Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I: Discovery of the novel cereal herbicide pinoxaden

Article abstract of DOI:10.1016/j.bmc.2008.12.062

Derivatives of the new class of 3-hydroxy-4-phenyl-5-oxo-pyrazolines were optimized towards both herbicidal activity on key annual grass weed species and selectivity in small grain cereal crops. The generic structure can be separated into three parts for the analysis of the structure-activity relationships, namely the aryl, the dione with its prodrug forms and the hydrazine moiety. Each area appears to play distinct and different roles in overall expression of biological performance which is further beneficially influenced by adjuvant response and safener action. Pinoxaden 6, a novel graminicide for use in wheat and barley incorporating a [1,4,5]oxadiazepane ring, eventually emerged as a development candidate from the discovery and optimization process.

Full text of DOI:10.1016/j.bmc.2008.12.062

Bioorganic & Medicinal Chemistry 17 (2009) 4241–4256
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I: Discovery
of the novel cereal herbicide pinoxaden q
a
a
a
a
Michel Muehlebach a, , Manfred Boeger , Fredrik Cederbaum , Derek Cornes , Adrian A. Friedmann ,
*
Jutta Glock a, Thierry Niderman a, André Stoller a, Trixie Wagner b
a Syngenta Crop Protection Münchwilen AG, Schaffhauserstrasse, CH-4332 Stein, Switzerland
b Novartis Institutes for Biomedical Research, Novartis Pharma AG, Lichtstrasse 35, CH-4056 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives of the new class of 3-hydroxy-4-phenyl-5-oxo-pyrazolines were optimized towards both her-
bicidal activity on key annual grass weed species and selectivity in small grain cereal crops. The generic
structure can be separated into three parts for the analysis of the structure–activity relationships, namely
the aryl, the dione with its prodrug forms and the hydrazine moiety. Each area appears to play distinct
and different roles in overall expression of biological performance which is further beneficially influenced
by adjuvant response and safener action. Pinoxaden 6, a novel graminicide for use in wheat and barley
incorporating a [1,4,5]oxadiazepane ring, eventually emerged as a development candidate from the dis-
covery and optimization process.
Received 29 October 2008
Revised 10 December 2008
Accepted 16 December 2008
Available online 3 January 2009
Keywords:
Pinoxaden
Cloquintocet-mexyl
Discovery
Ó 2009 Elsevier Ltd. All rights reserved.
Cyclic hydrazine
[1,4,5]Oxadiazepane
Crystal structure
Structure–activity relationship
Herbicide
Grass weed control
Post-emergence
Cereals
Wheat
Barley
1. Introduction
by Babczinski and Fischer to inhibit plant ACCase using isolated
corn enzyme.7 Shortly thereafter, the herbicidal activity of 4-mesi-
2-Aryl-1,3-diones (ADs) and their enol derivatives have
emerged as a new class of acetyl-coenzyme A carboxylase (ACCase,
EC 6.4.1.2) inhibitors over the last couple of years.1 Depending on
the structural nature of both aryl substitution and L–M–P bridge
(Fig. 1), ADs were found to be highly effective as either insecti-
cides/acaricides2 or herbicides.3 Union Carbide reported on the
acaricidal activity of 2-aryl-1,3-indandiones4 in 1973, and further
on the preparation of 2-aryl-1,3-cyclohexanedione and 2-aryl-
1,3-cyclopentanedione compounds5 with miticidal and herbicidal
properties in the early 1980s. A decade later, fused 3-aryl-pyrroli-
dine-2,4-diones6 were discovered at Bayer, who aggressively pub-
lished about 200 patents covering several diverse AD subclasses. In
particular the tetrahydro-indolizinedione derivative 1 was shown
tyl-pyrazolidine-3,5-dione 2 (CGA 271312) was almost simulta-
neously claimed by Cederbaum8 (Ciba-Geigy, now Syngenta) and
Krueger9 (Bayer, now Bayer CropScience).
A few ADs discovered in the late 1990s are currently in develop-
ment. Research in the field of this novel class has thus been fruitful
in delivering active ingredients ready to enter the market in differ-
ent agrochemical indications. Bayer already commercialized the
two tetronic acids spirodiclofen 310 and spiromesifen 4,11 while a
third keto-enol from the tetramic acid subclass named spirotetra-
mat 512 is under development. All three actives find applications
as acaricides and insecticides.
Inspired by some of this public domain background, we in-
tended conceptually to differentiate from competitor structures
like 1 by stepping into the class of 4-aryl-pyrazolidine-3,5-diones
where the AD bridge L–M–P thereby represents a simple N–N
bond, thus involving a hydrazine building block.8,13 Elaborating
on the confirmed herbicidal activity of lead CGA 271312 (2), a
more specific interest in cyclic hydrazine L–M–P motives emerged
quickly (Fig. 2).
q
Based in part on a presentation given at the 11th IUPAC International Congress
of Pesticide Chemistry, August 6–11, 2006, Kobe, Japan
* Corresponding author. Tel.: +41 61 323 43 41; fax: +41 61 323 87 26.
E-mail address: michel.muehlebach@syngenta.com (M. Muehlebach).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.12.062

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M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
O
O
O
Cl
O
P
L
N
N
N
M
Cl
(a)
R
O
O
2-Aryl-1,3-diones
(ADs)
1
2
O
O
O
Cl
O
O
O
O
NH
O
Cl
(b)
O
O
O
O
3
4
5
O
O
R1
R3
O
R1
R3
O
R5
R5
R4
N
N
N
N
N
O
(c)
R2
R2
N
R4
O
O
O
O
G
3-hydroxy-4-aryl-5-oxo-
pyrazoline derivatives
6
4-aryl-pyrazolidine-3,5-diones
Figure 1. General structure of aryldiones (ADs) and representative herbicidal lead structures 1 and 2 (a), insecticidal/acaricidal development candidates 3–5 (b) and
herbicidal chemical class of the novel cereal graminicide pinoxaden 6 (c).
orthogonally protected form of hydrazine18 applicable for 5- to
7-membered systems and hence useful to prepare optionally
substituted pyrazolidines (Fig. 2, [A] = –CH2–), hexahydro-pyrida-
zines ([A] = –(CH2)2–) and [1,2]diazepanes ([A] = –(CH2)3–), (ii)
hetero Diels–Alder19 cycloaddition between azodicarboxylates
and dienes to access optionally functionalized 6-membered cyclic
hydrazine skeletons and (iii) the more recent involvement of
ring-closing metathesis20 enabling the formation of medium-size
cyclic hydrazines.
R1
O
O
Cl
R5
R4
N
N
N
HN
HN
[A]
R2
Cl
R3
O
O
4-aryl-pyrazolidine-
3,5-diones
Cyclic
hydrazines
1
Figure 2. Design of new herbicidal ADs containing cyclic hydrazine derivatives.
Focussing on a potential crop protection use in the herbicide do-
main, we wish to report on how careful optimization of both
hydrazine R-groups and aryl substitution in the generic structure
of the 4-aryl-pyrazolidine-3,5-diones impacted decisively biologi-
cal features like herbicidal potency and crop tolerance. Satisfyingly,
this effort ultimately led to the discovery21 and market introduc-
Cyclic hydrazines represent a common template found in a
number of bioactive compounds, both in the area of medicinal14
and crop protection15,16 chemistry. Three main synthetic methods
towards simple carbocyclic hydrazine reagents and derivatives
have been reported:17 (i) N,N0-alkylation of a symmetrically or
O
R2
O
COOH
1) SOCl2
t-BuOK
Toluene, rflx
N
R2
R2
N
N
HN
2)
N
N
8
O
EtO2C
EtO2C
NEt3, Et2O, RT
7
9
10
7, 9, 10: a R2=CH2CH3; b R2=CH3; c R2=H
HN
HN
O
O
O
13
COOR
COOR
COOR
COOR
2HBr
NaH, CuI
N
I
O
+
N
NMP, 80°C
NEt3, xylene
rflx
- 2 ROH
14
11
12a R=CH3
12b R=CH2CH3
Scheme 1. General access to 4-aryl-pyrazolidine-3,5-diones via either a cyclization sequence (10) or a condensation route (14).

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4243
tion of the cereal herbicide pinoxaden 6 (Fig. 1), a novel AD incor-
porating a [1,4,5]oxadiazepane ring ([A] = –CH2–O–CH2–).
monoesters in a cyclization sequence.22 Thus, coupling of the acti-
vated form of acids 723 with tetrahydro-pyridazine monoester 819c
under standard conditions and cyclization of intermediates 9
through exposure to base gave the AD products 10 (Scheme 1).
Alternatively, thermal condensation of mesityl malonate 12, con-
veniently obtained through Cu(I)-mediated malonate arylation24
using iodide 11, with carbocyclic hydrazine 1315b while distilling
off the alcohol formed delivered dione 14. A number of analogs
incorporating 5- to 7-membered carbocyclic hydrazines were pre-
pared by using any of these two routes (Table 1).8,13
2. Chemistry
Synthetic routes for the preparation of 2-aryl-1,3-diones are
outlined in Schemes 1, 3, 4 and 6, whereas synthesis of the re-
quired hydrazine intermediates and aryl acetic acid or aryl malon-
ate building blocks in Schemes 2 and 5.
Aryl-pyrazolidine-3,5-diones were primarily prepared via a
thermal condensation reaction between hydrazines and aryl malo-
nates or by involving aryl acetic acid derivatives and hydrazine
Aiming to study the influence of the hydrazine moiety on bio-
logical activity, our attention was captured by the preparation of
Cl
Cl
BOC
BOC
BOC
N
Cl
NH
NH
N
NaOH 30%
TEBA-Br, 55°C
BOC
Cl
19
17
Na2S
EtOH, rflx
BOC
BOC
O
O
NH
NH
MsO
MsO
HO
HO
17
CH3SO2Cl
NEt3, Et2O
HBr / AcOH
Et2O, rflx
O
O
HN
HN
N
N
O
X
O
X
2HBr
NaH, DMF, RT
18 X=O, 20 X=S
21 X=SO, 22 X=SO2
15
16
23 X=O, 24 X=S
25 X=SO2
Scheme 2. Preparation of [1,4,5]oxadiazepane 23 and its thio analogs, [1,4,5]thiadiazepane 24 and [1,4,5]thiadiazepane 1,1-dioxide 25.
COOR
O
O
O
O
COOR
12
Piv-Cl
HN
HN
N
N
N
N
X
X
X
2HBr
NEt3, xylene
rflx
- 2 ROH
DMAP, NEt 3
THF, RT
23, 24 or 25
O
26 X=O, 27 X=S
28 X=SO2
30 X=O, 31 X=S
32 X=SO2
NaIO4
MeOH/H2O
MCPBA
(from 27)
(from 31)
CH2Cl2
O
O
N
N
N
N
S
O
S
O
O
O
O
29
33
Scheme 3. Methods for the preparation of [1,4,5]oxa(thia)diazepane containing ADs 26–29 and their enol pivaloyl esters 30–33.
HN
n
O
O
H2N
OH
[CH2O]n
COOEt
COOEt
34
NEt3, 80°C
N
N
N
N
n
n
OH
O
NEt3, xylene
rflx
- 2 EtOH
- or -
CH2O/H2O
THF, rflx
O
O
12b
35 n=1
36 n=2
37 n=1
38 n=2
Scheme 4. Synthetic approach to [1,3,4]oxadiazinane 37 and [1,3,4]oxadiazepane 38 containing ADs.

