Design, synthesis and herbicidal activity of new iron chelating motifs for HPPD-inhibitors

Article abstract of DOI:10.1016/j.bmc.2008.11.006

HPPD (p-hydroxyphenylpyruvate dioxygenase) is a herbicidal target that all major companies active in plant protection research have worked on intensely in the last decade. Several modern herbicides with this mode of action have been introduced recently, o

Full text of DOI:10.1016/j.bmc.2008.11.006

Bioorganic & Medicinal Chemistry 17 (2009) 4221–4229
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and herbicidal activity of new iron chelating motifs
for HPPD-inhibitors
*
Matthias Witschel
BASF SE, Crop Protection, GVA/HC – B009, 67056 Ludwigshafen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
HPPD (p-hydroxyphenylpyruvate dioxygenase) is a herbicidal target that all major companies active in
plant protection research have worked on intensely in the last decade. Several modern herbicides with
this mode of action have been introduced recently, or are currently in development. The activity of all
commercialized HPPD-inhibitors is based on a chelating functionality, which binds to the redoxactive
iron center in the enzyme. In the course of our research, leading to the new broad spectrum corn herbi-
cide topramezone by BASF, this chelating functionality has been examined thoroughly, and many new
chelating motifs have been synthesized. The chelating motif N–O in combination with C@O, which is
known for its iron-binding potential from many natural siderophores, was especially promising. Exami-
nation of several different motifs of this type resulted in the identification of benzoyl-N-hydroxyimidaz-
oles, which inhibited the HPPD-enzyme with potency comparable to the best known systems. Significant
herbicidal activity in the greenhouse could also be identified for some of these compounds, but this activ-
ity was weaker than for the analogous benzoylpyrazolones of the topramezone-type.
Received 7 October 2008
Revised 30 October 2008
Accepted 4 November 2008
Available online 8 November 2008
Keywords:
p-Hydroxyphenylpyruvate dioxygenase
Herbicide
Topramezone
N-Hydroxyimidazole
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
benzoylpyrazoles, exchanging the pyrazolone with a diketone sub-
structure. In course of this research the herbicides sulcotrione
In the early 1970s a group at Sankyo identified the herbicidal
activity of benzoylpyrazoles. Based on these findings the first com-
mercial product, pyrazolinate, was launched 1980 for the control of
annual and perennial weeds in rice. Pyrazolinate, which is a pro-
drug for the active principle DTP (detosylpyrazolate), is used at
rates of 3–4 kg/ha. In 1985 Ishihara Sangyo Kaisha commercialized
a second representative of this class, pyrazoxyfen, which is a differ-
ent prodrug of the same active principle DTP. In 1987 Mitsubishi
Petrochemical Co. introduced benzofenap, which is closely related
to pyrazoxyfen and is used in the same indication. By now more
than 600 patents covering herbicidal benzoylpyrazoles from all
major companies active in plant protection research have been
published, but it took until 2006 before the next benzoylpyrazole,
topramezone,1 was commercialized by BASF. This compound is
used as a postemergence herbicide with excellent selectivity in
corn at use rates of 12–75 g/ha, controlling all major grasses and
broadleaf weeds. A further new benzoylpyrazole, pyrasulfotole, is
currently introduced by Bayer in combination with a safener, for
post-emergence control of broadleaf weeds in cereals (Fig. 1).
Independent of this research a group at Stauffer Chemical
Company (then Zeneca, now Syngenta) identified 2-benzoyl-cyclo-
hexane-1,3-diones as a new herbicidal compound class, which
showed a very similar structure–activity relationship (SAR) to the
(1991) and later mesotrione (2001) were identified and commer-
cialized for the control of broadleaf weeds in corn. The prodrug
benzobicyclon was developed by SDS Biotech/Sandoz mainly for
the control of sedges and some broadleaf weeds in transplanted
rice. Bayer has introduced tembotrione in combination with a saf-
ener in 2007 for postemergence weed control in corn. Isoxaflutole,
which is a prodrug of the diketonitrile DKN, has been commercial-
ized 1996 by Rhone-Poulenc Agro (now Bayer CropScience) as a
pre-emergence herbicide in corn (Fig. 2).
At Zeneca2 (now Syngenta), simultaneously with a group at
Hoechst3 (now Bayer CropScience), the herbicidal mode of action
of the 2-benzoyl-cyclohexane-1,3-diones could be identified as
inhibition of the enzyme p-hydroxyphenylpyruvate dioxygenase
(HPPD). This was later shown to be the mode of action for the ben-
zoylpyrazoles and isoxaflutole as well.
The conversion of p-hydroxyphenylpyruvate (HPP) to homo-
gentisic acid (HGA) starts by chelation of HPP to an Fe(II)-ion in
the active site of the enzyme HPPD.
A complex decarboxylation-oxidation-rearrangement sequence
leads subsequently to the formation of homogentisate (HGA).4 All
commercialized HPPD-inhibitors block this enzyme by chelation
of the iron in the active site by a 1,3-dicarbonyl motif, in a manner
similar to HPP (Fig. 3).
The inhibition of HPPD has as its main herbicidal effect the
reduction of the plastoquinone-level in plants, as HGA is a key
intermediate in the biosynthesis of plastoquinone. Plastoquinone
* Tel.: +49 621 6041966; fax: +49 621 6021156.
E-mail address: matthias.witschel@basf.com
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.11.006

4222
M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
O
S
O
O
Cl
O
Cl
O
O
Cl
O
Cl
O
HO
O
O
O
O
N
N
N
N
N
N
N
N
Cl
Cl
Cl
O
Cl
Pyrazolinate
DTP
Pyrazoxyfen
Benzofenap
SO2Me
O
N
HO
HO
N
N
N
N
CF3
SO2Me
Topramezone
Pyrasulfotole
Figure 1. Chemical structures of benzoylpyrazole herbicides.
S
O
O
Cl
OH
O
O
NO2
OH
O
O
Cl
SO2Me
SO2Me
SO2Me
Sulkotrione
Mesotrione
Benzobicyclone
OH SO2Me
OH
O
Cl
O
O
SO2Me
O
CF3
O
N
O
SO2Me
CF3
CF3
N
Tembotrione
Isoxaflutole
DKN
Figure 2. Chemical structures of benzoylcyclohexanedione- and benzoylisoxazole herbicides.
Arg
Arg
Glu
O2
Fe2+
OH2
HPP
Glu
Arg
Arg
Arg
Glu
O
O
Fe2+
O2
Arg
Fe2+
OH2
HGA
OH
O
H2O
OH2
O
O
Arg
Arg
Glu
OH
O
Fe2+
Arg
O
N
OH O
Glu
OH
O
Arg
2
Fe2+
Arg
Fe4+
N
O
Glu
O
Arg
N
SO2Me
Arg
O
O
O
O
Arg
Fe2+
H
Arg
O
Glu
Arg
Glu
O
Fe4+
OH
O
O
O
O
O
CO2
O
OH
+
OH
Figure 3. Reaction mechanism of HPPD and inhibition by topramezone.
is an essential cofactor for the enzyme phytoene-desaturase, so
that a reduction in plastoquinone-levels results in a reduced pro-
duction of phytoene, and thereby of the carotenoids. This in turn
results in reduced protection of chlorophyll against photooxida-
tion, which leads to bleaching and subsequent necrosis and death
of the treated weeds. In addition to these effects, which are the
main contributors to the herbicidal activity, the reduced level of
homogentisate leads to a lower tocopherol production, for which
it is also an intermediate (Fig. 4).
