Regiospecific and highly flexible synthesis of 1,4,5-trisubstituted 2-sulfanylimidazoles from structurally diverse ethanone precursors

Article abstract of DOI:10.1055/s-2007-1000852

Imidazoles represent important bioactive scaffolds in medicinal chemistry. More than 2,500 structures are listed in drug discovery databases and over 3,000 patents have been claimed for imidazole-based structures. Recent imidazole pharmacophores have targ

Full text of DOI:10.1055/s-2007-1000852

PAPER
253
Regiospecific and Highly Flexible Synthesis of 1,4,5-Trisubstituted
2-Sulfanylimidazoles from Structurally Diverse Ethanone Precursors
H
ighly Substit
t
uted Py
e
r
idinylimid
f
azole-B
a
ase
d
p38 M
n
A
P
K
inase Inhibito
A
rs . Laufer,* Dominik R. J. Hauser, Andy J. Liedtke
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen,
Auf der Morgenstelle 8, 72076 Tübingen, Germany
Fax +49(7071)295037; E-mail: stefan.laufer@uni-tuebingen.de; E-mail: dominik.hauser@uni-tuebingen.de
E-mail: andy.liedtke@uni-tuebingen.de
Received 4 October 2007; revised 16 October 2007
base Integrity (Prous Science3), an integrated drug discov-
ery portal that is structure and sequence searchable. From
these, 165 compounds have been advanced to preclinical
development or clinical studies. In particular 18 imidazole
Abstract: Imidazoles represent important bioactive scaffolds in
medicinal chemistry. More than 2,500 structures are listed in drug
discovery databases and over 3,000 patents have been claimed for
imidazole-based structures. Recent imidazole pharmacophores
have targeted various MAP kinases. p38 Mitogen-activated protein derivatives have reached phase I and 12 compounds have
(MAP) kinase plays a central role in the signaling network respon-
sible for the upregulation of proinflammatory cytokines like IL-1b
and TNFa and offers, therefore, a valid target for small molecule
SB203580,4 SB242235,4 L-7900704 and RWJ676574
anti-inflammatory drugs. 2-Sulfanylimidazole derivatives offer
some advantages over prototype inhibitors (SB203580), e.g. lower
entered phase II of the clinical trials, e.g. the prototypical
p38 mitogen-activated protein (MAP) kinase inhibitors
(Figures 1 and 2) for the potential therapeutic intervention
of acute and chronic inflammatory diseases. Protein ki-
nases like p38 are critical enzymes of cellular signal trans-
duction cascades. p38 is a member of the highly
conserved serine/threonine protein MAP kinase family
mediating fundamental biological cell processes both at
the translation and the transcription level and is activated
in response to extracellular stress stimuli. Numerous se-
vere diseases, including inflammatory and autoimmune
disorders, neurodegenerative conditions, cardiovascular
diseases, and cancer are directly linked to dysfunction of
protein kinase-mediated cell signaling pathways.5 Ap-
proximately 20–25% of the druggable human genome6
encodes for kinases, which are involved in signal trans-
duction. Currently almost 200 compounds with kinase in-
hibitory activity against more than 50 different human
kinase targets are in the various stages of preclinical and
clinical development. The vast majority of these com-
pounds target the kinase’s ATP site, and, because all of
the more than 500 protein kinases identified in the human
genome7 have an ATP site, there is great potential for
cross-interaction. At present only six kinase inhibitors are
used in clinical practice in the field of cancer therapy.8,9
Several inhibitors of p38 MAP kinase have been demon-
strated to reduce efficiently cytokine levels in functional
assays as well as in animal tests.10,11 Many of these ATP
mimetics were derived from the prototypical 5-(4-py-
ridyl)imidazole SB 203580 (Figure 2), and the structural
requirements for p38 inhibition have been extensively dis-
cussed.12–17 Despite the fact that a few p38 imidazole-
based inhibitor candidates have, meanwhile, reached
phase II of clinical development, safety issues appear to
represent the main hurdle for successful development.
The selectivity profile, i.e. the extent of p38 inhibition
versus inhibition of other protein kinases, represents a
critical feature. However, exploitation of less-conserved
surrounding kinase areas that are not used by ATP can im-
prove the selectivity.18,19 To date, p38 MAP kinase20,21 re-
mains one of the most promising small molecule
cytochrom P450 interactions and better kinetic properties. We re-
port here three novel regioselective and, at the same time, highly
flexible synthetic approaches towards 1,4,5-trisubstituted 2-sulfa-
nylimidazoles starting from different ethanone regioisomers allow-
ing maximum variability of all substituents introduced. As a result,
a variety of selective and highly potent p38 MAPK inhibitors were
prepared and selected for further preclinical development. Synthe-
sis of structurally diverse inhibitor candidates, p38 inhibition data,
and selectivity profiling of some selected compounds are specified.