4244
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
[CH2O]n
HCl (g)
HCl conc.
NaCN
EtOH/H2O
Cl-COOEt
Pyridine
CN
CN
Cl
(CF3SO2)2O
TfO
HO
O
HO
O
Toluene, rflx
RT to 50°C
rflx
CH2Cl2, -30°C
O
O
OEt
OEt
43
42
39
41
40
AlMe3
HCOOH
Pd(PPh3)4 -or-
THF, rflx
Pd(OAc)2, PPh3
NEt3, DMF, 40°C
H2SO4 conc.
EtOH or MeOH
HCl (g)
NaH
O=C(OR)2
COOH
COOR
COOR
COOR
CN
H2O
R2
R2
rflx
rflx
rflx
(from 7b)
46a R=CH2CH3
46b R=CH3
45a R=CH2CH3
45b R=CH3
7b R2=CH3
7c R2=H
44a R2=CH3
44b R2=H
Scheme 5. First generation synthesis of aryl acetic acids 7, esters 45 and malonates 46 with a 2,6-diethyl substitution.
ADs incorporating a [1,4,5]oxadiazepane ring (also named hexahy-
dro-1,4,5-oxadiazepine) or one of its thio ring analogs. Little was
known in the literature about these ring systems at the outset of
this study. Akopyan and Paronikyan25 reported this motive in some
crown ethers containing a pyridazine ring and possessing antimu-
tagenic activity. Researchers at Konica Co. claimed for example N-
and 1,2-dichloroethane under phase transfer catalysis conditions.
Cyclization of the resulting 1,2-bis(2-chloroethyl) derivative 19
with sodium sulfide in ethanol gave the bis-Boc-protected cyclic
sulfide 20, from which sulfoxide 21 and sulfone 22 were obtainable
by treatment with MCPBA under standard conditions. Similar Boc-
deprotection as above delivered the hydrobromide salts of
[1,4,5]thiadiazepane 24 and its sulfone analog 25.
cyanoethyl-[1,4,5]oxadiazepane as
a photofading preventative
substance for color photographic materials.26 Bicyclic thiadiaze-
pines obtained via Michael-type addition of cyclic hydrazides to
divinyl sulfones have been detailed by Zinner27 and exploited by
Pissiotas28 to prepare herbicides. And finally Kotelko, Glinka and
others29 described N-mono- and N,N0-bis-alkylated or acylated
[1,4,5]oxadiazepanes with pharmacological activity on the central
nervous system in a few papers and specific polish patents. How-
ever, both [1,4,5]oxa- and [1,4,5]thiadiazepane (23, 24) to be used
as reagents/reactants had no literature precedent to the best of our
knowledge. The 7-membered cyclic hydrazine reagents 23–25
were easily prepared in multigram quantities and good overall
yields starting from cheap raw materials (Scheme 2). Double
deprotonation of 1,2-bis-Boc-hydrazine 17 with sodium hydride
and reaction with the bis-mesylate 16 of diethylene glycol 15 affor-
ded smoothly the bis-protected hydrazine cycle 18 in good yield.
Deprotection of the Boc groups using hydrogen bromide/acetic
acid in diethyl ether generated the hydrobromide salt of
[1,4,5]oxadiazepane 23 as a white, hygroscopic but easy to handle
solid. The sulfur interrupted 7-membered cyclic hydrazine equiva-
lents were approached by starting with a bis-alkylation of 17 using
concentrated sodium hydroxide, tetrabutylammonium bromide
Engaging the newly generated 7-membered, heteroatom-inter-
rupted cyclic hydrazine reagents 23–25 in a thermal coupling with
mesityl malonate 12 permitted the preparation of the unprece-
dented [1,4,5]oxa- and [1,4,5]thiadiazepane containing ADs 26–
28, from which the corresponding enol pivaloyl esters 30–32 were
easily derived by treatment with pivaloyl chloride and base
(Scheme 3).21 Adjustment of the sulfur-oxidation state was also
achievable directly on the AD sulfide products 27/31 (NaIO4 or
MCPBA) as illustrated with the preparation of the corresponding
sulfoxides 29 and 33.
[1,3,4]Oxadiazinane and [1,3,4]oxadiazepane containing ADs 37
and 38 were best synthesized from their pyrazolidine-dione pre-
cursors 35/36, themselves obtained by condensation of mesityl
malonate 12b with either (2-hydroxyethyl)hydrazine (n = 1) or
(3-hydroxypropyl)hydrazine (n = 2) 34. Ring closure of the hydraz-
ido-alcohols 35/36 was achieved by exposure to either paraformal-
dehyde in triethylamine or aqueous formaldehyde in
tetrahydrofuran (Scheme 4).30
As the triethyl-phenyl analog 10a displayed enhanced herbi-
cidal potency over its mesityl analog 2 (Table 4), we became inter-
ested in varying more carefully the 2,4,6-aryl motive. Scheme 5
HN
HN
. 2HBr
O
O
O
O
23
Cl
COOEt
COOEt
NEt3, xylene
N
N
N
O
O
N
reflux
78%
NEt3, DMAP
THF, 0°C to RT
85%
O
O
O
47
46a
6
NOA 407854
NOA 407855
Pinoxaden
Melting point
pKa
189-191°C
3.82
122-123°C
----
pH 7.4 pH 5
H2O Solubility
Log Pow
380
-1.1
5.2 g/L
0.6
0.2 g/L
3.2
Scheme 6. First synthesis of pinoxaden 6 and key physicochemical properties.

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4245
Table 1
Effects of substitution and ring size in the carbocyclic hydrazine seriesa on crop toleranceb and herbicidal grassc activity
O
N
[A]
N
O
Entry
Compound
[A]
Adjuvantd
HORVX
20
TRZAW
10
ALOMY
40
AVEFA
40
LOLPE
50
SETFA
Ref.
N
N
1e
48
80
8
2
3
4
5
6
49
50
14
51
2
–CH2–
40
50
0
90
90
0
40
0
60
60
40
50
20
100
60
20
90
20
90
90
80
60
20
90
90
40
50
60
90
NTf
8,9
–CH(CH3)–
–CH(OCH3)–
–C(CH3)2–
–CH2CH2–
X-77
X-77
9
8,9
7e
52
80
20
40
90
90
40
8
8
N
N
8
9
53
54
–CH(CH3)CH2–
–CH(CH3)CH(CH3)–
90
60
50
20
90
80
90
80
90
80
50
60
N
N
10e
55
56
X-77
60
50
50
50
60
60
80
90
60
N
N
11e
X-77
X-77
50
60
80
12
13
57
58
–CH2CH2CH2–
–CH2CH(CH3)CH2–
40
60
20
20
50
90
90
90
50
80
60
60
9
a
Post-emergence crop damage and grass control (%) at 500 g ai haꢀ1 on whole plants of compounds formulated as WP25.
HORVX = barley, TRZAW = wheat.
ALOMY = Alopecurus myosuroides, AVEFA = Avena fatua, LOLPE = Lolium perenne, SETFA = Setaria faberi.
If applicable adjuvant concentration is 0.2% X-77 (v/v).
In this entry [A] denotes the complete structure of the hydrazine moiety.
NT = not tested.
b
c
d
e
f
outlines our first generation pathway aimed at introducing substi-
(Scheme 6). Relevant physicochemical parameters for both AD 47
and pinoxaden 6 are given in Scheme 6.
tution in position-4 of the phenyl ring while retaining both ortho-
ethyl groups. Key aryl triflate intermediate 43 was synthesized
from 3,5-diethyl phenol31 39 over four steps in analogy to a pub-
lished protocol.32 Palladium-catalyzed cross-coupling of 43 with
trimethyl aluminum33 as methyl group donor was highly effective
in forming the 4-methyl-phenyl-acetonitrile derivative 44a, in
contrary to first unsuccessful attempts utilizing either higher order
mixed cuprate addition (MeLi, CuCN, THF)34 or tetramethyl tin
cross-coupling under various conditions (Me4Sn, Pd(PPh3)4, LiCl,
dioxane;35a Me4Sn, Pd2(dba)3, LiCl, AsPh3, NMP35b). On the other
hand, palladium-catalyzed reduction of triflate 43 to the analog
44b was achieved using triethylammonium formate as hydrogen
donor.36 Substituted phenyl-acetonitriles 44 were further con-
verted under conventional conditions into their corresponding
phenyl acetic acids 7, esters 45 and aryl malonates 46.
Essentially allADs describedhereinwerepresentintheuniquediketo
tautomeric form when recording the proton NMR in CDCl3. Two ortho-
ethyl groups on the phenyl ring will result in noticeable hindered rota-
tion along the bond between the aryl and the dione functionalities, ren-
dering sets of nuclei anisochronous. For example, two significant
different chemical shifts for each of the CH2 of the ethyl groups were ob-
served for AD 47 (quartets at 2.26 ppm and 2.69 ppm). Likewise two sets
of chemical shifts were obtained for the CH3 signal of the ethyl groups
(triplets at 1.18 ppm and 1.24 ppm) and for the aromatic protons (sing-
lets at 6.90 ppm and 6.93 ppm).
The structure of pinoxaden 6 was confirmed by a single crystal
X-ray structure determination. Crystals suitable for diffraction
experiments were obtained from hot tert-butyl methyl ether. Pin-
ꢀ
oxaden 6 crystallizes in the triclinic space group P1 with two inde-
Availability of the specific phenyl-malonic ester 46a allowed its
cyclocondensation with [1,4,5]oxadiazepane 23 under concomi-
tant off-distillation of ethanol to form the aryl-pyrazolidine-dione
NOA 407854 47 efficiently. Final esterification with pivaloyl chlo-
ride delivered pinoxaden 6 (NOA 407855)21 without problems
pendent molecules in the asymmetric unit which slightly differ in
their conformation (Fig. 3): in molecule I the dihedral angle be-
tween the phenyl moiety and the 5-membered planar 3-hydro-
xy-5-oxo-pyrazoline ring is 83.0(1)°, in molecule II it is 70.2(1)°.
This (in both cases) nearly orthogonal geometry can be explained

4246
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
scribe both degree of injury on two major cereal crops (wheat
and barley) and weed control efficacy on four key grasses (Alopecu-
rus myosuroides, Avena fatua, Lolium perenne, Setaria faberi) after fo-
liar application of a spray solution derived from a formulation of
the test compounds and in dependency of various structural
modifications.
Herbicidal activity at 500 g ai haꢀ1 in the carbocyclic hydra-
zine series fixing the aromatic part to a 2,4,6-trimethyl (mesityl)
pattern is summarized in Table 1. The simple acyclic analog 488
was used as an internal reference compound. Ring size of the car-
bocyclic hydrazine was not necessarily of primary significance as
5-membered (entries 2–5), 6-membered (entries 6–11) and even
7-membered (entries 12 and 13) analogs displayed decent levels
of grass control. Substitution as simple as small alkyls can play
a role for a slight activity increase, in instances generating com-
pounds (e.g., 51, entry 5) superior to the standard 48. However,
cereal tolerance of these first generation compounds was clearly
insufficient. Noticeably the degree of barley damage was consis-
tently higher than phytotoxicity on wheat. Small plot field valida-
tion trials (data not shown) with a number of these early lead
structures essentially confirmed post-emergence grass activity,
and identified crop selectivity, spectrum reliability and use rates
as the major critical issues.
Figure 3. Structure of pinoxaden 6 in the crystal. Anisotropic displacement on the
left, ball-and-stick model on the right.
Three main areas of the 4-aryl-pyrazolidine-3,5-dione scaffold
were modified during the optimization phase towards graminicid-
al activity and selectivity in small grain cereals: the cyclic hydra-
zine moiety, the aryl part and the dione area which serves as an
anchor for prodrug formation.
by the steric repulsion between the two ortho-ethyl groups on the
phenyl ring and the two oxygen functionalities on the 5-membered
pyrazoline ring. The [1,4,5]oxadiazepane ring of both conformers
adopts a chair-like conformation,37 only slightly distorted due to
the N,N0-annelated unsymmetrical 5-membered pyrazoline ring.
Bond lengths and angles within the planar 5-membered 3-hydro-
xy-5-oxo-pyrazoline ring are close to the expected values.27a
3.1.1. Structure–activity relationships for the cyclic hydrazine
moiety
Table 2 outlines investigations on ADs incorporating a 7-
membered cyclic hydrazine (mesityl series), especially studying
the influence of the heteroatom which interrupts the cycle. Effi-
cacy against target grasses is given for the actual active ingredi-
ent (aryldione structure I) and for its enol pivaloyl prodrug
3. Results and discussion
(structure II) at application rates of 2000 and 500 g ai haꢀ1
.
3.1. Herbicidal activity and crop tolerance
The oxygenated representatives 26/30 (entry 2) clearly demon-
strated enhanced activity on grasses compared to the purely car-
bocyclic hydrazine standards 57/59, or to the sulfur analogs 27/
Post-emergence herbicidal activity of ADs was evaluated using
standard in vivo greenhouse screening conditions. Tables 1–6 de-
Table 2
Herbicidal activity of 7-membered cyclic hydrazine containing analogs, influence of the heteroatoma
O
O
O
N
N
N
[B]
[B]
N
O
O
II
I
Entry
1
Compound I/II
[B]
Use rate (g ai haꢀ1
)
AVEFA
LOLPE
SETFA
57/59
–CH2–
2000
500
2000
500
2000
500
2000
500
2000
500
2000
500
90/90b
50/60
100/100
80/90
90/90
60/50
80/80
60/20
80/80
40/20
10/NTc
0/NT
90/100
60/80
100/90
90/90
90/80
50/40
60/50
20/10
80/50
40/20
60/NT
10/NT
90/90
90/90
100/100
80/90
100/100
90/60
60/50
20/10
90/80
60/40
90/NT
40/NT
2
3
4
5
6
26/30
27/31
28/32
29/33
60/—
–O–
–S–
–SO2–
–S(O)–
–N(CH3)–
a
Post-emergence grass control (%) at 2000 and 500 g ai haꢀ1 on whole plants of compounds formulated as IF50.
xx/yy denotes herbicidal activity (%) of structures I and II, respectively.
NT = not tested.
b
c