The strongest known iron-binding motifs in nature are those
that chelate the iron ion between an N–O- and a carbonyl-function-
ality, used by many organisms, for example, in siderophores.5–7 So

M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
4223
NH2
O
R
Phytoene
HO
O
HO
HO
OH
OH
O
O
O
O
TAT
HPPD
PDS
(Phytoenedesaturase)
OH
Tyrosine
OH
p-Hydroxy-
phenylpyruvate
Homogentisate
Plastoquinone
cofactor for PDS
Carotenoids
UV/O2-protection
Chlorophyll
Figure 4. Role of HPPD in chlorophyll-protection (TAT, tyrosine aminotransferase).
far this concept has not been described for inhibitors of HPPD.
Therefore we examined to what extent the 1,3-dicarbonyl-motif
could be replaced by an isosteric N–O-carbonyl chelation.
Using a published method for the synthesis of 1-phenylbutane-
1,3-diones 711 from benzoylchlorides 3, these could be oximated
with butylnitrite,12 resulting in inseparable E/Z-isomeric mixtures
of the 1-phenylbutane-1,2,3-trione-2-oximes 5 (Scheme 2).
These oximes showed in combination with the most active phe-
nyl substitution patterns some activity on the HPPD-target, but the
activity level was significantly lower than for comparable butane-
dione systems (Table 1).
2. Results and discussion
2.1. Replacement of a cyclohexane-1,3-dione by a pyridine N-
oxide
At the highest tested use rates in the greenhouse only low activ-
ity for the most active analogue 5d could be detected in postemer-
gence application on important weeds.
It has been shown that substituted 2-benzoylcyclohexanones
lacking the third carbonyl-group8 present in sulcotrione do have
target-activity on HPPD, only slightly lower than the ‘trione’-sys-
tems like 1. Therefore we set out to synthesize the isosteric 2-ben-
zoylpyridine-N-oxide 2 (Fig. 5).
This compound was readily made by coupling 2-tributylstan-
nylpyridine without catalysis9 with the benzoylchloride 3,10 fol-
lowed by oxidation with m-CPBA (Scheme 1).
Unfortunately 2 showed no significant activity on the HPPD
enzyme at 2 Â 10À5 M concentration, and consequently also no
activity in the greenhouse. One explanation might be the neutral
character of 2, as all other known inhibitors of HPPD are weak acids
and are binding in the deprotonated form.
It has been described that acetylacetone gives stronger Fe(III)-
complexes than their corresponding 2-oximated analogues.13 For
these oximes in solution the chelation can take the form of either
a 5- or 6-membered ring, depending on the complexation condi-
tions. These factors, together with the 2:1 predominance of the
E-isomer of the oxime, which is not capable of a simultaneous che-
lation of the N–O-functionality with the benzylic carbonyl to the
iron, might explain the relatively low target and greenhouse
activity.
2.3. ReplacementofahydroxypyrazolebyanN-hydroxy-imidazole
2.2. Replacement of a cyclohexane-1,3-dione by a 1,2,3-trione-
2-oxime
Reaction of the 1-phenylbutane-1,2,3-trione-2-oximes 5 with
aldehydes and ammonium acetate resulted in a cyclization to the
5-benzoyl-N-hydroxy-imidazoles 814,15 (Scheme 3 and Table 2).
For the various substitution patterns on the imidazole, the
highest activity on the HPPD-enzyme was observed in the sequence
Me = i-Pr > Et > H >> phenyl, 2-4-Cl2-phenyl, thienyl, and 1-methyl-
Chelation of the iron in HPPD by a 1,2,3-trione-2-oxime like 5
could result in a binding motif isosteric to that of 1,3-dicarbonyl-
compounds like 1: (Fig. 6).
O
O
O
O
N
N
N
Cl
N
Cl
Cl
Cl
O
O
O
O
O
O
O
O
OH
OH
OH
N
N+
SO2Me
SO2Me
SO2Me
SO2Me
1
2
1
5
Figure 5. Analogy of 1,3-dicarbonyl- and 2-acylpyridine-N-oxide chelating motifs.
Figure 6. Analogy of 1,3-dicarbonyl and butanetrione-oxime chelating motifs.
O
O
N
N
Cl
O
O
O
Cl
O
Cl
N
O
N+
a
b
N
Cl
SO2Me
SO2Me
SO2Me
3
4
2
Scheme 1. Reagents and conditions: (a) 2-(tributylstannyl)pyridine, THF, 30 °C; (b) MCPBA, CH2Cl2, 40 °C.

4224
M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
O
O
O
O
O
OH
N
O
O
R
R
R
R
c
a
b
Cl
tBuO
O
3
6
7
5
Scheme 2. Reagents and conditions: (a) t-BuO2CCH2COCH3, Mg, MeOH, CCl4, 25 °C; MeCN; (b) p-TsOH, toluene,
D
; (c) n-BuONO, HCl/ether, toluene.
Table 1
O
O
O
OH
N
HO
R'
R'
HPPD-inhibition and herbicidal activity of 5a–d
a
N
R
N
O
OH
N
R
5
8
O
Scheme 3. Reagents and conditions: (a) RCHO, NH4OAc, AcOH.
5a-d
Compound Phenyl-substitution HPPD IC50 ECHCG GR50 SETIT GR50 CENCY GR50
(
l
M)
(kg/ha)
(kg/ha)
(kg/ha)
2-oximes showed some activity on HPPD, but no significant activity
in the greenhouse. Substituted benzoyl-N-hydroxyimidazoles
showed very high activity in the HPPD assay, comparable to or even
better than the activity of the isosteric benzoylpyrazoles. Herbicidal
activity of these compounds in the greenhouse was on an interesting
level, but significantly lower than for the benzoylpyrazoles like 10 or
topramezone.
5a
5b
2-Cl-3-OEt-4-SO2
2-Me-3-OMe-4-
SO2Me
Et
20
>3
>3
>3
>3
>3
>3
>20
5c
5d
2-Me-3-Cl-4-SMe
2-Cl-3-(3-
>20
13
>3
2.5
>3
>3
>3
>3
isoxazolinyl)-4-
SO2Me
GR50: 50% growth reduction 21 days after postemergence spray application at given
concentration in kg/ha.
ECHCG, Echinochloa crus-galli; SETIT, Setaria italica; CENCY, Centaurea cyanus.
