[A]
N O
N O
N
R3
R4
G
5-Methoxy-[1,2,5]triazepane
Cyclic hydrazines