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4247
Table 3
Effects of oxadiazinane and oxadiazepane containing analogs on crop selectivity and herbicidal grass activitya
O
N
[A]
N
O
Entry
Compound
[A]
HORVX
TRZAW
ALOMY
AVEFA
LOLPE
SETFA
1
2
3
37
38
26
–OCH2–
–OCH2CH2–
–CH2OCH2–
0
10
20
20
10
50
40
0
80
90
0
90
90
20
90
90
50
90
a
Post-emergence crop damage and grass control (%) at 250 g ai haꢀ1 on whole plants of compounds formulated as WP25 with 1% adjuvant MergeÒ (v/v).
31 (entry 3). Adjusting the sulfur oxidation state (entries 4 and
5) resulted in activity loss, whereas the NMe analog 60 (entry
6) displayed the weakest performance.
strated with hexahydro-pyridazine derivative 10b when
evaluated either in combination with adjuvant X-77c or Merged un-
der otherwise identical greenhouse screening conditions (Table 5,
entries 1 and 2). Use of the more appropriate adjuvant Merge, trig-
gering better bioavailability within leaves and plant tissues, allowed
to lower the application rate to 30 g ai haꢀ1, however at the moment
still with acute loss of cereal tolerance.
Subsequent SAR studies with oxadiazinane and oxadiazepane
scaffolds (Table 3; use rate 250 g ai haꢀ1) permitted to gain a
more detailed picture about the influence of an oxygen inter-
rupted hydrazine moiety on activity/tolerance. The 6-membered
[1,3,4]oxadiazinane derivative 37 proved interesting, but exhib-
ited a clear gap on ALOMY. The corresponding 7-membered
[1,3,4]oxadiazepane analog 38 was disappointingly weak, a re-
sult which can be explained by stability issues of the N-acyl
hemiaminal moiety towards hydrolysis. In contrary, aryldione
26 incorporating a [1,4,5]oxadiazepane ring expressed good lev-
els of activity over all weed species and particularly noteworthy
demonstrated a trend to reduce cereal phytotoxicity, especially
dramatically improving tolerance in barley (compare with
Table 1).
Active ingredients 10b, 26 and 4739a (entries 2–4, Merge only)
are actually demonstrating and summarizing how judicious frag-
ment combination was key to activity level against grass weed
species (aryl moiety) and tolerance in cereal crops (hydrazine
moiety). Complementary contributions of adjuvant effect and pre-
ferred 2,6-diethyl-4-methyl aromatic substitution pattern im-
proved drastically herbicidal potency against grasses. Crop
injury reduction by incorporation of the [1,4,5]oxadiazepane ring
nicely topped this upshot, revealing AD 47 (NOA 407854) as an
exciting new selective herbicide.
Field validation trials conducted with ADs 26/30 confirmed
this trend and moreover revealed that safener action38 (clo-
quintocet-mexyl39) on 30 reduced crop phytotoxicity in both
wheat and barley with only slight activity loss, allowing for a
selective control of Apera spica-venti and Lolium multiflorum at
125 g ai haꢀ1, and of Alopecurus myosuroides and Avena fatua
at P250 g ai haꢀ1. While still weaker than market standards,
the potential use of [1,4,5]oxadiazepane containing analogs for
grass weed control in barley as an innovation value began to
emerge.
With a pKa of about 3.8 (vinylogous acid), the dione area of 47
is well suited for prodrug formation with the aim to further in-
crease leaf penetration. Various pro-herbicides have been synthe-
sized (Table 6), most enol carbamates, ethers or N,N0-
dialkylsulfamate esters (entries 3, 5, 7) were weakly active
reflecting lack of hydrolysis under plant physiological conditions.
Conversely, most enol esters (e.g., 6; hydrolysis half-life [pH 7] at
50 °C: t50 = 20.6 h), sulfonates (65; t50 = 3.0 h) and carbonates (61)
were found to hydrolyze easily in planta releasing the active prin-
ciple AD 47, which is responsible for the target site activity. Enol
pivaloate 6 (NOA 407855, pinoxaden, entry 1) was finally selected
as a candidate for development following intensive screening in
field trials.
3.1.2. Structure–activity relationships for the aromatic part
A breakthrough with regard to the level of herbicidal activity
was achieved by systematic manipulation of the aromatic re-
gion and a 2,4,6-substitution pattern proved beneficial in this
respect. The hexahydro-pyridazine series was used to probe
substitution in position-4 of the phenyl ring while retaining
two ortho-ethyl groups (Table 4; use rate 125 g ai haꢀ1).
2,4,6-Triethyl-phenyl derivative 10a (R2 = CH2CH3, entry 2), eas-
ily accessible by synthesis, showed to be more potent than its
mesityl equivalent 2. Sensitivity of the para-position was illus-
trated with the preparation of 10c (R2 = H, entry 3) presenting
inconsistent spectrum control. Surprisingly however, a simple
methyl group (R2 = CH3, entry 4) at the 4-position (10b)
boosted the graminicidal activity decisively, despite of showing
severe cereal damage.
3.2. Pinoxaden–safener combination
As described in Table 5, minimization of crop injury by AD 47
and pinoxaden 6 in wheat and barley has been obtained through
chemical optimization essentially via incorporation of the
[1,4,5]oxadiazepane ring into the AD template. To ensure excel-
lent crop tolerance and secure substantial selectivity margin un-
der agronomical relevant application conditions, the herbicides
47 and 6 have been evaluated in combination with the proprie-
tary safener cloquintocet-mexyl.39
A comparative greenhouse
study of 47 or 6 applied either alone or each in combination with
the safener revealed two key aspects regarding crop safety and
herbicidal efficacy (Table 7). The herbicide–safener mixture, in
combination with the adjuvant Merge, eliminated early crop phy-
totoxicity (assessed 12 days after application) at a use rate of 60 g
3.1.3. Adjuvant effect, fragment combination and pro-
herbicide preparation
Some of the test compounds were shown to also have a signif-
icant bioefficacy enhancement by addition of certain adjuvants, a
well known feature when dealing with foliar-applied agrochemi-
cals.40 Such an improvement in uptake was for example demon-
c
X-77 is a mixture of alkyl aryl polyoxyethylene glycols and free fatty acids in
isopropanol; a product from Loveland Industries.
d
MergeÒ is a mixture of surfactant blends (ca. 10%) and hydrocarbon solvents and
oils (ca. 90%); a registered trademark of BASF Canada Inc.

4248
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
Table 4
Influence of the ortho- and para-alkyl substitution on crop tolerance and herbicidal activitya of 2-phenyl-tetrahydro-pyrazolo[1,2-a]pyridazine-1,3-diones
O
R1
N
N
R2
R3
O
Entry
Compound
R1
R2
R3
HORVX
TRZAW
ALOMY
AVEFA
LOLPE
SETFA
1b
2
3
2
CH3
CH3
CH2CH3
H
CH3
40
40
0
0
40
0
40
90
60
90
50
100
80
40
60
40
90
NTc
50
40
10a
10c
10b
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
4
CH3
90
80
100
80
a
Post-emergence crop damage and grass control (%) at 125 g ai ha-1 on whole plants of compounds formulated as WP25 with 0.2% adjuvant X-77 (v/v).
No adjuvant.
NT = not tested.
b
c
ai haꢀ1 in different cereal varieties of wheat and barley, but
importantly did not impair herbicidal efficacy on grass weeds at
30 g ai haꢀ1 which was evaluated conventionally 20 days after
treatment.
ing of beneficial structural requirements to herbicidal activity
and crop tolerance gathered during the chemical optimization pro-
cess was further positively impacted by these two effects.
In summary, pinoxaden 6 is a new graminicide for cereal crops,
an enol pivaloyl AD prodrug from the chemical class of the 3-hy-
droxy-4-phenyl-5-oxo-pyrazolines (often just simply called phen-
ylpyrazolines). Its active principle at the ACCase target site is AD
47, a novel member of the 4-aryl-pyrazolidine-3,5-dione family
incorporating a [1,4,5]oxadiazepane ring. Pinoxaden 6 has been
launched by Syngenta in 2006 under the tradename AxialÒ for
worldwide use in both wheat and barley.41 AxialÒ is applied
post-emergence at low use rates and offers outstanding levels of
herbicidal activity against key annual grass weed species together
with unrivaled cereal crop safety.
4. Conclusions
A series of chemical investigations in the AD area of 4-aryl-pyr-
azolidine-3,5-diones and analysis of the structure–activity rela-
tionship information allowed to identify key structural factors
influencing both weed control efficacy against grasses and crop tol-
erance in cereals. Interruption of the alkylene fragment in the cyc-
lic hydrazine derivatives with heteroatoms, oxygen in particular,
resulted in the discovery of oxadiazinane and oxadiazepane ana-
logs with reduced crop injury. Worth mentioning are ADs incorpo-
rating a [1,4,5]oxadiazepane ring with improved tolerance in
wheat and especially barley allowing for a single active ingredient
application in these two major cereal markets. Their preparation
was made easily possible through the use of the cyclic hydrazine
building block [1,4,5]oxadiazepane (23), a simple reagent/reactant
with no precedent in the chemical literature. Adjusting the aryl
2,4,6-substitution pattern to the specific 2,6-diethyl-4-methyl-
phenyl motive permitted to lower use rates decisively and to se-
cure broad spectrum grass control. Key fragment combination
and pro-herbicide preparation finally unveiled AD 47 and pinoxa-
den 6 as exciting herbicides. The first generation synthetic se-
quence towards 6 disclosed herein, rather lengthy with some
steps suffering from low yields and poor practicality, could never-
theless be successfully upscaled to satisfy first amount demands
for field trials. The drug discovery of 47 and 6 was complemented
by two further capital findings leading to the development of pin-
oxaden 6: adjuvant response and safener action. The understand-
5. Experimental
5.1. Chemical synthesis
All new compounds were characterized by standard spectroscop-
ical and analytical methods. 1H NMR (300 or 400 MHz) and 13C NMR
(75 or 100 MHz) spectra were recorded on Bruker Avance spectrom-
eters, using CDCl3, (CD3)2SO or CD3OD as solvents and tetramethyl-
silane as internal standard. Chemical shifts are reported in ppm
downfield from the standard (d = 0.00). Mass spectra were obtained
on Waters ZQ (LC-MS; HP 1100 HPLC from Agilent), Finnigan MAT 90
andMicromass QTOFmassspectrometers. IRspectraweretakenona
Bruker FT-IR IFS48 and recorded as KBr pellets. Melting points were
determinedin open-endcapillarytubeson a Büchi530meltingpoint
apparatus and are uncorrected. Analytical thin-layer chromatogra-
phy (TLC) was performed using Silica Gel 60 F254 precoated plates.
Preparative flash chromatography was performed using Silica Gel
Table 5
Summary of the aryl-pyrazolidine-dione optimization demonstrating key fragment contributions to activity level against grass weed species (aryl moiety) and tolerance in cereal
crops (hydrazine moiety)a
O
O
R1
R3
N
N
[A]
Entry
Compound
R1
R3
[A]
HORVX
TRZAW
ALOMY
AVEFA
LOLPE
SETFA
1b
2
3
10b
10b
26
CH2CH3
CH2CH3
CH3
CH2CH3
CH2CH3
CH3
–CH2CH2–
–CH2CH2–
–CH2OCH2–
–CH2OCH2–
10
80
0
40
80
0
80
100
10
90
100
60
50
80
80
90
40
90
50
90
4
47
CH2CH3
CH2CH3
0
10
100
100
a
Post-emergence crop damage and grass control (%) at 30 g ai haꢀ1 on whole plants of compounds formulated as WP25 with 1% adjuvant MergeÒ (v/v).
Adjuvant is 0.2% X-77 (v/v).
b