4. Experimental
4.1. Materials and methods
2-pyrrolyl. This sequence of target activities corresponds very well
with the SAR of the analogous pyrazole derivatives.
Melting points were recorded on a Büchi 530 apparatus and are
uncorrected. TLC was carried out on precoated silica gel plates (F
254 Merck). 1H and 13C NMR spectra were recorded on a Bruker
DRX 500 spectrometer. Chemical shifts are given in d units (ppm)
relative to the internal standard Me4Si. HR-MS-ESI-spectra were
recorded on a Micromass LCT, and the exact MÀH-mass (M-1) was
determined. Unless stated otherwise, all materials were obtained
from commercial suppliers and used without further purification.
The synthesis of 7a, 7b, and 7c has been described in the liter-
ature.9 The other substituted phenyl butane-1,3-diones have been
prepared from the corresponding substituted benzoic acids10,17,18
The 1-oxo-imidazole analogue 9, which was prepared in a
similar fashion by condensation of the 1-phenylbutane-1,2,3-tri-
one-2-oxime 5a with acetaldoxime,14 gave a slightly weaker target
activity compared to the imidazole analogues 8, and showed no
significant herbicidal effect (Scheme 4).
Next we studied the variation of the phenyl residue, keeping the
methyl-substitution on the hydroxyimidazole as in 8b, which
showed the best herbicidal activity of the series (Table 3).
The highest target activity was identified for 8n, which is clo-
sely related to topramezone, with an IC50 of 3.6 Â 10À8 M. This
activity on the HPPD target is even higher than for the isosteric
dimethyl-hydroxypyrazole 10,16 which is one of the most active
HPPD-inhibitors in the greenhouse in our experience. Again the
SAR was very similar to the sequence found in the topramezone
optimization program, giving much weaker activities for com-
pounds not having a heterocyclic or alkoxy-residue in the 3-posi-
tion of the benzoyl group.
In the greenhouse some herbicidal activity could be observed
even below 100 g/ha for the most active derivatives, but this activ-
ity was still significantly lower than that observed for comparable
hydroxypyrazole-derivatives like 10 or for topramezone. Potential
reasons for this reduced activity could be either unfavorable phys-
icochemical properties of the N-hydroxyimidazoles such as lower
acidity and therefore reduced systemicity compared to the hydrox-
ypyrazoles; or metabolic and/or UV-instability, which has not been
examined so far.
Table 2
HPPD-inhibition and herbicidal activity of 8a–h and 9
O
Cl
HO
N
OEt
R
N
SO2Et
8a-h
Compound R
HPPD IC50 ECHCG GR50 ABUTH GR50 CHEAL GR50
(lM)
(kg/ha)
(kg/ha)
(kg/ha)
8a
8b
8c
8d
8e
8f
H
CH3
CH2CH3
CH(CH3)2
2-Thienyl
20
>0.5
0.5
>0.5
>3
>3
>3
>0.5
0.1
>0.5
>3
>3
>3
0.4
0.05
0.2
1.5
>3
0.048
0.071
0.043
>20
2-(N-Methyl)- >20
>3
pyrrolyl
Phenyl
2,4-Cl2-phenyl >20
0.19
3. Conclusions
8g
8h
9
>20
>0.5
>0.5
>3
>0.5
>0.5
>3
>0.5
>0.5
>3
We could show for the first time that the p-hydroxyphenylpyru-
vate dioxygenase enzyme (HPPD) can be inhibited with iron
chelators, that do not have a 1,3-dicarbonyl substructure. Pyridine-
N-oxides do not show activity on HPPD, so a charged interaction
might be necessary. Substituted 1-phenylbutane-1,2,3-trione-
GR50: 50% growth reduction 21 days after postemergence spray application at given
concentration in kg/ha.
ECHCG, Echinochloa crus-galli; ABUTH, Abutilon theophrasti; CHEAL, Chenopodium
album.

M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
4225
methylene chloride (30 ml), and MCPBA (70%; 1.1 g, 4.4 mmol) was
added at room temperature. The solution was heated 11 h to 35–
40 °C, during which time further MCPBA (2Â 0.2 g) was added.
After cooling to room temperature the suspension was filtered
and washed with methylene chloride, the organic phase was
washed with saturated NaHSO3 and NaHCO3 solutions and water,
dried with sodium sulphate and evaporated. The residue was
chromatographed on silica with a methylene chloride/methanol
gradient to give [2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-meth-
anesulfonyl-phenyl]-(1-oxy-pyridin-2-yl)-methanone 2 (0.4 g, 48%)
as a colorless oil.
Cl
Cl
O
O
O
OH
N
HO
N
N+
O
a
OEt
OEt
SO2Et
SO2Et
5a
9
Scheme 4. Reagents and conditions: (a) CH3CHNOH, NH4OAc, AcOH.
Table 3
HPPD-inhibition and herbicidal activity of 8b, 8i–n and 10
1H NMR (CDCl3): d 4.23 (s, 3H); 3.42 (t, 2H); 4.48 (t, 2H); 7.47
(m, 2H); 7.78 (d, 1H); 7.84 (q, 1H); 8.10 (d, 1H); 8.18 (d, 1H).
HR-MS (MÀH): 379.0193 (calc. for C16H12ClN2O5: 379.0155).
O
O
N
O
Cl
HO
N
R
HO
N
N
N
4.4. 1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-
1,2,3-trione-2-oxime (5a)
SO2Me
8i-n
10
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,3-dione
(7.6 g, 23 mmol) was dissolved in toluene (100 ml), HCl–saturated
diethyl ether (19 ml) was added at À15 °C to À10 °C, and n-buty-
lnitrite (3.5 g, 34 mmol) in 60 ml diethyl ether was added. After
16 h at room temperature the solution was added to ice water
(200 ml) and extracted 3Â with 10% NaOH. The aqueous phase
was than acidified to pH 4 with 10% sulfuric acid and extracted
3Â with ethyl acetate. This organic phase was dried with sodium
sulfate and evaporated to give 1-(2-chloro-4-ethanesulfonyl-3-
ethoxy-phenyl)-butane-1,2,3-trione-2-oxime 5a (7.2 g; 87%) in a
ca. 3:2 E/Z isomeric mixture as a colorless oil.
Compound Phenyl-substitution HPPD
IC50
ECHCG GR50 ABUTH GR50 CHEAL GR50
(l
M) (kg/ha)
(kg/ha)
(kg/ha)
8b
8i
2-Cl-3-OEt-4-SO2Et 0.048
0.5
>1
0.1
0.7
0.05
0.06
2-Me-3-OMe-4-
SO2Me
18
8j
8k
8l
2-Me-3-Cl-4-SMe
2- Cl-4-SO2Me
8-SO2Me-5-
quinolinoyl
>20
>20
>20
>0.5
>0.5
>1
>0.5
>0.5
>1
>0.5
>0.5
>1
8m
8n
2,4,6-trimethyl
2-Cl-3-(3-
>20
0.036
>3
2
>3
>3
>3
0.3
isoxazolinyl)-4-
SO2Me
1H NMR (CDCl3, major isomer): d 1.22 (t, 3H); 1.50 (t, 3H); 2.48
(s, 3H); 3.47 (q, 2H); 4.32 (q, 2H); 7.61 (d, 1H); 7.95 (d, 1H).