Furthermore, the benefits of the useful, brief synthetic sequences
are outlined and contrasted with already published multistep routes.
Key words: medicinal chemistry, heterocycles, ring closure, nu-
cleophilic aromatic substitutions, regioselectivity, p38 MAP kinase
inhibitors
Imidazoles are widespread scaffolds in highly significant
biomolecules exhibiting interesting biological activities.1
Imidazole derivatives have also been found to possess
many pharmacological properties and are largely impli-
cated in biochemical processes.1 Members of this class of
1,3-diazoles are known to possess NO synthase inhibition,
antibiotic, antifungal, and antiulceratice activities and in-
clude compounds that are inhibitors of phosphodiesterase
(PDE4), 5-lipoxygenase, or substances with VEGF recep-
tor I and II antagonistic activities.1 In addition, these het-
erocycles comprise several inhibitors of p38 MAP
kinases, a subgroup of mitogen-activated protein kinases,
which are thought to be involved in a variety of inflamma-
tory and immunological disorders. To date 3,312 patent
files dealing with heterogeneous imidazole structures are
registered in the electronical patent document archive
DEPATISnet.2 About 2,500 ‘imidazole’ hits alone could be
found in the structure–activity relationship(s) (SAR) data-
SYNTHESIS 2008, No. 2, pp 0253–0266
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000852; Art ID: Z23507SS
© Georg Thieme Verlag Stuttgart · New York

254
S. A. Laufer et al.
PAPER
F
F
(a) Hydrogen donor/acceptor functions of the 2-aminopy-
ridyl residues (mainly gaining activity).
OH
N
N
N
N
(b) Space-filling lipophilic aryl residues, binding to the
hydrophobic back pocket (mainly gaining selectivity).
(c) Interactions of additional substituents at the pyridine
C2 position with the hydrophobic front region (gaining
both activity and selectivity).
N
N
N
O
N
H
Me
(d) Further interactions with both the sugar pocket and the
phosphate binding region by imidazole N1, and C2-S res-
idues, respectively (importance less clear; preferred posi-
tions to modify physicochemical properties).
SB242235
RWJ67657
CF3
Thus, despite the prejudices (lack of selectivity, CYP-in-
hibition), imidazoles are still preferred scaffolds for p38
MAPK inhibition for the reasons discussed. Suitable syn-
thetic procedures would make a high chemical diversity
possible and at the same time offer a great challenge. As
there is still a deficit of promising development candi-
dates, our aim was to develop short syntheses useful for
fast and regioselective access to various di- and trisubsti-
tuted 2-sulfanylimidazoles. We report here multifunction-
al synthetic methods allowing flexible and regioselective
modification of substituents to yield bioactive (1,)2,4,5-
substituted imidazoles starting from structural diverse
ethanone scaffolds.
N
NH
N
Me
N
Me
HN
L-790070
Figure 1 p38 MAP kinase inhibitors that have been advanced to
preclinical or clinical studies for therapeutic intervention of acute and
chronic inflammatory diseases.
F
F
therapeutic targets for treatment of autoimmune and in-
flammatory diseases.22
N
N
N
R
Although binding at the ATP-binding site, imidazole scaf-
folds allow the design of selective MAPK inhibitors (e.g.,
SB202190 or SB203580 vs BIRB796),23,24 thereby target-
ing all major interaction regions.19 Many first generation
imidazole-based inhibitors, however, suffer from non-
mechanistic side effects [particularly inhibition of cyto-
chrome P-450 enzymes (CYP)] making more structural
modification necessary.25 For this reason newer py-
ridylimidazole inhibitors have been tried to further opti-
mize by incorporating different substituents on the
imidazole core itself and/or by introducing additional
(amino)-substituents at the ortho-position of the pyridine
ring. Especially the nature of the substituents at the imida-
zole N1 and C2 position has been varied extensively
mainly in order to improve physicochemical properties
and to reduce toxicity. The different design strategies
have led to several inhibitors with high potency and en-
hanced selectivity among closely related kinases. 2-Sulfa-
nylimidazoles have proved to have decisive advantages
over prototype SB203580-like 2-arylimidazoles, e.g. few-
er interactions with metabolic enzymes like CYP-450s
and better kinetic and metabolic properties.26 These com-
pounds can be regarded as open-chain analogues of the
early lead SK&F 86002 (Figure 2).