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4249
Table 6
Crop tolerance and herbicidal grass activity of AD 47 in various prodrug formsa
O
O
N
N
O
G
Entry
Compound
G
Formulation
HORVX
TRZAW
ALOMY
AVEFA
LOLPE
SETFA
1
2
3
4
5
6
7
6
C(O)C(CH3)3
WP25
WP25
WP25
WP10
WP10
IF50
0
0
0
0
0
0
0
10
0
0
10
0
20
0
100
80
0
60
0
100
90
0
100
0
100
100
0
100
20
90
100
0
90
0
61
62
63
64
65
66
C(O)OCH(CH3)2
C(O)N(CH2CH3)2
CH2OC(O)C(CH3)3
CH2CH3
SO2(CH2)7CH3
SO2N(CH3)2
80
0
100
10
100
50
90
20
IF50
a
Post-emergence crop damage and grass control (%) at 30 g ai haꢀ1 on whole plants of compounds formulated as WP10, WP25 or IF50 with 1% adjuvant MergeÒ (v/v).
60 (40–63
l
m, E. Merck). All reactions were carried out under anhy-
1:9). Yield: 14.82 g (80%) as a viscous oil. 1H NMR (CDCl3): d 1.17
(t, 6H), 1.22 (t, 3H), 1.32 (t, 3H), 1.60–1.80 (m, 4H), 2.50–2.63 (m,
6H), 2.72 (m, 1H), 2.97 (m, 1H), 3.7 (q, 2H), 4.20–4.35 (m, 3H),
4.55 (m, 1H), 6.90 (s, 2H).
drous conditions in an inert atmosphere (nitrogen or argon) with dry
solvents. All reagents were purchased from commercial suppliers
and used without further purification. Representative procedures
are given below; the yields were not optimized.
5.1.3. 2-[2-(2,6-Diethyl-4-methyl-phenyl)-acetyl]-tetrahydro-
pyridazine-1-carboxylic acid ethyl ester (9b)
5.1.1. 2-(2,4,6-Trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-
a]pyridazine-1,3-dione (2, CGA 271312)
Obtained from the acid chloride of (2,6-diethyl-4-methyl-phe-
nyl)-acetic acid 7b and tetrahydro-pyridazine-1-carboxylic acid
ethyl ester 8 according to procedure 5.1.2. Yield: 73% as a viscous
oil. 1H NMR (CDCl3): d 1.17 (t, 6H), 1.32 (t, 3H), 1.72 (m, 4H),
2.30 (s, 3H), 2.55 (q, 4H), 2.74 (m, 1H), 2.97 (m, 1H), 3.62 (d,
JAB = 17 Hz, 1H), 3.76 (d, JAB = 17 Hz, 1H), 4.19–4.37 (m, 3H), 4.55
(m, 1H), 6.88 (s, 2H).
Prepared according to WO 1992/16510.8 Yield: 47% as a white
solid, mp 244–246 °C. 1H NMR (CDCl3): d 1.79 (m, 4H), 2.02 (s,
3H), 2.24 (s, 3H), 2.38 (s, 3H), 3.65 (m, 4H), 4.64 (s, 1H), 6.82 (s,
1H), 6.91 (s, 1H). 13C NMR (CDCl3): d 20.0, 20.8, 20.9, 22.4, 43.2,
48.7, 126.0, 129.3, 129.9, 136.0, 137.9, 138.3, 169.5. MS (ES+) m/
z: 273 (C16H20N2O2 + H)+.
5.1.2. 2-[2-(2,4,6-Triethyl-phenyl)-acetyl]-tetrahydro-
pyridazine-1-carboxylic acid ethyl ester (9a)
5.1.4. 2-[2-(2,6-Diethyl-phenyl)-acetyl]-tetrahydro-pyridazine-
1-carboxylic acid ethyl ester (9c)
To a solution of tetrahydro-pyridazine-1-carboxylic acid ethyl
ester 819c (8.2 g, 51.7 mmol), triethylamine (7.9 ml, 5.75 g,
56.8 mmol) and a catalytic amount of 4-dimethylaminopyridine
in tetrahydrofuran (120 ml) at 0–5 °C was added a solution of the
acid chloride of (2,4,6-triethyl-phenyl)-acetic acid 7a23 (12.32 g,
51.7 mmol, prepared using thionyl chloride and a catalytic amount
of DMF) dropwise. The suspension was stirred at room tempera-
ture overnight, then poured on ice-water and ethyl acetate. The
layers were separated, the aqueous phase extracted with ethyl ace-
tate, the combined organic layers washed twice with water and
brine, dried over sodium sulfate and evaporated. The residue was
purified by chromatography on silica gel (ethyl acetate/hexane
Obtained from the acid chloride of (2,6-diethyl-phenyl)-acetic
acid 7c and tetrahydro-pyridazine-1-carboxylic acid ethyl ester 8
according to procedure 5.1.2 (reaction run in diethyl ether). Yield:
77% as a viscous oil. 1H NMR (CDCl3): d 1.20 (t, 6H), 1.33 (t, 3H),
1.68–1.80 (m, 4H), 2.60 (q, 4H), 2.78 (m, 1H), 2.98 (m, 1H), 3.72
(q, 2H), 4.22–4.38 (m, 3H), 4.58 (m, 1H), 7.03–7.20 (m, 3H).
5.1.5. 2-(2,4,6-Triethyl-phenyl)-tetrahydro-pyrazolo[1,2-a]
pyridazine-1,3-dione (10a)
To a solution of potassium tert-butoxide (5.0 g, 45 mmol)
in toluene (70 ml) at reflux was added
a solution of 2-[2-
(2,4,6-triethyl-phenyl)-acetyl]-tetrahydro-pyridazine-1-carboxylic
Table 7
Herbicidal grass activity and crop tolerance of AD 47 and pinoxaden 6 (H) applied either alone or in combination with the safener (S) cloquintocet-mexyla
O
O
N
N
N
N
O
O
O
O
O
47
6
Pinoxaden
Compound
Winter barley (cv Fanfare)
Winter wheat (cv Arina)
Summer wheat (cv Remia)
Avena fatua
H + S
Lolium rigidum
H
H + S
H
H + S
H
H + S
H
H
H + S
47
6
40
20
0
0
20
30
0
0
50
30
0
0
90
90
90
90
90
90
90
95
a
Post-emergence crop damage and weed control (%) at 30 g ai haꢀ1 on grasses (evaluation 20 DAT) and at 60 g ai haꢀ1 on barley and wheat varieties (evaluation 12 DAT) of
compounds formulated as EC200 with 1% adjuvant MergeÒ (v/v), with and without cloquintocet-mexyl (EC100 formulation) added at 25% the rate of the herbicide.

4250
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
acid ethyl ester 9a (10.8 g, 30 mmol) in toluene (30 ml) drop-
wise. The mixture was stirred at reflux for 1 h. To the cooled
reaction mixture was added ice-water, the organic layer sepa-
rated and discarded after being reextracted twice with 1 N aque-
ous sodium hydroxide. The combined aqueous alkaline phases
were acidified with cooling to pH 2–3 by addition of a 4 N HCl
solution, the resulting precipitate was filtered off and recrystal-
lized from hot ethyl acetate. Yield: 6.4 g (69%) as a white solid,
mp 189–191 °C. 1H NMR (CDCl3): d 1.17 (t, 3H), 1.21 (t, 3H),
1.25 (t, 3H), 1.81 (m, 4H), 2.25 (q, 2H), 2.59 (q, 2H), 2.70 (q,
2H), 3.67 (m, 4H), 4.64 (s, 1H), 6.92 (s, 1H), 6.93 (s, 1H). 13C
NMR (CDCl3): d 14.3, 15.3, 16.0, 22.5, 25.6, 28.2, 28.6, 43.4,
48.1, 124.8, 126.4, 126.7, 142.2, 144.4, 144.6, 170.2. MS (ES+)
m/z: 315 (C19H26N2O2 + H)+.
were filtered off, the layers of the filtrate separated, the aqueous
phase extracted twice with ethyl acetate, the combined organic
layers washed with water and brine, dried over sodium sulfate
and evaporated. The residue was purified by chromatography on
silica gel (ethyl acetate/hexane 1:5). Yield: 34.0 g (65%) as a white
solid, mp 75–77 °C. 1H NMR (CDCl3): d 2.25 (s, 3H), 2.31 (s, 6H),
3.74 (s, 6H), 5.02 (s, 1H), 6.88 (s, 2H). 13C NMR (CDCl3): d 20.6,
20.8, 52.5, 52.6, 127.9, 129.9, 137.5, 137.6, 169.0. MS (ES+) m/z:
251 (C14H18O4 + H)+, 273 (C14H18O4 + Na)+.
5.1.9. 2-(2,4,6-Trimethyl-phenyl)-malonic acid diethyl ester
(12b)
Obtained from malonic acid diethyl ester, 2-iodo-1,3,5-tri-
methyl-benzene and copper(I) iodide according to procedure
5.1.8. Yield: 57% as an off-white solid, mp 48–49 °C. 1H NMR
(CDCl3): d 1.27 (t, 6H), 2.23 (s, 3H), 2.32 (s, 6H), 4.22 (q, 4H), 4.98
(s, 1H), 6.87 (s, 2H). 13C NMR (CDCl3): d 14.1, 20.7, 20.9, 53.0,
61.6, 128.1, 129.8, 137.4, 137.6, 168.7. MS (ES+) m/z: 279
(C16H22O4 + H)+, 301 (C14H18O4 + Na)+.
5.1.6. 2-(2,6-Diethyl-4-methyl-phenyl)-tetrahydro-
pyrazolo[1,2-a]pyridazine-1,3-dione (10b)
Method (a): Obtained from 2-[2-(2,6-diethyl-4-methyl-phenyl)-
acetyl]-tetrahydro-pyridazine-1-carboxylic acid ethyl ester 9b
(6.8 g, 19.6 mmol) and potassium tert-butoxide (3.83 g,
34.1 mmol) in toluene (70 ml) according to procedure 5.1.5. Yield:
28% as a white solid, mp 175–177 °C. 1H NMR (CDCl3): d 1.17 (t,
3H), 1.24 (t, 3H), 1.81 (m, 4H), 2.24 (q, 2H), 2.29 (s, 3H), 2.68 (q,
2H), 3.67 (m, 4H), 4.63 (s, 1H), 6.90 (s, 1H), 6.92 (s, 1H). 13C NMR
(CDCl3): d 14.2, 16.0, 21.2, 22.5, 25.5, 28.1, 43.4, 48.1, 124.6,
127.6, 127.9, 138.3, 142.2, 144.6, 170.2. MS (ES+) m/z: 301
(C18H24N2O2 + H)+.
Method (b): A solution of 2-(2,6-diethyl-4-methyl-phenyl)-
malonic acid dimethyl ester 46b (4.18 g, 15.0 mmol) in xylene
(100 ml) was treated with hexahydro-pyridazine (1.57 g,
18.2 mmol). The reaction mixture was flushed with argon and
stirred under argon atmosphere. The flask was placed in a pre-
heated oil bath at 150 °C and the mixture heated for 4.5 h, while
ethanol was distilled off. The cooled reaction mixture was trea-
ted with a 2 N aqueous sodium hydroxide solution (ꢁ15 ml)
and the aqueous layer extracted with diethyl ether. The aqueous
alkaline phase was acidified with cooling by careful addition of a
1 N HCl solution and the product extracted with dichlorometh-
ane. The chlorinated organic phase was dried over sodium sul-
fate, evaporated and the residue purified by chromatography
on silica gel. Yield: 3.49 g (77%) as yellowish crystals, mp 174–
176 °C. The spectral data were identical to those reported above
under method (a).
5.1.10. 6-Methoxy-2-(2,4,6-trimethyl-phenyl)-dihydro-
pyrazolo[1,2-a]pyrazole-1,3-dione (14)
Obtained from 4-methoxy-pyrazolidine dihydrobromide 1315b
and 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl ester 12b
according to procedure 5.1.19. Yield: 55% as a white solid, mp
147–149 °C. 1H NMR (CDCl3): d 1.99 (s, 3H, isomer A + B), 2.24 (s,
3H, isomer A + B), 2.36 (s, 3H, isomer A + B), 3.28 (s, 2.4H, isomer
A), 3.38 (s, 0.6H, isomer B), 3.39 (dd, J = 12.4 Hz, 3.7 Hz, 1.6H, isomer
A), 3.78 (dd, J = 11.7 Hz, 3.3 Hz, 0.4H, isomer B), 3.90 (dd, J = 11.7 Hz,
5.3 Hz, 0.4H, isomer B), 4.18 (t, J = 3.7 Hz, 0.8H, isomer A), 4.27 (m,
0.2H, isomerB), 4.29 (d, J = 12.4 Hz, 1.6H, isomerA), 4.86(s, 0.2H, iso-
mer B), 4.96 (s, 0.8H, isomer A), 6.83 (s, 1H, isomer A + B), 6.89 (s, 1H,
isomer A + B). 13C NMR (CDCl3): d 20.1 (isomer A + B), 20.8 (isomer
A + B), 48.2 (isomer B), 48.9 (isomer A), 51.1 (isomer A), 51.6 (isomer
B), 56.0 (isomer A), 57.3 (isomer B), 79.3 (isomer B), 79.6 (isomer A),
124.8 (isomer A), 125.7 (isomer B), 129.0 (isomer A + B), 129.8 (iso-
mer A + B), 137.4 (isomer A + B), 138.0 (isomer A + B), 168.8 (isomer
B), 170.1 (isomer A) (two diketo-form isomers in a ratio A/B = 4:1).
MS (ES+) m/z: 289 (C16H20N2O3 + H)+.
5.1.11. Diethylene glycol dimethanesulfonate (16)
Diethylene glycol 15 was bis-mesylated in nearly quantitative
yield under standard conditions.21 White solid, mp 51–52 °C (from
ethyl acetate/toluene 4:3). 1H NMR (CDCl3): d 3.07 (s, 6H), 3.80 (t,
4H), 4.38 (t, 4H).
5.1.7. 2-(2,6-Diethyl-phenyl)-tetrahydro-pyrazolo[1,2-
a]pyridazine-1,3-dione (10c)
Obtained from 2-[2-(2,6-diethyl-phenyl)-acetyl]-tetrahydro-
pyridazine-1-carboxylic acid ethyl ester 9c according to procedure
5.1.5. Yield: 33% as a white solid. 1H NMR (CDCl3): d 1.18 (t, 3H),
1.25 (t, 3H), 1.80 (m, 4H), 2.27 (q, 2H), 2.72 (q, 2H), 3.66 (m, 4H),
4.68 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.22
(t, J = 7.7 Hz, 1H). 13C NMR (CDCl3): d 14.1, 15.9, 22.4, 25.5, 28.1,
43.4, 48.3, 126.6, 126.9, 127.7, 128.7, 142.4, 144.8, 169.9. MS
(ES+) m/z: 287 (C17H22N2O2 + H)+.
5.1.12. 4,5-Bis-tert-butyloxycarbonyl-[1,4,5]oxadiazepane (18)
A solution of 1,2-bis-Boc-hydrazine 17 (174.5 g, 0.75 mol) in
350 ml of dimethylformamide was added dropwise over 2 h to
a stirred suspension of sodium hydride (60.6 g, 60% w/w disper-
sion in mineral oil, 1.52 mol) in dimethylformamide (1270 ml)
at 0–5 °C. The mixture was allowed to warm to room temperature
and subsequently heated to 30 °C for 15 min to bring hydrogen
evolution to completion (caution!). A solution of diethylene glycol
dimethanesulfonate 16 (203 g, 0.77 mol) in 210 ml of dimethyl-
formamide was then added dropwise over 1.5 h at 0–5 °C. The
reaction mixture was stirred overnight at room temperature
and poured on a mixture of ice, saturated aqueous ammonium
chloride and tert-butyl methyl ether. The layers were separated,
the aqueous phase extracted with tert-butyl methyl ether
(4 ꢂ 500 ml), the combined organic layers washed with water
(4 ꢂ 500 ml) and brine, dried over sodium sulfate, evaporated
and the residue dried at 40 °C under reduced pressure. Yield:
216 g (95%) as an oil, this material was used without further puri-
fication. An analytical sample of 18 was obtained through purifi-
cation by chromatography on silica gel (tert-butyl methyl ether/
5.1.8. 2-(2,4,6-Trimethyl-phenyl)-malonic acid dimethyl ester
(12a)
To a stirred suspension of sodium hydride (18.3 g, 60% w/w dis-
persion in mineral oil, 0.46 mol) in 1-methyl-2-pyrrolidone (NMP,
300 ml) at 0–5 °C was added malonic acid dimethyl ester (55.4 g,
0.42 mol) dropwise over 3 h. The mixture was stirred at room tem-
perature overnight. After further addition of 2-iodo-1,3,5-tri-
methyl-benzene 11 (51.7 g, 0.21 mol) and copper(I) iodide (80 g,
0.42 mol), the reaction mixture was heated at 80–85 °C for 5 h,
cooled and poured on a cold solution of 1 N HCl (800 ml) and ethyl
acetate (500 ml) followed by vigorous stirring. The copper salts