13C NMR (CDCl3): d 7.0, 15.2, 25.9, 49.4, 72.0, 125.9, 128.7,
129.3, 137.3, 140.4, 154.5, 155.3, 189.4, 195.0.
10
0.19
<0.01
<0.01
<0.01
GR50: 50% growth reduction 21 days after postemergence spray application at given
concentration in kg/ha.
ECHCG, Echinochloa crus-galli; ABUTH, Abutilon theophrasti; CHEAL, Chenopodium
album.
HR-MS (MÀH): 360.0335 (calc. for C14H17ClNO6S: 360.0309).
4.5. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
5-methyl-3H-imidazol-4-yl)-methanone (8a)
according to this literature, and were used crude without further
purification.
The HPPD assay was performed with recombinant Arabidopsis
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.8 g, 2.2 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.25 g, 3.2 mmol) and paraformalde-
hyde (0.10 g, 3.3 mmol) were added, and the solution was stirred
at room temperature for 16 h. The solvents were evaporated, and
the residue was redissolved with MTBE and 5% NaOH and
extracted. The aqueous phase was acidified with concentrated
HCl, and extracted with ethyl acetate, the organic phase dried with
sodium sulphate and evaporated. The residue was chromato-
graphed on silica with a methylene chloride/methanol gradient,
resulting in (2-chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hy-
droxy-5-methyl-3H-imidazol-4-yl)-methanone 8a (0.60 g, 73%) as
colorless crystals.
thaliana enzyme as described by Grossmann et al.1
4.2. [2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-
phenyl]-pyridin-2-yl-methanone (4)
2-Tributylstannylpyridine (1.8 g, 5.0 mmol) was dissolved in
40 ml THF and 2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methane-
sulfonyl-benzoyl chloride 3 (1.6 g, 5.0 mmol) was added under
cooling with an ice bath (internal temperature <30 °C). After the
addition the solution was stirred for 14 h at room temperature.
The solvents were evaporated, and the residue was triturated with
n-hexane, dissolved with ethyl acetate (70 ml), and washed with
saturated NaHCO3 solution and water. The organic phase was dried
with sodium sulphate and the solvents were evaporated, resulting
in [2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-phe-
nyl]-pyridin-2-yl-methanone 4 (1.25 g, 69%) as a colorless oil that
still contained ca. 10% stannane-impurities and was used without
further purification.
Mp 155 °C (dec.).
1H NMR (CDCl3): d 1.27 (t, 3H); 1.52 (t, 3H); 1.98 (s, 3H); 3.47 (q,
2H); 4.30 (q, 2H); 7.29 (d, 1H); 7.95 (d, 1H); 9.05 (s, 1H).
13C NMR (CDCl3): d 7.2, 15.1, 15.3, 49.4, 72.1, 123.0, 123.7,
126.9, 129.5, 133.7, 135.6, 144.3, 144.4, 154.4, 183.7.
HR-MS (MÀH): 371.0500 (calc. for C15H16ClN2O5S: 371.0468).
1H NMR (CDCl3): d 3.27 (s, 3H); 3.42 (t, 2H); 4.50 (t, 2H); 7.57 (m,
1H); 7.69 (d, 1H); 7.94 (t, 1H); 8.18 (d, 1H); 8.28 (d, 1H); 8.65 (d, 1H).
HR-MS (MÀH): 363.0244 (calc. for C16H12ClN2O4: 363.0206).
4.6. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
2,5-dimethyl-3H-imidazol-4-yl)-methanone (8b)
4.3. [2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-
phenyl]-(1-oxy-pyridin-2-yl)-methanone (2)
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (1.3 g, 3.3 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.35 g, 4.5 mmol) and acetaldehyde
(0.15 g, 3.4 mmol) were added, and the solution was stirred at
room temperature for 16 h. The solvents were evaporated, and
[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-phe-
nyl]-pyridin-2-yl-methanone 4 (0.80 g, 2.2 mmol) was dissolved in

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M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
the residue was redissolved with MTBE and 5% NaOH and ex-
tracted. The aqueous phase was acidified with concentrated HCl,
and extracted with ethyl acetate, the organic phase dried with
sodium sulphate and evaporated. The residue was chromato-
graphed on silica with a methylene chloride/methanol gradient,
resulting in [2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesul-
fonyl-phenyl]-(3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-metha-
none 8b (0.70 g, 55%) as colorless crystals.
carbaldehyde (0.30 g, 2.7 mmol) were added, and the solution
was stirred at room temperature for 16 h. The solvents were evap-
orated, and the residue was chromatographed on silica with a
cyclohexane/ethyl acetate gradient, resulting in (2-chloro-4-etha-
nesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-5-methyl-2-thiophen-2-
yl-3H-imidazol-4-yl)-methanone 8e (0.60 g, 94%) as colorless
crystals.
Mp 150–155 °C.
Mp 110–115 °C.
1H NMR (CDCl3): d 1.26 (t, 3H); 1.53 (t, 3H); 2.03 (s, 3H); 3.48 (q,
2H); 4.32 (q, 2H); 7.4-7.5 (m, 3H); 7.50 (d, 1H); 7.99 (d, 1H).
13C NMR (CDCl3): d 7.2, 15.2, 15.8, 49.3, 71.7, 123.1, 124.6,
126.8, 126.8, 127.0, 128.2, 128.7, 129.1, 134.8, 140.6, 145.7,
145.9, 181.0.
1H NMR (CDCl3): d 1.25 (t, 3H); 1.52 (t, 3H); 1.93 (s, 3H); 2.44
(s, 3H); 3.48 (q, 2H); 4.32 (q, 2H); 7.40 (d, 1H); 7.90 (d, 1H).
13C NMR (CDCl3): d 7.2, 10.7, 14.7, 15.3, 49.4, 72.1, 122.1, 123.0,
127.0, 129.5, 135.8, 142.4, 143.9, 144.3, 154.5, 183.2.
HR-MS (MÀH): 387.0786 (calc. for C16H18ClN2O5S: 387.0781).
HR-MS (MÀH): 453.0333 (calc. for C19H18ClN2O5S2: 453.0346).