S
N
H
N
N
SB202190: R = OH
SB203580: R = S(=O)Me
SKF86002
substitution
not tolerated
R1
R1 = 4-F, 2,4-F2, 3-CF3;
N
N
R2 = (substituted) alkyl, (hetero)arylalkyl, or
(hetero)aryl;
R3 = (substituted) alkyl or alkylaryl;
R4 = (substituted) alkyl, (hetero)arylalkyl, or
(hetero)aryl;
S
R3
R2
N
X
substitution
tolerated
X = NH, NHCO, O, S
R4
Figure 2 Vicinal aryl-/heteroaryl-substituted imidazoles under in-
vestigation for p38 MAP kinase inhibition derived from the early lead
SK&F 86002.
State of the art in 2-sulfanylimidazole chemistry: brief
synthetic methods for the preparation of highly substitut-
ed imidazole cores are rare and generally not practicable
under neutral reaction conditions.30 Moreover, the first
synthetic approaches towards 1,4,5-trisubstituted 2-sulfa-
nylimidazoles derived from SK&F86002 (Figure 2) did
not allow the introduction of imidazole N1 substituents in
a regioselective manner and/or the arrangement of any
further substituents at the pyridine moiety.31–33
The general architecture of the ATP site in protein kinases
has been reviewed in recent years.19,27 Essential interac-
tions of the class of p38 pyridylimidazole inhibitors with
the ATP-binding cleft are:28,29
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Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
255
Due to the drastic reaction conditions of the Neber rear- Retrosynthetic analysis of an exemplary tetrasubstituted
rangement (NaOMe) typically used to synthesize the in- target molecule in Scheme 1 demonstrates two principal
termediate amino ketones, halogen atoms at C2 of the approaches to arrange substituents at the pyridine bridged
pyridine ring would also be substituted early in the syn- by a heteroatom. The starting aminopyridine derivatives
thetic sequence by either solvent or base.32,33 Although the exemplified by formula 1 (Scheme 2) used in strategy II
latest published method34,35 can perform the regioselec- can be derived via a previously published multistep meth-
tive construction of a variety of such imidazole scaffolds, od.26,34 However, the existing route is complicated and
the introduction of substituents in the corresponding pyri- needs repeated protection of the exocyclic amino group
dine position was still limited to nitrogen residues; chiral during the reaction course. Imidazole C4/C5 residues as
N-, O- or S-(aryl)alkyl substituents could not be intro- well as the N1 position need to be defined at a very early
duced. In addition this multistep reaction sequence suffers stage. Unfortunately, beside the expenditure of time, over-
from low overall yield and requires repeated protection of all yields of 1 are low. Moreover as a result of the SN
the exocyclic NH group. As some substituents that should mechanism in strategy II, the configuration of introduced
be varied need to be defined in early reaction steps, the haloalkyl substituents will be inverted or racemized (com-
whole process is quite inflexible and time consuming. pounds 3).
Therefore, our aim was to develop a novel regioselective,
The SNAr mechanism in strategy I allows the introduction
but extremely flexible and short, reaction strategy for rap-
of chiral building blocks (N-, O-, or S-nucleophiles) on
id access to 1,2,4,5-tetrasubstituted imidazoles.
the one hand and even tolerates aniline-like substituents
(e.g., 3h) that cannot be coupled by strategy II as well as
chiral amines. The commercial availability of various pri-
F
mary or secondary amines allows rapid variation leading
Me
N
N
Strategy I
Strategy II
to a broad substitution pattern; C2 of the pyridine is acti-
vated for SNAr reactions. Substituents are directed ortho
(or para) by the –M effect of the heterocyclic sp2-N. Ad-
ditionally the reactivity is enhanced by the high electrone-
gativity of the fluorine, making it the preferred leaving
group. Thus, strategy I seems to be more promising and
flexible. The starting amino pyridine derivatives 1, how-
ever, are suitable for the simple production of varied (acyl-
amino)pyridyl-substituted imidazoles using acid halides.
To obtain the tetrasubstituted imidazole precursors bear-
ing a fluorine atom at the 2-position of the pyridine, com-
pounds 1 were successfully subjected to a mild variant of
the Schiemann reaction according to Minor et al.36 using
sodium nitrite in aqueous tetrafluoroboric acid
S
SNAr under
conservation of
the configuration
SN under inversion
of the configuration
or racemization
Me
N
HN
Me
R
N
N
+
+
Hal
NH2
R = (substituted) alkyl/
alkylaryl/aryl moiety
H2N
*
R
Hal
H
R
*
Me
Me
H
Scheme 1 Vicinal aryl-/heteroaryl-substituted imidazoles under in-
vestigation for p38 MAP kinase inhibition derived from the early lead
SK&F 86002.