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4251
hexane 1:1). White solid, mp 67–69 °C. 1H NMR (CDCl3): d 1.48
(appar t, 18H), 3.12–4.17 (m, 8H). 13C NMR (CDCl3): d 28.3,
49.9, 69.4, 80.8, 154.4 (mixture of rotamers/conformers, major
isomer reported).
5.1.17. [1,4,5]Thiadiazepane dihydrobromide (24)
Obtained from 4,5-bis-tert-butyloxycarbonyl-[1,4,5]thiadiaze-
pane 20 (4.1 g, 12.9 mmol) and hydrogen bromide in acetic acid
(11.9 ml, 4.1 M, 48.8 mmol) in diethyl ether (80 ml) according to
procedure 5.1.16. Yield: 85% as a white solid. 1H NMR (DMSO-
d6): d 2.84 (t, 4H), 3.28 (t, 4H), 8.5 (br s, 4H).
5.1.13. 1,2-Bis-Boc-1,2-bis-(2-chloroethyl)-hydrazine (19)
A mixture of 1,2-bis-Boc-hydrazine 17 (23.2 g, 0.1 mol), 30%
aqueous sodium hydroxide (100 ml) and a catalytic amount of tet-
rabutylammonium bromide (1 g) in 1,2-dichloroethane (200 ml,
2.54 mol) was heated 5 h at 55 °C. The layers were separated upon
cooling, the aqueous phase extracted with dichloromethane, the
combined organic layers washed with water and brine, dried over
magnesium sulfate and evaporated. The residue was purified by
chromatography on silica gel (ethyl acetate/hexane 1:12 to 1:8).
Yield: 27.8 g (78%) as an oil. 1H NMR (CDCl3): d 1.49 (appar t,
18H), 3.53–3.97 (m, 8H).
5.1.18. 1,1-Dioxo-1k6- [1,4,5]thiadiazepane dihydrobromide
(25)
Obtained from 4,5-bis-tert-butyloxycarbonyl-1,1-dioxo-1k6-
[1,4,5]thiadiazepane 22 (5.73 g, 16.4 mmol) and hydrogen bromide
in acetic acid (10.5 ml, 5.7 M, 59.9 mmol) in diethyl ether (80 ml)
and dichloromethane (20 ml) according to procedure 5.1.16. Yield:
73% as a white solid. 1H NMR (DMSO-d6): d 3.39 (m, 4H), 3.52 (m,
4H), 9.2 (br s, 4H).
5.1.19. 8-(2,4,6-Trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-
d][1,4,5]oxadiazepine-7,9-dione (26)
5.1.14. 4,5-Bis-tert-butyloxycarbonyl-[1,4,5]thiadiazepane (20)
A solution of 1,2-bis-Boc-1,2-bis-(2-chloroethyl)-hydrazine 19
(22 g, 61.6 mmol) and sodium sulfide (8.8 g, Na2SꢃxH2O 60%,
67.7 mmol) in ethanol (1000 ml) was heated at reflux for 20 h.
The reaction mixture was evaporated, diluted with tert-butyl
methyl ether and the resulting precipitate removed by filtration.
The filtrate was evaporated and the residue purified by chromatog-
raphy on silica gel (ethyl acetate/hexane 1:9). Yield: 12.4 g (63%) as
an oil. 1H NMR (CDCl3): d 1.47 (appar t, 18H), 2.45–2.61 (m, 2H),
2.73–2.89 (m, 2H), 3.23–3.56 (m, 2H), 3.92–4.37 (m, 2H).
A degassed suspension of [1,4,5]oxadiazepane dihydrobromide
23 (40 g, 151.5 mmol) and triethylamine (99 ml, 71.8 g,
710 mmol) in 1000 ml of xylene was stirred under argon at
60 °C for 3 h. After further addition of 2-(2,4,6-trimethyl-phe-
nyl)-malonic acid diethyl ester 12b (42.5 g, 152.7 mmol), the
reaction mixture was heated to 150 °C (oil bath temperature)
while distilling off the formed ethanol and part of the excess tri-
ethylamine. The cooled reaction mixture was poured on ice-water
(500 ml), the pH made alkaline by addition of 1 N aqueous so-
dium hydroxide (ꢁ100 ml) and the aqueous layer extracted twice
with ethyl acetate. The combined organic layers were discarded
after being reextracted twice with 1 N aqueous sodium hydrox-
ide. The combined aqueous alkaline phases were acidified with
cooling to pH 2–3 by addition of a 4 N HCl solution. The resulting
precipitate was filtered off, washed with water and hexane, and
the solid dried over phosphorus pentoxide under vacuum at
60 °C overnight. Yield: 34.6 g (79%) as a slight tan solid, mp
242–244 °C (dec). 1H NMR (CDCl3): d 2.06 (s, 3H), 2.25 (s, 3H),
2.39 (s, 3H), 3.81 (ddd, 2H), 3.92–4.02 (m, 4H), 4.22 (ddd, 2H),
4.72 (s, 1H), 6.83 (s, 1H), 6.93 (s, 1H). 13C NMR (CDCl3): d 20.0,
20.9, 21.0, 46.1, 48.3, 70.5, 125.9, 129.5, 130.0, 136.1, 138.2,
138.4, 165.5. MS (ES+) m/z: 289 (C16H20N2O3 + H)+.
5.1.15. 4,5-Bis-tert-butyloxycarbonyl-1,1-dioxo-1k6-[1,
4,5]thiadiazepane (22) and 4,5-bis-tert-butyloxycarbonyl-1-
oxo-1k4-[1,4,5]thiadiazepane (21)
To a solution of 4,5-bis-tert-butyloxycarbonyl-[1,4,5]thiadiaze-
pane 20 (8.3 g, 26.1 mmol) in dichloromethane (20 ml) was added
m-chloroperbenzoic acid (10.9 g, MCPBA ꢁ70%, 44.2 mmol) in
dichloromethane (50 ml) at 0–5 °C dropwise. The mixture was stir-
red at room temperature overnight, then poured on 0.5 N aqueous
sodium hydroxide and the layers separated. The aqueous phase
was extracted with dichloromethane, the combined organic layers
washed with water and brine, dried over magnesium sulfate and
evaporated. The residue was purified by chromatography on silica
gel (ethyl acetate/hexane 1:2) to first afford the sulfone 22. Yield:
5.73 g (63%) as white solid. 1H NMR (CDCl3): d 1.48 (appar t,
18H), 3.07–3.63 (m, 6H), 4.01–4.39 (m, 2H).
5.1.20. 8-(2,4,6-Trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-d]
[1,4,5]thiadiazepine-7,9-dione (27)
Obtained from [1,4,5]thiadiazepane dihydrobromide 24 (3.55 g,
12.7 mmol), 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl
ester 12b (3.98 g, 14.3 mmol) and triethylamine (8 ml, 5.8 g,
57.4 mmol) in xylene (150 ml) according to procedure 5.1.19.
Yield: 80% as an off-white solid, mp 225 °C (dec). 1H NMR (CDCl3):
d 2.03 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H), 2.81–2.95 (m, 4H), 4.20
(ddd, 2H), 4.44 (ddd, 2H), 4.69 (s, 1H), 6.83 (s, 1H), 6.93 (s, 1H).
13C NMR (CDCl3): d 20.1, 20.9, 21.0, 31.8, 47.7, 48.2, 125.9,
129.5, 130.0, 136.0, 138.1, 138.4, 166.1. MS (ES+) m/z: 305
(C16H20N2O2S + H)+. Anal. Calcd for C16H20N2O2S: C, 63.13; H,
6.62; N, 9.20; O, 10.51; S, 10.53. Found: C, 62.43; H, 6.71; N,
9.13; O, 10.84; S, 10.32.
Further elution delivered the sulfoxide 21. Yield: 1.7 g (20%) as
an oil. 1H NMR (CDCl3): d 1.46 (appar t, 18H), 2.82–3.29 (m, 4H),
3.31–3.80 (m, 2H), 4.07–4.48 (m, 2H).
5.1.16. [1,4,5]Oxadiazepane dihydrobromide (23)
To a solution of 4,5-bis-tert-butyloxycarbonyl-[1,4,5]oxadiaze-
pane 18 (216 g, 0.71 mol) in 2800 ml of diethyl ether cooled at
0–5 °C under nitrogen was added a solution of hydrogen bromide
in acetic acid (376 ml, HBr 33% w/w in glacial acetic acid, 5.7 M,
2.14 mol) dropwise over 1.5 h. The reaction mixture was stirred
overnight at room temperature, and further 20 h at reflux. In be-
tween the mixture was diluted with another 200 ml of diethyl
ether and treated with additional hydrogen bromide in acetic acid
(30 ml, 0.17 mol). The resulting suspension was cooled to room
temperature, filtered under nitrogen and the white solid washed
with diethyl ether. The solid was dried over phosphorus pentox-
ide under vacuum at 50 °C. Yield: 131.9 g (70%) as a white hygro-
scopic solid, mp 138–141 °C (dec). 1H NMR (DMSO-d6): d 3.22 (t,
4H), 3.79 (t, 4H), 8.3 (br s, 4H). 13C NMR (DMSO-d6): d 49.8, 67.5.
Differential scanning calorimetry (DSC): energy of exothermic
decomposition = 0.61 kJꢃgꢀ1 (peak at 140 °C, peak width ꢁ22 °C)
5.1.21. 3,3-Dioxo-8-(2,4,6-trimethyl-phenyl)-tetrahydro-3k6-
pyrazolo[1,2-d][1,4,5]thiadiazepine-7,9-dione (28)
Obtained from 1,1-dioxo-1k6-[1,4,5]thiadiazepane dihydrobro-
mide 25 (3.72 g, 11.9 mmol), 2-(2,4,6-trimethyl-phenyl)-malonic
acid diethyl ester 12b (3.32 g, 11.9 mmol) and triethylamine
(6.7 ml, 4.9 g, 48.1 mmol) in xylene (120 ml) according to proce-
dure 5.1.19. Yield: 90% as an off-white solid, mp >250 °C. 1H
NMR (CDCl3): d 2.01 (s, 3H), 2.26 (s, 3H), 2.39 (s, 3H), 3.29–3.43
(m, 4H), 4.35–4.49 (m, 4H), 4.71 (s, 1H), 6.85 (s, 1H), 6.95 (s, 1H).
MS (ES+) m/z: 337 (C16H20N2O4S + H)+.
measured in the range 50–460 °C, 4 °C minꢀ1
.