4.7. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(2-ethyl-3-
hydroxy-5-methy-3H-imidazol-4-yl)-methanone (8c)
4.10. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-[3-hydroxy-
5-methyl-2-(1-methyl-1H-pyrrol-2-yl)-3H-imidazol-4-yl]-metha-
none (8f)
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.5 g, 1.4 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.16 g, 2.1 mmol) and propionalde-
hyde (0.12 g, 2.1 mmol) were added, and the solution was stirred
at room temperature for 16 h. The solvents were evaporated, and
the residue was redissolved with MTBE and 5% NaOH and ex-
tracted. The aqueous phase was acidified with concentrated HCl,
and extracted with ethyl acetate, the organic phase dried with so-
dium sulphate and evaporated. The residue was chromatographed
on silica with a methylene chloride/methanol gradient, resulting
in [(2-chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(2-ethyl-3-hydro-
xy-5-methy-3H-imidazol-4-yl)-methanone 8c (0.50 g, 89%) as col-
orless crystals.
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.50 g, 1.4 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.20 g, 2.6 mmol) and 1-methyl-1H-
pyrrol-2-carbaldehyde (0.23 g, 2.1 mmol) were added, and the solu-
tion was stirred at room temperature for 16 h. The solvents were
evaporated, and the residue was chromatographed on silica with a
cyclohexane/ethyl acetate gradient, resulting in (2-chloro-4-etha-
nesulfonyl-3-ethoxy-phenyl)-[3-hydroxy-5-methyl-2-(1-methyl-1H-
pyrrol-2-yl)-3H-imidazol-4-yl]-methanone 8f (0.35 g, 56%) as
colorless crystals.
Mp. 85 °C (dec.).
1H NMR (CDCl3): d 1.23 (t, 3H); 1.52 (t, 3H); 1.88 (s, 3H); 3.48
(q, 2H); 4.03 (s, 3H); 4.37 (q, 2H); 6.78 (s, 1H); 6.82 (s, 1H); 7.18
(s, 1H); 7.32 (d, 1H); 8.03 (d, 1H).
Mp 105–108 °C.
1H NMR (CDCl3): d 1.24 (t, 3H); 1.30 (t, 3H); 1.51 (d, 6H); 2.45 (q,
1H); 2.76 (s, 3H); 3.48 (q, 2H); 4.35 (q, 2H); 7.28 (d, 1H); 7.88 (d, 1H).
13C NMR (CDCl3): d 7.2, 10.9, 15.1, 15.3, 19.3, 49.4, 71.9, 121.5,
123.0, 126.9, 129.3, 135.1, 142.0, 144.2, 145.4, 154.3, 182.0.
HR-MS (MÀH): 399.0809 (calc. for C16H18ClN2O5S: 399.0781).
13C NMR (CDCl3): d 7.3, 15.2, 15.8, 37.2, 49.4, 72.1, 109.0, 115.4,
118.9, 120.7, 123.1, 127.1, 127.8, 129.5, 135.6, 137.9, 143.9, 147.8,
54.5, 182.7.
HR-MS (MÀH): 450.0925 (calc. for C20H21ClN3O5S: 450.0890).
4.8. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
2-isopropyl-5-methyl-3H-imidazol-4-yl)-methanone (8d)
4.11. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
5-methyl-2-phenyl-3H-imidazol-4-yl)-methanone (8g)
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (1.0 g, 2.8 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.21 g, 2.8 mmol) and isobutyralde-
hyde (0.20 g, 2.8 mmol) were added, and the solution was stirred
at room temperature for 30 h. The solvents were evaporated, and
the residue was redissolved with MTBE and 5% NaOH and ex-
tracted. The aqueous phase was acidified with concentrated HCl,
and extracted with ethyl acetate, the organic phase dried with so-
dium sulphate and evaporated. The residue was chromatographed
on silica with a methylene chloride/methanol gradient, resulting
in (2-chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-2-iso-
propyl-5-methyl-3H-imidazol-4-yl)-methanone 8d (0.85 g, 74%)
as a colorless oil.
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.5 g, 1.4 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.12 g, 1.6 mmol) and benzaldehyde
(0.16 g, 1.5 mmol) were added, and the solution was stirred at room
temperature for 16 h. As the reaction was not complete by TLC
further ammonium acetate (0.12 g, 1.6 mmol) and benzaldehyde
(0.20 g, 1.89 mmol)wereadded, and thesolutionwasstirredat room
temperature for another 64 h. The solvents were evaporated, and the
residue was chromatographed on silica with a cyclohexane/ethyl
acetate gradient, resulting in (2-chloro-4-ethanesulfonyl-3-ethoxy-
phenyl)-(3-hydroxy-5-methyl-2-phenyl-3H-imidazol-4-yl)-metha-
none 8g (0.50 g, 80%) as colorless crystals.
Mp 135–140 °C.
1H NMR (CDCl3): d 1.24 (t, 3H); 1.35 (t, 3H); 1.50 (t, 3H); 2.66 (s,
3H); 2.80 (q, 2H); 3.48 (q, 2H); 4.35 (q, 2H); 7.28 (d, 1H); 7.88 (d, 1H).
13C NMR (CDCl3): d 7.1, 15.2, 15.4, 19.9 (2C), 21.3, 49.5, 72.3,
121.3, 125.0, 128.1, 128.4, 137.3, 140.7, 144.2, 145.4, 150.7, 179.2.
HR-MS (MÀH): 413.0924 (calc. for C18H22N2O5SCl: 413.0938).
1HNMR(CDCl3): d1.27 (t, 3H); 1.56 (t, 3H); 1.91 (s, 3H); 3.50 (q, 2H);
4.37 (q, 2H); 7.29 (d, 2H); 7.4-7.5 (m, 3H); 8.02 (d, 1H); 8.23 (dd, 2H).
13C NMR (CDCl3): d 7.3, 15.3, 15.6, 49.4, 72.2, 121.9, 123.0,
126.6, 127.0, 128.3 (2C); 128.7 (2C); 129.6, 130.7, 135.9, 142.3,
143.6, 147.8, 154.6, 183.9.
HR-MS (MÀH): 447.0824 (calc. for C21H20ClN2O5S: 447.0781).
4.9. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
5-methyl-2-thiophen-2-yl-3H-imidazol-4-yl)-methanone (8e)
4.12. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-[2-(2,4-dichloro-
phenyl)-3-hydroxy-5-methyl-3H-imidazol-4-yl]-methanone (8h)
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.5 g, 1.4 mmol) was dissolved in acetic acid
(20 ml), ammonium acetate (0.20 g, 2.6 mmol) and thiophene-2-
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (0.5 g, 1.4 mmol) was dissolved in acetic acid

M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
4227
(20 ml), ammonium acetate (0.20 g, 2.6 mmol) and 2,4-dichloro-
benzaldehyde (0.41 g, 2.7 mmol) were added, and the solution
was stirred at room temperature for 16 h. The solvents were evap-
orated, and the residue was chromatographed on silica with a
cyclohexane/ethyl acetate gradient, resulting in (2-chloro-4-etha-
nesulfonyl-3-ethoxy-phenyl)-[2-(2,4-dichloro-phenyl)-3-hydroxy-
5-methyl-3H-imidazol-4-yl]-methanone 8h (0.44 g, 61%) as
colorless crystals.
was dissolved in toluene (250 ml), and p-toluensulfonicacid
(2.0 g, 12 mmol) was added. The solution was heated for 5 h under
reflux, cooled, extracted with water, dried with sodium sulphate
and evaporated to give 1-[2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-
4-methanesulfonyl-phenyl]-butane-1,3-dione 7d (9.5 g, 77%) as
colorless crystals.