F
R1
R3
Strategy II
R4-Hal
N
N
R3
N
S
S
N
R2
R2
N
N
HN
NH2
1
3a–q
R4
aq HBF4
47–59%
Strategy I
R4NH2
R1
69–100%
R1
R3
R3
N
S
N
N
N
S
R4OH or
R4SH
R2
R2
N
N
38–58%
F
2
X
3r, 3s
R4
X = O, S
Scheme 2 Preparation of compounds 2 using a modified Balz–Schiemann fluorination reaction starting from 1 and different coupling reac-
tions at the pyridine moieties via either strategy I or II.
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

256
S. A. Laufer et al.
PAPER
(Scheme 2, Table 1) giving 2 in 47–59% isolated yields be easily performed according to previously reported
depending on N1 residue. Though, under these aqueous practices toward 2,4,5-trisubstituted imidazoles in glacial
conditions side reactions resulting in 2-hydroxypyridine acetic acid with sodium nitrite, yielding 6.26 Ring closure
derivatives are likely to take place. For every molecule with the appropriate triazinane afforded 7 in excellent
represented by general formula 2, fluorination conditions yields (70–86%). Imidazole N-oxides 7 then were con-
had to be optimized. Moreover the preparation of 2 from verted into imidazole-2-thiones 8 by treatment with a
1 requires an additional reaction step in an already labor- small excess of 2,2,4,4-tetramethylcyclobutane-1,3-
some reaction sequence further decreasing the overall dithione at room temperature; yields were approx. 80%.
yield. Therefore we developed an alternative, much short- Subsequent alkylation of imidazole-2-thiones 8 was car-
er, synthetic strategy and introduced the fluorine in an ear- ried out in methanol and in the presence of potassium car-
lier reaction step.
bonate at ambient temperature yielding the corresponding
2-(alkylsulfanyl)imidazoles 3 almost quantitatively.38,39
Other protocols that favor higher temperatures constantly
gave elevated amounts of side and decomposition prod-
ucts. In contrast, our mild method was also suitable with
arylalkyl- or even polar-substituted alkyl residues, e.g.,
benzyl or 2,3-dihydroxypropyl, to achieve compounds
that potentially interact with the enzyme’s phosphate
binding region.19 By this means the production of 1,2,4,5-
tetrasubstituted imidazoles 2 was obviously shortened
while yields were commonly high. Various aminonucleo-
philes could be readily introduced at the 2-position of the
pyridine using known SNAr methods (Scheme 2, 3a–q),
and both the substrate 2 as well as the resulting products 3
proved to be surprisingly thermostable. In each case
yields were excellent (<100%) and much higher than re-
ported previously for such SNAr reactions at analogous
2,4,5-trisubstituted derivatives.26 Moreover, as expected,
the 2-fluoro-4-pyridyl intermediate 2 could be also suc-
cessfully undergo nucleophilic substitution with (ionic)
O- and S-nucleophiles (Scheme 2, 3r and 3s). However,
the multistep production of ethanone 4 was still a limiting
factor. As reported earlier 4 could be obtained in low
overall yield in four steps starting from 2-aminopicoline.34
Therefore, we were still required a shorter reaction se-
quence.