4252
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
5.1.22. 3-Oxo-8-(2,4,6-trimethyl-phenyl)-tetrahydro-3k4-
pyrazolo[1,2-d][1,4,5]thiadiazepine-7,9-dione (29)
5.1.26. 2,2-Dimethyl-propionic acid 3,9-dioxo-8-(2,4,6-
trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-3k4-pyrazolo[1,2-
d][1,4,5]thiadiazepin-7-yl ester (33)
A solution of sodium periodate (720 mg, 3.37 mmol) in meth-
anol (3 ml) and water (3 ml) was added dropwise to a solution of
8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-d][1,4,5]thia
diazepine-7,9-dione 27 (500 mg, 1.64 mmol) in methanol (20 ml)
at 0–5 °C. The reaction mixture was stirred 2 h at 5 °C and 6 h at
room temperature, then poured on saturated aqueous sodium
chloride and extracted three times with tetrahydrofuran. The
aqueous phase was acidified to pH 3–4 by addition of a 2 N HCl
solution and further extracted with tetrahydrofuran. The com-
bined organic layers were washed with saturated aqueous
Na2S2O3 and brine, dried over magnesium sulfate and evaporated.
The residue was triturated with diethyl ether, filtered and dried.
Yield: 530 mg (ꢁ100%) as a yellowish solid, mp 212 °C (dec). 1H
NMR (CDCl3): d 1.98 (s, 1.2H), 2.03 (s, 1.8 H), 2.25 (s, 3H), 2.39
(s, 3H), 2.61 (ddd, 0.8H), 2.75 (ddd, 1.2H), 3.30–3.39 (m, 2H),
4.10–4.21 (m, 2H), 4.64–4.78 (m, 3H), 6.84 (br s, 1H), 6.93 (br s,
1H) (two diketo-form isomers in a ratio 3:2). MS (ES+) m/z: 321
(C16H20N2O3S + H)+.
To a solution of 2,2-dimethyl-propionic acid 9-oxo-8-(2,4,6-
trimethyl-phenyl)-1,2,4,5-tetrahydro-9H-pyrazolo[1,2-d][1,4,5]
thiadiazepin-7-yl ester 31 (500 mg, 1.29 mmol) in dichlorometh-
ane (3 ml) was added a solution of m-chloroperbenzoic acid
(320 mg, MCPBA ꢁ70%, 1.29 mmol) in dichloromethane (2 ml)
at 0–5 °C dropwise. The mixture was stirred at this temperature
for 1 h, then poured on 1 N aqueous sodium hydroxide and the
layers separated. The aqueous phase was extracted with dichloro-
methane, the combined organic layers washed with water and
brine, dried over magnesium sulfate and evaporated. Yield:
520 mg (ꢁ100%) as an off-white solid, mp 191 °C. 1H NMR
(CDCl3): d 1.07 (s, 9H), 2.13 (s, 6H), 2.23 (s, 3H), 2.69 (m, 2H),
3.21 (m, 2H), 3.80 (dd, 1H), 4.31 (dd, 1H), 4.58 (dd, 1H), 4.79
(m, 1H), 6.83 (s, 2H).
5.1.27. 1-(2-Hydroxy-ethyl)-4-(2,4,6-trimethyl-phenyl)-
pyrazolidine-3,5-dione (35)
A solution of 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl
ester 12b (42.35 g, 0.151 mol) in xylene (300 ml) was treated with
(2-hydroxyethyl)hydrazine (34, n = 1) (11.50 g, 0.151 mol). The
reaction mixture was heated and stirred at 100 °C under nitrogen
atmosphere. The progression of the reaction was checked by TLC
analysis (methanol/ethyl acetate 3:7). After completion of the reac-
tion, the resulting white suspension was filtered and the filter cake
thoroughly washed with n-hexane, then recrystallized from ethyl
acetate. Yield: 24.65 g (62%) as white crystals, mp 203–209 °C. 1H
NMR (MeOH-d4): d 2.15 (s, 6H), 2.24 (s, 3H), 3.76 (appar s, 4H),
6.88 (s, 2H). 13C NMR (MeOH-d4): d 20.6, 21.2, 48.6, 60.9, 89.2,
127.1, 128.9, 138.0, 140.5, 163.4, 166.7. MS (ES+) m/z: 263
(C14H18N2O3 + H)+.
5.1.23. 2,2-Dimethyl-propionic acid 9-oxo-8-(2,4,6-trimethyl-
phenyl)-1,2,4,5-tetrahydro-9H-pyrazolo[1,2-
d][1,4,5]oxadiazepin-7-yl ester (30)
To a solution of 8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo
[1,2-d][1,4,5]oxadiazepine-7,9-dione 26 (3.0 g, 10.4 mmol) and
triethylamine (2.2 ml, 1.60 g, 15.8 mmol) in tetrahydrofuran
(100 ml) at 0–5 °C was added a catalytic amount of 4-dimethyl-
aminopyridine (DMAP, ꢁ5 mol %), followed by pivaloyl chloride
(1.6 ml, 1.57 g, 13.0 mmol) dropwise. The reaction mixture was
stirred at 0 °C for 30 min and at room temperature for 1 h, then
poured on saturated aqueous sodium chloride and extracted with
ethyl acetate. The combined organic layers were washed with
water and brine, dried over magnesium sulfate and evaporated.
The residue was purified by chromatography on silica gel (ethyl
acetate/methanol 19:1), and the crude product triturated with
diethyl ether, filtered and dried. Yield: 2.94 g (76%) as a crystalline
white solid, mp 135–136 °C. 1H NMR (CDCl3): d 1.06 (s, 9H), 2.17 (s,
6H), 2.24 (s, 3H), 3.81–3.89 (m, 4H), 3.93 (m, 2H), 4.25 (m, 2H),
6.83 (s, 2H).
5.1.28. 1-(3-Hydroxy-propyl)-4-(2,4,6-trimethyl-phenyl)-
pyrazolidine-3,5-dione (36)
5.1.28.1. Step 1: (3-Hydroxypropyl)hydrazine (34, n = 2).
To
a solution of sodium hydroxide pellets (48.09 g, 1.2 mol) in hydra-
zine monohydrate (300 g, 6.0 mol) at 98 °C under nitrogen atmo-
sphere was added 3-chloropropanol (113.1 g, 1.2 mol) dropwise
while maintaining the temperature between 95 °C and 100 °C.
The reaction mixture was concentrated under reduced pressure,
the resulting suspension filtered and the filtrate submitted to dis-
tillation under reduced pressure. Yield: 61.6 g (43%) as a colorless
liquid, bp 105 °C/0.08 mbar. 1H NMR (MeOH-d4): d 1.72 (quint,
2H), 2.85 (t, 2H), 3.65 (t, 2H), 4.70–5.00 (br s, 4H). 13C NMR
(MeOH-d4): d 29.9, 51.8, 69.8.
5.1.24. 2,2-Dimethyl-propionic acid 9-oxo-8-(2,4,
6-trimethyl-phenyl)-1,2,4,5-tetrahydro-9H-pyrazolo[1,2-
d][1,4,5]thiadiazepin-7-yl ester (31)
Obtained from 8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo
[1,2-d][1,4,5]thiadiazepine-7,9-dione 27 (1.5 g, 4.93 mmol), piva-
loyl chloride (0.62 ml, 0.60 g, 4.98 mmol), triethylamine (0.7 ml,
0.51 g, 5.02 mmol) and a catalytic amount of 4-dimethylaminopyr-
idine in tetrahydrofuran (50 ml) according to procedure 5.1.23.
Yield: 82% as a white solid, mp 173–174 °C. 1H NMR (CDCl3): d
1.07 (s, 9H), 2.16 (s, 6H), 2.23 (s, 3H), 2.78 (m, 2H), 2.91 (m, 2H),
4.07 (m, 2H), 4.42 (m, 2H), 6.83 (s, 2H).
5.1.28.2. Step 2: 1-(3-Hydroxy-propyl)-4-(2,4,6-trimethyl-phe-
nyl)-pyrazolidine-3,5-dione (36).
A solution of 2-(2,4,6-tri-
methyl-phenyl)-malonic acid diethyl ester 12b (8.40 g,
30.2 mmol) in xylene (200 ml) was treated with (3-hydroxypro-
pyl)hydrazine (34, n = 2) (2.70 g, 30.0 mmol). The reaction mixture
was flushed with argon and stirred under argon atmosphere. The
flask was placed in a preheated oil bath at 150 °C and the mixture
heated for 35 min, while ethanol was distilled off. The cooled reac-
tion mixture was poured on a 1 N aqueous sodium hydroxide solu-
tion (50 ml) and the aqueous layer extracted twice with
dichloromethane. The aqueous alkaline phase was acidified with
cooling by careful addition of a 1 N HCl solution and the product
extracted with dichloromethane. The organic phase was dried over
sodium sulfate and evaporated. Yield: 1.10 g (13%) as beige crys-
tals. 1H NMR (MeOH-d4): d 1.92 (quint, 2H), 2.13 (s, 6H), 2.26 (s,
3H), 3.59 (t, 2H), 3.92 (t, 2H), 6.93 (s, 2H). MS (ES+) m/z: 277
(C15H20N2O3 + H)+.
5.1.25. 2,2-Dimethyl-propionic acid 3,3,9-trioxo-8-(2,4,6-
trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-3k6-pyrazolo[1,2-
d][1,4,5]thiadiazepin-7-yl ester (32)
Obtained from 3,3-dioxo-8-(2,4,6-trimethyl-phenyl)-tetra-
hydro-3k6-pyrazolo[1,2-d][1,4,5]thiadiazepine-7,9-dione
28
(1.0 g, 2.97 mmol), pivaloyl chloride (0.37 ml, 0.36 g, 3.0 mmol),
triethylamine (0.42 ml, 0.30 g, 3.01 mmol) and catalytic
a
amount of 4-dimethylaminopyridine in tetrahydrofuran
(35 ml) according to procedure 5.1.23. Yield: 82% as a white so-
lid, mp 186 °C. 1H NMR (CDCl3): d 1.06 (s, 9H), 2.13 (s, 6H), 2.23
(s, 3H), 3.22 (m, 2H), 3.40 (m, 2H), 4.15 (m, 2H), 4.46 (m, 2H),
6.84 (s, 2H).