Mp: 130–132 °C.
1H NMR (enol-tautomer, CDCl3): d 2.22 (s, 3H); 3.22 (s, 3H); 3.47
(t, 2H); 4.63 (t, 2H); 7.78 (d, 1H); 8.13 (d, 1H); 15.5 (OH, 1H).
13C NMR (enol-tautomer, CDCl3): d 25.3, 39.1, 45.6, 70.0, 102.0,
128.2, 130.6, 131.1, 133.0, 141.5, 143.2, 155.5, 183.4, 192.9.
HR-MS (MÀH): 342.0217 (calc. for C14H13ClNO5S: 342.0203).
Mp 158–160 °C.
1H NMR (CDCl3): d 1.28 (t, 3H); 1.55 (t, 3H); 1.90 (s, 3H); 3.48
(q, 2H); 4.35 (q, 2H); 7.30 (d, 1H); 7.38 (d, 1H); 7.49 (d, 1H); 7.52
(s, 1H); 8.03 (d, 1H).
13C NMR (CDCl3): d 7.2, 15.3, 15.5, 49.4, 72.2, 122.1, 123.0,
124.6, 127.0, 128.5, 129.6, 130.2, 132.6, 135.0, 136.0, 137.4,
140.5, 143.7, 146.7, 154.6, 184.3.
4.16. 1-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesul-
fonyl-phenyl]-butane-1,2,3-trione-2-oxime (5d)
HR-MS (MÀH): 515.0032 (calc. for C21H18Cl3N2O5S: 515.0002).
1-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-
phenyl]-butane-1,3-dione 7d (9.8 g, 28 mmol) was dissolved in tol-
uene (100 ml), HCl–saturated diethyl ether (23 ml) was added at
À15 °C to À10 °C andn-butylnitrite(4.4 g, 43 mmol) in60 mldiethyl
ether was added. After 16 h at room temperature further n-butylni-
trite (1.5 g, 14 mmol) was added, and stirring was continued for 2 h.
The solution was than added to 400 ml ice water and extracted 3Â
with 10% NaOH. The aqueous phase was acidified to pH 4 with 10%
sulfuric acid and extracted 3Â with ethyl acetate. This organic phase
was dried with sodium sulfate and evaporated. The residue was
chromatographed on silica with a cyclohexane/ethyl acetate gradi-
ent, to give 1-[2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methane-
sulfonyl-phenyl]-butane-1,2,3-trione-2-oxime 5d (3.9 g; 36%) in a
ca. 2:1 E/Z isomeric mixture as a colorless oil.
4.13. (2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-(3-hydroxy-
2,5-dimethyl-1-oxy-3H-imidazol-4-yl)-methanone (9)
1-(2-Chloro-4-ethanesulfonyl-3-ethoxy-phenyl)-butane-1,2,3-
trione-2-oxime 5a (1.0 g, 2.8 mmol) was dissolved in methanol
(20 ml), acetaldoxime (0.33 g, 9.5 mmol) and concentrated aque-
ous HCl (1.0 ml) were added, and the solution was stirred at room
temperature for 60 h. As the reaction was not complete by TLC, fur-
ther acetaldoxime (0.10 g, 1.7 mmol) was added, and the solution
was refluxed for 3 h. After cooling Na2CO3 (0.30 g) was added,
the suspension was filtered, the solvents were evaporated, and
the residue was chromatographed on silica with a methylene
chloride/methanol gradient, resulting in (2-chloro-4-ethanesulfo-
nyl-3-ethoxy-phenyl)-(3-hydroxy-2,5-dimethyl-1-oxy-3H-imidazol-
4-yl)-methanone 9 (0.70 g, 62%) as a colorless oil.
1H NMR (CDCl3, major isomer): d 2.45 (s, 3H); 3.20 (s, 3H); 3.40
(t, 2H); 4.58 (t, 2H); 7.95 (d, 1H); 8.18 (d, 1H); 9.4 (br s, 1H).
HR-MS (MÀH): 371.0118 (calc. for C14H12ClN2O6S: 371.0105).
1H NMR (CDCl3): d 1.24 (t, 3H); 1.55 (t, 3H); 2.4 (br, 6H); 3.47
(q, 2H); 4.35 (q, 2H); 7.41 (d, 1H); 7.99 (d, 1H).
13C NMR (CDCl3): d 7.3, 9.1, 9.3, 15.3, 49.5, 72.2, 124.5, 124.6,
127.1, 129.5, 134.7, 136.1, 144.6, 144.9, 154.0, 181.1.
4.17. [2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfo-
nyl-phenyl]-(3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-metha-
none (8n)
HR-MS (MÀH): 401.0574 (calc. for C16H18ClN2O6S: 401.0574).
4.14. 2-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesul-
fonyl-benzoyl]-3-oxo-butyric acid tert-butylester (6d)
1-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-
phenyl]-butane-1,2,3-trione-2-oxime 5d (1.0 g, 2.68 mmol) was
dissolved in acetic acid (20 ml), ammonium acetate (0.2 g,
2.68 mmol) and acetaldehyde (0.12 g, 2.73 mmol) were added,
and the solution was stirred at room temperature for 16 h. The sol-
vents were evaporated, and the residue was redissolved with MTBE
and 5% NaOH and extracted. The aqueous phase was acidified with
concentrated HCl and extracted with ethyl acetate, and the organic
phase dried with sodium sulphate and evaporated, resulting in [2-
chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-phenyl]-
(3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-methanone 8n (0.9 g,
84%) as a colorless oil.
Mg-turnings (1.0 g, 42 mmol) were suspended in methanol
(100 ml) and tert-butyl-acetoacetate (5.2 g, 33 mmol) was added.
Under cooling to 20–25 °C carbon tetrachloride (6 ml) was added.
After 3 h at room temperature, the suspension was evaporated,
the residue was dissolved in acetonitrile (70 ml), and 2-chloro-3-
(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-benzoylchloride 3
(11 g, 33 mmol) in acetonitrile (30 ml) was added dropwise. After
stirring for 16 h, 3% aqueous HCl (100 ml) was added. This mixture
was extracted with ethyl acetate and the organic phase was evap-
orated to give 2-[2-chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-meth-
anesulfonyl-benzoyl]-3-oxo-butyric acid tert-butylester 6d (16 g,
86%) as colorless crystals.
1H NMR (CDCl3): d 1.82 (s, 3H); 2.45 (s, 3H); 3.26 (s, 3H); 3.43 (t,
2H); 4.62 (t, 2H); 7.62 (d, 1H); 8.21 (d, 1H).
HR-MS (MÀH): 396.0449 (calc. for C16H15ClN3O5S: 396.0419).
Mp 129–130 °C.
1H NMR (enol-tautomer, CDCl3):d 1.13 (s, 9H); 2.58 (s, 3H); 3.22(s,
3H);3.42(t,2H);4.63(t, 2H);7.56(d, 1H);8.15(d, 1H), 15.0(enol,1H).
13C NMR (enol-tautomer, CDCl3): d 23.0, 25.4, 27.5 (3C); 39.0,
45.7, 69.9, 81.8, 128.2, 129.1, 130.4, 131.9, 142.3, 144.2, 155.2,
164.2, 189.9, 197.7.
4.18. 1-(2-Chloro-4-methanesulfonyl-phenyl)-butane-1,2,3-tri-
one-2-oxime
1-(2-Chloro-4-methanesulfonyl-phenyl)-butane-1,3-dione (10 g,
36 mmol) was dissolved in toluene (100 ml), HCl–saturated diethyl
ether (10 ml) was added at À15 °C to À10 °C and n-butylnitrite
(6.0 g, 55 mmol) in diethyl ether (20 ml) was added. After 16 h at
room temperature, the solution was added to ice water (200 ml)
and extracted 3Â with 10% NaOH. The aqueous phase was acidified
to pH 2.3 with 10% sulfuric acid and extracted 3Â with ethyl
acetate. This organic phase was dried with sodium sulfate and
evaporated. The residue was chromatographed on silica with a
HR-MS (MÀH): 442.0706 (calc. for C19H21ClNO7S: 442.0727).
4.15. 1-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesul-
fonyl-phenyl]-butane-1,3-dione (7d)
2-[2-Chloro-3-(4,5-dihydro-isoxazol-3-yl)-4-methanesulfonyl-
benzoyl]-3-oxo-butyric acid tert-butylester 6d (16 g, 36 mmol)

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M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
methylene chloride/methanol gradient, to give 1-(2-chloro-4-meth-
anesulfonyl-phenyl)-butane-1,2,3-trione-2-oxime (5.8 g; 36%) as a
colorless oil, that was used without further purification.
4.22. 1-(3-Chloro-2-methyl-4-methylsulfanyl-phenyl)-butane-
1,2,3-trione-2-oxime (5c)
1-(3-Chloro-2-methyl-4-methylsulfanyl-phenyl)-butane-1,3-
dione (5.0 g, 19 mmol) was dissolved in toluene (80 ml), HCl–satu-
rated diethyl ether (15 ml) was added at À15 °C to À10 °C and
n-butylnitrite (3.0 g, 29 mmol) in diethyl ether (20 ml) was added.
After 16 h at room temperature the solution was added to ice
water (250 ml) and extracted 3Â with 10% NaOH. The aqueous
phase was acidified to pH 3 with 10% sulfuric acid and extracted
3Â with ethyl acetate. This organic phase was dried with sodium
sulfate and evaporated. The residue was chromatographed on silica
with a methylene chloride/methanol gradient to give 1-(3-chloro-
2-methyl-4-methylsulfanyl-phenyl)-butane-1,2,3-trione-2-oxime 5c
(2.5 g; 46%) in a ca. 2:1 E/Z isomeric mixture as colorless crystals.
Mp: 150–151 °C.
4.19. (2-Chloro-4-methanesulfonyl-phenyl)-(3-hydroxy-2,5-
dimethyl-3H-imidazol-4-yl)-methanone (8k)
1-(2-Chloro-4-methanesulfonyl-phenyl)-butane-1,2,3-trione-
2-oxime (0.5 g, 1.6 mmol) was dissolved in acetic acid (20 ml),
ammonium acetate (0.19 g, 2.5 mmol) and acetaldehyde (0.10 g,
2.3 mmol) were added, and the solution was stirred at room tem-
perature for 62 h. The solvents were evaporated, and the residue
chromatographed on silica with a methylene chloride/methanol
gradient to give (2-chloro-4-methanesulfonyl-phenyl)-(3-hydro-
xy-2,5-dimethyl-3H-imidazol-4-yl)-methanone 8k (0.47 g, 89%)
as colorless crystals.
1H NMR (CDCl3, major isomer): d 2.47 (s, 3H); 2,48 (s, 3H); 2.74
(s, 3H); 7.01 (d, 1H); 7.32 (d, 1H).
Mp: 175–180 °C.
1H NMR (CDCl3): d 2.31 (s, 3H); 2.66 (s, 3H); 3.20 (s, 3H); 7.60
(d, 1H); 8.00 (s, 1H); 8.39 (d, 1H).
13C NMR (CDCl3, major isomer): d 17.2, 15.1, 25.9, 120.9, 130.1,
131.0, 133.2, 138.3, 146.5, 157.0, 191.9, 195.1.
13C NMR (CDCl3): d 11.5, 15.1, 44.0, 122.6, 126.0, 128.7, 129.9,
132.0, 137.4, 143.1, 143.3, 146.2, 181.4.
HR-MS (MÀH): 284.0127 (calc. for C12H11ClNO3S: 284.0148).
HR-MS (MÀH): 327.0236 (calc. for C13H12ClN2O4S: 327.0206).
4.23. (3-Chloro-2-methyl-4-methylsulfanyl-phenyl)-(3-hydroxy-
2,5-dimethyl-3H-imidazol-4-yl)-methanone (8j)
4.20. 1-(4-Methanesulfonyl-3-methoxy-2-methyl-phenyl)-butane-1,
2,3-trione-2-oxime (5b)
1-(3-Chloro-2-methyl-4-methylsulfanyl-phenyl)-butane-1,2,3-
trione-2-oxime 5c (0.70 g, 1.9 mmol) was dissolved in acetic acid
(15 ml), ammonium acetate (0.20 g, 2.6 mmol) and acetaldehyde
(0.12 g, 2.6 mmol) were added, and the solution was stirred at
room temperature for 16 h. The solvents were evaporated, and
the residue chromatographed on silica with a methylene chlo-
ride/methanol gradient to give (3-chloro-2-methyl-4-methylsulfa-
nyl-phenyl)-(3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-methanone
8j (0.74 g, 97%) as colorless crystals.
1-(4-Methanesulfonyl-3-methoxy-2-methyl-phenyl)-butane-1,3-
dione (5.0 g, 18 mmol) was dissolved in toluene (80 ml), HCl–satu-
rated diethyl ether (12 ml) was added at À15 °C to À10 °C and
n-butylnitrite (2.7 g, 26 mmol) in diethyl ether (20 ml) was added.
After 16 h at room temperature the solution was added to ice
water (250 ml) and extracted 3Â with 10% NaOH. The aqueous
phase was acidified to pH 3 with 10% sulfuric acid and extracted
3Â with ethyl acetate. This organic phase was dried with sodium
sulfate and evaporated. The residue was chromatographed on silica
with a methylene chloride/methanol gradient, to give 1-(4-meth-
anesulfonyl-3-methoxy-2-methyl-phenyl)-butane-1,2,3-trione-
2-oxime 5b.