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4253
5.1.29. 7-(2,4,6-Trimethyl-phenyl)-dihydro-pyrazolo[1,2-
c][1,3,4]oxadiazine-6,8-dione (37)
5.1.33. (2,6-Diethyl-4-hydroxy-phenyl)-acetonitrile (42)
To a solution of sodium cyanide (5.38 g, 109.8 mmol) in ethanol
(130 ml) and water (130 ml) was added a solution of carbonic acid
4-chloromethyl-3,5-diethyl-phenyl ester ethyl ester 41 (16.98 g,
62.7 mmol) in ethanol (40 ml) dropwise. The reaction mixture was
heated to reflux for 17 h. The ethanol was evaporated, the residue di-
luted with ethyl acetate and poured on ice-water. The aqueous layer
was extracted with ethyl acetate, the combined organic phases
washed with brine, dried over magnesium sulfate and evaporated.
Yield:10.35 g (87%) as a solid, this material was used withoutfurther
purification. An analytical sample of 42 was obtained through puri-
fication by chromatography on silica gel (ethyl acetate/hexane 1:4).
White solid, mp 112 °C. 1H NMR (CDCl3): d 1.22 (t, 6H), 2.63 (q, 4H),
3.61 (s, 2H), 5.69 (br s, 1H), 6.58 (s, 2H). 13C NMR (CDCl3): d 14.7, 16.1,
26.5, 113.5, 115.5, 118.3, 144.5, 155.6.
A mixture of 1-(2-hydroxy-ethyl)-4-(2,4,6-trimethyl-phenyl)-
pyrazolidine-3,5-dione 35 (500 mg, 1.91 mmol), paraformaldehyde
(126 mg, 4.20 mmol CH2O) and triethylamine (5 ml) was stirred at
80 °C. The reaction was followed by TLC analysis. After complete
conversion, the reaction mixture was evaporated under reduced
pressure and the residue subjected to column chromatography
on silica gel (ethyl acetate/methanol 8:2). Yield: 320 mg (62%) as
white crystals, mp 212–213 °C. 1H NMR (MeOH-d4): d 2.16 (s,
6H), 2.27 (s, 3H), 3.65 (t, 2H), 4.05 (t, 2H), 5.10 (s, 2H), 6.93 (s,
2H). 1H NMR (CDCl3): d 2.06 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H),
3.68 (ddd, 1H), 3.79 (ddd, 1H), 3.94 (m, 2H), 4.67 (s, 1H), 5.06 (d,
JAB = 9.2 Hz, 1H), 5.19 (d, JAB = 9.2 Hz, 1H), 6.84 (s, 1H), 6.93 (s,
1H). 13C NMR (CDCl3): d 20.2, 20.9, 21.0, 43.6, 48.7, 65.0, 75.2,
125.4, 129.5, 130.0, 136.0, 138.3, 138.5, 166.9, 170.4. MS (ES+) m/
z: 275 (C15H18N2O3 + H)+.
5.1.34. Trifluoromethanesulfonic acid 4-cyanomethyl-3,5-
diethyl-phenyl ester (43)
5.1.30. 8-(2,4,6-Trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-
d][1,3,4]oxadiazepine-7,9-dione (38)
A suspension of 1-(3-hydroxy-propyl)-4-(2,4,6-trimethyl-phe-
nyl)-pyrazolidine-3,5-dione 36 (1.0 g, 3.62 mmol) in tetrahydrofu-
To a solution of (2,6-diethyl-4-hydroxy-phenyl)-acetonitrile 42
(19.5 g, 103.0 mmol) and triethylamine (17.8 ml, 12.9 g,
127.7 mmol) in dichloromethane (215 ml) at ꢀ35 °C was added tri-
fluoromethanesulfonic anhydride (19.1 ml, 32.8 g, 116.4 mmol)
dropwise. The reaction mixture was stirred at ꢀ30 °C for 30 min,
then allowed to warm to room temperature. The mixture was
poured on cold saturated aqueous sodium hydrogen carbonate
and extracted with dichloromethane. The combined organic layers
were washed twice with saturated aqueous sodium hydrogen car-
bonate and brine, dried over sodium sulfate and evaporated. The
residue was purified by chromatography on silica gel (ethyl ace-
tate/hexane 1:9). Yield: 27.0 g (82%) as an oil. 1H NMR (CDCl3): d
1.29 (t, 6H), 2.77 (q, 4H), 3.69 (s, 2H), 7.02 (s, 2H). 13C NMR (CDCl3):
d 14.2, 16.4, 26.4, 117.0, 118.7 (q, 1J(C,F) = 321 Hz), 119.1, 126.8,
145.6, 149.5.
ran (10 ml) was treated with
a 37% aqueous solution of
formaldehyde (6.8 ml, 90.5 mmol) and heated at reflux for 1 h.
The reaction mixture was poured on water and extracted with
ethyl acetate. The organic phase was dried over sodium sulfate
and evaporated. The residue was subjected to column chromatog-
raphy on silica gel (ethyl acetate/hexane 1:1 to 100% ethyl acetate).
Yield: 510 mg (49%) as white crystals, mp 223–227 °C. 1H NMR
(CDCl3): d 1.90–2.08 (m, 2H), 2.05 (s, 3H), 2.25 (s, 3H), 2.39 (s,
3H), 3.66–3.75 (m, 2H), 4.00–4.07 (ddd, 1H), 4.43–4.51 (ddd, 1H),
4.69 (s, 1H), 4.84 (d, JAB = 12.5 Hz, 1H), 5.62 (d, JAB = 12.5 Hz, 1H),
6.83 (s, 1H), 6.92 (s, 1H). 13C NMR (CDCl3): d 20.1, 20.9, 21.0,
31.2, 41.6, 48.4, 72.4, 73.5, 125.9, 129.4, 130.0, 136.5, 138.1,
138.3, 164.6, 166.3. MS (ES+) m/z: 289 (C16H20N2O3 + H)+.
5.1.35. (2,6-Diethyl-4-methyl-phenyl)-acetonitrile (44a)
To a solution of trifluoromethanesulfonic acid 4-cyanomethyl-
3,5-diethyl-phenyl ester 43 (27.0 g, 84.0 mmol) in tetrahydrofuran
(70 ml) at room temperature was added tetrakis(triphenylphos-
phine)palladium(0) (430 mg, 0.37 mmol), followed by a 2 M trim-
ethylaluminum solution in hexane (27.5 ml, 55.0 mmol)
dropwise. The reaction mixture was heated at reflux for 4 h, trea-
ted with another portion of 2 M trimethylaluminum solution in
hexane (3 ml, 6.0 mmol) and refluxed further for 1 h. The mixture
was evaporated, the residue diluted with dichloromethane and the
solution carefully treated with ice-water dropwise. The mixture
was filtered through hyflo (calcined diatomaceous earth) to re-
move inorganic residues, the layers separated, the aqueous phase
extracted with dichloromethane, the combined organic phases
washed four times with water and brine, dried over sodium sulfate
and evaporated. The residue was purified by chromatography on
silica gel (1% ethyl acetate in hexane). Yield: 12.77 g (81%) as a col-
orless oil. 1H NMR (CDCl3): d 1.27 (t, 6H), 2.31 (s, 3H), 2.69 (q, 4H),
3.64 (s, 2H), 6.92 (s, 2H). 13C NMR (CDCl3): d 14.9, 16.2, 21.0, 26.3,
118.2, 123.0, 127.5, 138.1, 142.4. MS (ES+) m/z: 188 (C13H17N + H)+.
5.1.31. Carbonic acid 3,5-diethyl-phenyl ester ethyl ester (40)
To a solution of 3,5-diethyl-phenol 3931 (100.6 g, 0.67 mol) and
pyridine (53 ml, 52 g, 0.66 mol) in toluene (300 ml) was added
ethyl chloroformate (108 g, 1.0 mol) dropwise. The suspension
was heated at reflux overnight. The reaction mixture was poured
on water, the layers separated and the aqueous phase extracted
with ethyl acetate. The combined organic layers were washed with
water and brine, dried over magnesium sulfate and evaporated.
Yield: 143.1 g (96%) as an oil, this material was used without fur-
ther purification. 1H NMR (CDCl3): d 1.21 (t, 6H), 1.37 (t, 3H),
2.62 (q, 4H), 4.30 (q, 2H), 6.82 (s, 2H), 6.91 (s, 1H).
5.1.32. Carbonic acid 4-chloromethyl-3,5-diethyl-phenyl ester
ethyl ester (41)
Through a milky solution of carbonic acid 3,5-diethyl-phenyl
ester ethyl ester 40 (27.4 g, 123.3 mmol) and paraformaldehyde
(3.7 g, 123.2 mmol CH2O) in concentrated HCl (170 ml) at ꢀ5 °C
was bubbled gaseous hydrogen chloride slowly over 1.5 h. The
reaction mixture was stirred at room temperature overnight.
Over the next three days, the mixture was further treated with
paraformaldehyde (2 ꢂ 5 g, 1 ꢂ 2 g) and gaseous hydrogen chlo-
ride, and stirring continued at 50 °C until the reaction was
judged complete by thin layer chromatography. The reaction
mixture was flushed with argon, extracted twice with toluene,
the combined organic phases washed twice with water and
brine, dried over magnesium sulfate and evaporated. The residue
was purified by chromatography on silica gel (ethyl acetate/hex-
ane 1:20). Yield: 16.98 g (51%) as an oil. 1H NMR (CDCl3): d 1.27
(t, 6H), 1.38 (t, 3H), 2.78 (q, 4H), 4.31 (q, 2H), 4.66 (s, 2H), 6.91
(s, 2H).
5.1.36. (2,6-Diethyl-phenyl)-acetonitrile (44b)
To a solution of trifluoromethanesulfonic acid 4-cyanomethyl-
3,5-diethyl-phenyl ester 43 (11.16 g, 35 mmol) in dimethylform-
amide (280 ml) at room temperature was added triethylamine
(19.5 ml, 14.2 g, 140 mmol), formic acid (6.44 g, 140 mmol), tri-
phenylphosphine (1.8 g, 6.9 mmol) and palladium acetate
(390 mg, 1.74 mmol). The reaction mixture was heated to 40 °C
and stirred for 17 h. After dilution with dichloromethane, the or-
ganic phase was washed twice with 1 N aqueous hydrogen chlo-
ride and brine, dried over sodium sulfate and evaporated. The
residue was purified by chromatography on silica gel (ethyl ace-