Mp: 118 °C (dec.).
1H NMR (CDCl3): d 1.78 (s, 3H); 2.32 (s, 6H); 2.48 (s, 3H); 6.97
(d, 1H); 7.13 (d, 1H).
13C NMR (CDCl3): d 10.1, 15.2, 16.0, 17.1, 121.6, 123.2, 126.0,
132.3, 134.4, 135.4, 142.3 (2C); 145.4, 187.6.
(1.9 g; 34%) in a ca. 2:1 E/Z isomeric mixture as colorless
crystals.
HR-MS (MÀH): 309.0468 (calc. for C14H14ClN2O2S: 309.0465).
Mp: 145–147 °C.
4.24. 1-(8-Methanesulfonyl-quinolin-5-yl)-butane-1,2,3-trione-
2-oxime
1H NMR (CDCl3, major isomer): d 2.49 (s, 3H); 2.54 (s, 3H), 3.26
(s, 3H); 3.97 (s, 3H); 7.38 (d, 1H); 7.86 (d, 1H).
13C NMR (CDCl3, major isomer): 13.1, 25.8, 43.4, 62.8, 126.0,
126.5, 134.9, 137.5, 140.9, 155.9, 157.4, 194.4, 195.7.
HR-MS (MÀH): 312.0508 (calc. for C13H14NO6S: 312.0542).
1-(8-Methanesulfonyl-quinolin-5-yl)-butane-1,3-dione (5.0 g,
17 mmol) was dissolved in toluene (80 ml), HCl–saturated diethyl
ether (12 ml) was added at À15 °C to À10 °C and n-butylnitrite
(2.7 g, 26 mmol) in diethyl ether (20 ml) was added. After 16 h at
room temperature the solution was added to ice water (250 ml)
and extracted 3Â with 10% NaOH. The aqueous phase was acidified
to pH 3 with 10% sulfuric acid and extracted 3Â with ethyl acetate.
This organic phase was dried with sodium sulfate and evaporated
to give 1-(8-methanesulfonyl-quinolin-5-yl)-butane-1,2,3-trione-
2-oxime (3.5 g) as an oil, which was used in the next step without
further purification.
4.21. (4-Methanesulfonyl-3-methoxy-2-methyl-phenyl)-(3-
hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-methanone (8i)
1-(4-methanesulfonyl-3-methoxy-2-methyl-phenyl)-butane-
1,2,3-trione-2-oxime 5b (0.60 g, 1.9 mmol) was dissolved in acetic
acid (15 ml), ammonium acetate (0.15 g, 1.9 mmol) and acetalde-
hyde (0.10 g, 2.3 mmol) were added, and the solution was stirred
at room temperature for 62 h. The solvents were evaporated, and
the residue chromatographed on silica with a methylene chlo-
ride/methanol gradient to give (4-methanesulfonyl-3-methoxy-2-
methyl-phenyl)-(3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-metha-
none 8i (0.40 g, 62%) as colorless crystals.
4.25. (3-Hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-(8-methane-
sulfonyl-quinolin-5-yl)-methanone (8l)
1-(8-Methanesulfonyl-quinolin-5-yl)-butane-1,2,3-trione-2-oxime
(1.0 g, 3.1 mmol) was dissolved in acetic acid (20 ml), ammonium
acetate (0.24 g, 3.1 mmol) and acetaldehyde (0.10 g, 2.3 mmol)
were added, and the solution was stirred at room temperature
for 16 h. The solvents were evaporated, and the residue chromato-
graphed on silica with a methylene chloride/methanol gradient
to give (3-hydroxy-2,5-dimethyl-3H-imidazol-4-yl)-(8-methane-
Mp: 150–153 °C.
1H NMR (CDCl3): d 1.88 (s, 3H); 2.31 (s, 3H); 2.38 (s, 3H); 3.27
(s, 3H); 3.98 (s, 3H); 7.22 (d, 1H); 7.87 (d, 1H).
13C NMR (CDCl3): d 11.2, 12.7, 15.7, 43.5, 62.6, 122.5, 124.0,
127.0, 131.1 135.5, 144.0, 144.8, 146.8, 157.1, 185.3.
HR-MS (MÀH): 337.0854 (calc. for C15H17N2O5S: 337.0858).

M. Witschel / Bioorg. Med. Chem. 17 (2009) 4221–4229
4229
sulfonyl-quinolin-5-yl)-methanone 8l (0.62 g, 58%) as colorless
crystals.
1H NMR (CDCl3): d 1.67 (s, 3H); 2.18 (s, 6H); 2.32 (s, 3H); 2.42
(s, 3H); 6.91 (s, 2H).
Mp: >210 °C.
13C NMR (CDCl3): d 11.0, 14.6, 18.9 (2C), 21.2, 122.1, 128.7 (2C);
133.7 (2C); 135.3, 139.5, 141.5, 145.9, 191.6.
1H NMR (CDCl3): d 1.97, (s, 3H); 2.39 (s, 3H); 3.67 (s, 3H); 7.64
(q, 1H); 7.80 (d, 1H); 8.48 (d, 1H); 8.56 (d, 1H); 9.17 (d, 1H).
13C NMR (CDCl3): d 11.4, 16.1, 44.3, 123.0, 125.1, 125.2, 125.3,
130.1, 134.3, 139.0, 143.4, 144.0, 145.0, 145.2, 151.7, 183.4.
HR-MS (MÀH): 344.0703 (calc. for C16H14N3O4S: 344.0705).
HR-MS (MÀH): 257.1271 (calc. for C15H19N2O2: 257.1290).
Acknowledgments
The author thanks Dr. Thomas Ehrhardt, Peter Seiler, Dr. Ricarda
Niggeweg and Yvonne Wunder for measurement of the enzymatic
activity, and Sandra Schläger and Manfred Schmidt for technical
assistance in the laboratory.
4.26. 1-(2,4,6-Trimethyl-phenyl)-butane-1,2,3-trione-2-oxime
1-(2,4,6-Trimethyl-phenyl)-butane-1,3-dione (5.0 g, 25 mmol)
was dissolved in toluene (50 ml), HCl–saturated diethyl ether
(10 ml) was added at À15 °C to À10 °C and n-butylnitrite (4.0 g,
37 mmol) in diethyl ether (10 ml) was added. After 16 h at room
temperature the solution was added to ice water (200 ml) and ex-
tracted 3Â with 10% NaOH. The aqueous phase was acidified to pH
4 with 10% sulfuric acid and extracted 3Â with ethyl acetate. This or-
ganic phase was dried with sodium sulfate and evaporated to give
1-(2,4,6-trimethyl-phenyl)-butane-1,2,3-trione 2-oxime (2.2 g) as
a colorless oil, that was used in the next step without further
purification.
References and notes
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1-(2,4,6-Trimethyl-phenyl)-butane-1,2,3-trione-2-oxime (0.50 g,
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