4254
M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
tate/hexane 1:9). Yield: 5.43 g (90%) as a colorless oil. 1H NMR
(CDCl3): d 1.27 (t, 6H), 2.73 (q, 4H), 3.70 (s, 2H), 7.08–7.36 (m, 3H).
5.1.42. 2-(2,6-Diethyl-4-methyl-phenyl)-malonic acid dimethyl
ester (46b)
Data for the dimethyl malonate analog of 46a. White solid, mp
54–55 °C. 1H NMR (CDCl3): d 1.18 (t, 6H), 2.30 (s, 3H), 2.64 (q, 4H),
3.73 (s, 6H), 5.06 (s, 1H), 6.93 (s, 2H). 13C NMR (CDCl3): d 15.2, 21.1,
26.6, 51.5, 52.6, 126.4, 127.9, 137.9, 143.6, 169.3. MS (ES+) m/z:
279 (C16H22O4 + H)+, 301 (C16H22O4 + Na)+.
5.1.37. (2,6-Diethyl-4-methyl-phenyl)-acetic acid (7b)
To a cold solution of concentrated sulfuric acid (71 ml) in
water (82 ml) was added (2,6-diethyl-4-methyl-phenyl)-acetoni-
trile 44a (12.92 g, 69.0 mmol) and the mixture was heated at re-
flux until the reaction was judged complete by thin layer
chromatography. The reaction mixture was diluted with water
and ethyl acetate, the layers separated and the aqueous phase ex-
tracted with ethyl acetate. The combined organic layers were
washed with water and brine, dried over sodium sulfate and
evaporated. Yield: 13.86 g (97%) as an off-white solid, mp 123–
125 °C. 1H NMR (CDCl3): d 1.19 (t, 6H), 2.30 (s, 3H), 2.61 (q,
4H), 3.72 (s, 2H), 6.90 (s, 2H), 10.94 (br s, 1H). 13C NMR (CDCl3):
d 15.1, 21.2, 26.4, 33.5, 126.3, 127.2, 137.2, 143.0, 178.5. MS (ESꢀ)
m/z: 205 (C13H18O2–H)ꢀ.
5.1.43. 8-(2,6-Diethyl-4-methyl-phenyl)-tetrahydro-
pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (47, NOA 407854)
Obtained from [1,4,5]oxadiazepane dihydrobromide 23 (4.4 g,
16.6 mmol), 2-(2,6-diethyl-4-methyl-phenyl)-malonic acid diethyl
ester 46a (5.07 g, 16.5 mmol) and triethylamine (10.6 ml, 7.7 g,
76.1 mmol) in xylene (174 ml) according to procedure 5.1.19.
Yield: 4.08 g (78%) as an off-white solid, mp 189–191 °C. 1H NMR
(CDCl3): d 1.18 (t, 3H), 1.24 (t, 3H), 2.26 (q, 2H), 2.29 (s, 3H), 2.69
(q, 2H), 3.74 (ddd, J = 13.3 Hz, 8.0 Hz and 0.9 Hz, 2H), 3.92 (ddd,
J = 15.3 Hz, 8.0 Hz and 0.9 Hz, 2H), 3.96 (ddd, J = 13.3 Hz, 6.3 Hz
and 0.9 Hz, 2H), 4.25 (ddd, J = 15.3 Hz, 6.3 Hz and 0.9 Hz, 2H),
4.70 (s, 1H), 6.90 (s, 1H), 6.93 (s, 1H). 13C NMR (CDCl3): d 14.1,
15.9, 21.0, 25.5, 28.0, 45.9, 47.4, 70.3, 124.5, 127.5, 127.9, 138.3,
142.1, 144.5, 165.9. MS (ES+) m/z: 317 (C18H24N2O3 + H)+. HRMS
(EI+) m/z: Calcd for (C18H24N2O3)+: 316.1787; Found: 316.1783.
5.1.38. (2,6-Diethyl-phenyl)-acetic acid (7c)
Obtained from (2,6-diethyl-phenyl)-acetonitrile 44b (5.43 g,
31.3 mmol) in concentrated sulfuric acid (32 ml) and water
(36 ml) according to procedure 5.1.37. Yield: 87% as a white solid,
mp 71–73 °C. 1H NMR (CDCl3): d 1.23 (t, 6H), 2.68 (q, 4H), 3.78 (s,
2H), 7.05–7.26 (m, 3H).
IR (KBr):
m 3418, 2963m, 1739, 1692, 1550, 1453, 1277, 1129,
.
1000 cmꢀ1
5.1.39. (2,6-Diethyl-4-methyl-phenyl)-acetic acid ethyl ester
(45a)
5.1.44. 2,2-Dimethyl-propionic acid 8-(2,6-diethyl-4-methyl-
phenyl)-9-oxo-1,2,4,5-tetrahydro-9H-pyrazolo[1,2-
Through a solution of (2,6-diethyl-4-methyl-phenyl)-acetic acid
7b (19.31 g, 93.6 mmol) in ethanol (390 ml) was bubbled gaseous
hydrogen chloride under cooling to keep the temperature below
35 °C. The reaction mixture was then heated at reflux for 5 h, al-
lowed to cool, flushed with argon and evaporated. The residue
was purified by chromatography on silica gel (2% ethyl acetate in
hexane). Yield: 19.02 g (87%) as a colorless oil. 1H NMR (CDCl3): d
1.19 (t, 6H), 1.24 (t, 3H), 2.30 (s, 3H), 2.62 (q, 4H), 3.68 (s, 2H),
4.14 (q, 2H), 6.89 (s, 2H). 13C NMR (CDCl3): d 14.2, 15.1, 21.2,
26.4, 33.9, 60.7, 127.1, 127.2, 136.8, 143.0, 172.0. MS (ES+) m/z:
235 (C15H22O2 + H)+, 257 (C15H22O2 + Na)+.
d][1,4,5]oxadiazepin-7-yl ester (6, NOA 407855, pinoxaden)
Obtained from 8-(2,6-diethyl-4-methyl-phenyl)-tetrahydro-
pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione 47 (NOA 407854,
1.0 g, 3.16 mmol), pivaloyl chloride (0.5 ml, 0.49 g, 4.06 mmol),
triethylamine (0.9 ml, 0.65 g, 6.46 mmol) and a catalytic amount
of 4-dimethylaminopyridine (DMAP, ꢁ3 mol %) in tetrahydrofuran
(30 ml) according to procedure 5.1.23. The crude product ob-
tained after extractive workup was purified by chromatography
on silica gel (ethyl acetate/methanol 20:1). Yield: 1.07 g (85%)
as a crystalline white solid, mp 122–123 °C. 1H NMR (CDCl3): d
1.03 (s, 9H), 1.12 (t, 6H), 2.29 (s, 3H), 2.35–2.63 (m, 4H), 3.81–
3.90 (m, 4H), 3.93 (m, 2H), 4.26 (m, 2H), 6.88 (s, 2H). 13C NMR
(CDCl3): d 14.7, 21.3, 26.3, 26.4, 39.1, 45.6, 49.5, 69.4, 70.6, 97.3,
122.7, 126.0, 137.7, 144.3, 149.1, 162.0, 174.1. FD-MS m/z: 400
(C23H32N2O4)+. HRMS (EI+) m/z: Calcd for (C23H32N2O4)+:
5.1.40. (2,6-Diethyl-4-methyl-phenyl)-acetic acid methyl ester
(45b)
Data for the methyl ester of acid 7b. Colorless oil, bp 95–98 °C/
0.2 mbar. 1H NMR (CDCl3): d 1.19 (t, 6H), 2.30 (s, 3H), 2.62 (q, 4H),
3.66 (s, 3H), 3.70 (s, 2H), 6.89 (s, 2H). 13C NMR (CDCl3): d 15.0, 21.1,
26.3, 33.7, 51.9, 126.9, 127.1, 136.8, 142.9, 172.4. MS (ES+) m/z:
221 (C14H20O2 + H)+, 243 (C14H20O2 + Na)+.
400.2362; Found: 400.2361. IR (KBr):
m 2968m, 1778, 1639,
1603, 1473m, 1389, 1330m, 1275, 1122, 1077, 1013 cmꢀ1
.
5.2. Crystal structure determination
5.1.41. 2-(2,6-Diethyl-4-methyl-phenyl)-malonic acid diethyl
ester (46a)
Pinoxaden 6 was dissolved in hot tert-butyl methyl ether, filtered
through a cotton-wool plug, and the resulting colorless solution
allowed to cool to room temperature to obtain needle-like crystals.
A solution of (2,6-diethyl-4-methyl-phenyl)-acetic acid ethyl
ester 45a (19.02 g, 81.2 mmol) in 50 ml of diethyl carbonate
was added dropwise to a stirred suspension of sodium hydride
(10.6 g, 55% w/w dispersion in mineral oil, 243 mmol) in diethyl
carbonate (200 ml) at 100 °C (caution!). The mixture was heated
at reflux overnight and quenched by slow addition of water
dropwise under cooling. Upon destruction of the excess sodium
hydride, the mixture was diluted with ethyl acetate and acidified
to pH 1–2 by addition of a 1 N aqueous hydrogen chloride solu-
tion at 0–5 °C. The layers were separated, the aqueous phase ex-
tracted with ethyl acetate, the combined organic layers washed
three times with water and twice with brine, dried over sodium
sulfate and evaporated. The residue was purified by chromatog-
raphy on silica gel (2% ethyl acetate in hexane). Yield: 18.32 g
(73%) as a colorless viscous oil. 1H NMR (CDCl3): d 1.19 (t, 6H),
1.27 (t, 6H), 2.30 (s, 3H), 2.65 (q, 4H), 4.22 (m, 4H), 5.02 (s,
1H), 6.92 (s, 2H).
Acolorlesssingle crystalof dimensions280 ꢂ 80 ꢂ 70
l
m3 was used
to carry out the structure determination. Diffraction data were
collected at 100 K with a Bruker AXS SMART 6000 CCD detector on
a three-circle platform goniometer with graphite monochromatized
Cu(Ka) radiation from a sealed tube generator. A semi-empirical
absorption correction was applied, based on the intensities of sym-
metry-related reflections measured at different angular settings
(Sheldrick, G. M. SADABS, University of Göttingen, Göttingen,
Germany). The structure was solved and refined on F2 with the SHEL-
XTL suite of programs (Sheldrick, G. M. SHELXTL, Bruker AXS Inc. Madi-
son, Wisconsin, USA). The asymmetric unit contains two
crystallographically independent molecules. All non-hydrogen
atoms were refined with anisotropic displacement parameters,
hydrogen atoms were located in a Difference Fourier map and re-
fined in idealized positions using a riding model.

M. Muehlebach et al. / Bioorg. Med. Chem. 17 (2009) 4241–4256
4255
Final crystallographic data and structure refinement parameters
Acknowledgments
ꢀ
for pinoxaden 6: C23H32N2O4, Mr = 400.51, triclinic, space group P1
with a = 9.450(3), b = 14.759(4), c = 17.368(5) Å, = 69.935(14)°,
V = 2207.1(11) Å3,
Z = 4,
a
The authors wish to thank all Syngenta colleagues involved in
the discovery, development and launch of pinoxaden. The authors
are also grateful to Peter Moser, Domenico Bloise, Mathias Brod-
mann, Claire Grenouillet and Iwan Kuster for skillful technical
assistance.
b = 75.975(13)°,
c = 86.187(17)°,
Dc = 1.205 g cmꢀ3, 26327 reflections measured, 7600 independent,
2.79° < h < 66.61°, T = 100(2) K, 535 parameters, no restraints,
R1 = 0.0388, wR2 = 0.0979 for 6583 reflections with I > 2r(I),
R1 = 0.0456, wR2 = 0.1062 for all 7600 data, GoF = 1.065, res. el.
dens. = +0.41/ꢀ0.29 e Å3.
References and notes
Crystallographic data (excluding structure factors) for 6 have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 706870. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1 EZ, UK (fax: +44-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
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The following crops and weed species have been used to evalu-
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Plant cultivation, herbicide application and damage evaluation
were conducted as follows: Monocotyledonous test plants were
sown in plastic pots filled with standard soil. After cultivation un-
der controlled glasshouse conditions, the plants were sprayed at
the 3- to 6-leaf stage with an aqueous spray solution (500 L haꢀ1
carrier volume) prepared by diluting appropriately a formulation
of the technical active ingredient with water and with optional
addition of either the adjuvant X-77 (0.2%, v/v) (Registry number
11097-66-8) or MergeÒ (1%, v/v) (Registry number 147230-14-6).
Application rates were between 2000 and 30 g ai haꢀ1. Formula-
tions used in this study included either wettable powders (WP10
or WP25) or instant formulations (IF50) obtained by dissolving
an acetone solution of the test compound into a blank formulation
containing 10.6% Emulsogen EL (Registry number 61791-12-6),
42.2% N-methyl pyrrolidone, 42.2% dipropylene glycol mono-
methyl ether (Registry number 34590-94-8) and 0.2% X-77. After
further cultivation in the greenhouse under optimum conditions
for 21 days, visual assessment of weed control and crop damage
was made using a 0–100% rating scale (100% = total damage to test
plant; 0% = no damage to test plant).
5.3.3. Safener effect on herbicidal activity
Forthecomparativestudy of NOA40785447andpinoxaden6 ap-
plied alone or in combination with the safener cloquintocet-mexyl39
(Registry number 99607-70-2) (Table 7), the above protocol 5.3.2
was slightly modified. Test plants sown in plastic pots filled with
sandy clay loam and grown under controlled glasshouse conditions
were sprayed at the 3- to 6-leaf stage with an aqueous spray solution
(500 L haꢀ1) derived either from an EC200 formulation of the herbi-
cides47or6 alone, orfromamixtureofanEC200formulationofeach
herbicide (H) with an EC100 formulation of the safener (S) cloquint-
ocet-mexyl at a ratio H/S of 4:1. MergeÒ (0.7%, v/v) was incorporated
to the spray solution as adjuvant. Visual assessment of weed control
and crop damage upon treatments with and without safener was
made using a 0–100% rating scale (100% = total damage to test plant;
0% = no damage to test plant). Crop injury 12 days after treatment
(DAT) on winter barley (cv Manitou), winter wheat (cv Arina) and
summer wheat (cv Lona) was assessed at a use rate of 60 g haꢀ1 47
or 6, whereas grass control on AVEFA and LOLRI was evaluated 20
DAT at 30 g haꢀ1 47 or 6.
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