To avoid repeated protection of the exocyclic amino
group, we accomplished the fluorination step first starting
from ethanone 4 (Scheme 3, route A). We readily ob-
tained the 1-(2-fluoro-4-pyridyl)ethanone 5 in good yields
(<85%) when reacting 4 with sodium nitrite in dry hydro-
gen fluoride/pyridine consistent with the protocol of
Fukuhara et al.37 The following a-oximination could now
Table 1 Substitution for Compounds 1–3
Comp. R1
R2
R3
NHR4 or XR4
1a
1b
2a
2b
2c
3a
3b
3c
3d
3e
3f
–
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
–
–
(CH2)2OMe
H
–
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
–
Me
–
(CH2)2OMe
Me
–
(R)-CH(Me)Ph
(S)-CH(Me)Ph
(R)-CH(Me)Ph
(S)-CH(Me)Ph
(R/S)-CH(Me)CH2OH
(R)-CH(Me)CH2OH
(S)-CH(Me)CH2OH
Ph
Me
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
H
In contrast the regioisomeric ethanone 9 of compound 5 is
accessible in only one step in excellent yield. In addition
the variation of the aryl moiety is easily possible as the
corresponding precursors (acids, esters) are commercially
available.40,41 In either case we directly yielded 9 (84–
88%) by reacting 2-halo-4-methylpyridines with substi-
tuted benzoic acid esters. However, exercising route A
(Scheme 3, Table 2) starting from 9 in order to receive tet-
rasubstituted imidazole scaffolds specified by the routes
discussed would result in the wrong regioisomers with
low or no bioactivity.42 For that reason a third synthetic
methodology was investigated, which allows, finally, the
most elegant access to key intermediate 2 (Scheme 3,
route B). To obtain tetrasubstituted imidazole derivatives
of the desired regiochemistry and to diversify substituents
at the intended N1 position, we first tried to a-monofunc-
tionalize the ethanones 9 by acid-catalyzed treatment with
bromine. The reaction was generally carried out according
to Revesz43 by adding one equivalent of bromine to a so-
lution of 9 in acetic acid at room temperature. The re-
ceived products 10 were viscous oils that were directly
used in the following reaction. Initial attempts to substi-
3g
3h
3i
(R)-2-hydroxycyclohexyl
trans-4-hydroxycyclohexyl
(R)-CH(Me)Cy
tetrahydropyran-4-yl
2-hydroxycyclohexylmethyl
CH2CH(OH)Me
tetrahydropyran-4-yl
trans-4-hydroxycyclohexyl
Cy
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
H
(CH2)2OMe
H
2-thienylmethoxy
SPh
H
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Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
257
tute the bromine of 10 with primary (aryl)alkylamines cleophiles (Scheme 1). This reaction sequence allows the
(e.g. methoxyethylamine) failed. Heating 10 with the ap- regioselective introduction and variation of all relevant
propriate amine in ethanol indeed formed the desired substituents within only four (to five) steps. Solely pro-
product (DC; LC/MS), which was not stable, however, duction of 11 from the brominated 10 gave 30% maxi-
and could not be isolated or successfully further converted mum yield and requires further optimization. Comparison
with thiocyanic acid ethers in N,N-dimethylformamide.32 of analytical data of compounds 3 obtained either by route
The procedure was changed as follows. A twofold excess A or by route B (Scheme 3) confirmed that both routes
of the amine was dissolved in dichloromethane at 0 °C and lead to identical products.
a cold solution of 10 in dichloromethane was slowly add-
ed. Products 11 precipitated as fine white salts after treat-
An even more flexible and efficient synthetic variant to
provide 1,2,4,5-tetrasubstituted imidazoles is shown in
ing the organic residue with hydrogen chloride saturated
Scheme 4 (Table 3). Initially the pyridine moiety was
ethanol, evaporation of the solvent, and repeated washing
omitted and should be introduced later. In the procedures
with a mixture of Et2O and acetone (1:1). From these iso-
presented above the aryl moieties are defined very early in
the synthesis. We, therefore, developed an alternative
route which allows the introduction of the 5-(hetero)aryl
lated key intermediate salts, compounds 2 could be readi-
ly derived by either reacting 11 with different (aryl)alkyl-
substituted thiocyanates or with potassium thiocyanate in
moiety in the final step. We chose a cross-coupling proce-
N,N-dimethylformamide and subsequent S-alkylation of
dure to provide a variety of compounds represented by
general structures 2 and 18.
the resulting 2-sulfanylimidazoles 8 (Scheme 3). Using
the first variant gave predominantly 2 (52%) and the sec-
Compounds 13 were realized by treating fluoro-substitut-
ed 1-arylethanones 12 with bromine according to Ridge et
al.44 The less sterically hindered 13 underwent coupling
with relevant primary amines by the synthesis described
for the preparation of 11 to give the amino hydrochlorides
14 in moderate to high yields (42–76%). The subsequent
ring closure was carried out with either potassium thiocy-
anate or methylrhodanide leading to the imidazole-2-
thiones 15 and to the 2-(methylsulfanyl)imidazoles 16, re-
spectively; alkylation of 15 with iodomethane gave 16
ond 8 (12%) (when R1 = 4-F, R2 = (CH2)2OMe). The un-
wanted formation of 8 may be explained by an (acid- or)
chloride-catalyzed cleavage of the sulfanyl function dur-
ing the thermal reaction. With potassium thiocyanate the
reactions ran smoothly and 8a–c were formed in high
yields (<82%) as the sole product. The following S-alky-
lation yielded the desired key intermediates 2 quantita-
tively, which is in line with the results from route A.
Compounds 2 are again well-suited for the synthesis of
target compounds 3 upon substitution with all kinds of nu-
F
F
F
Route A
N
a
b
OH
56–85%
66–90%
O
O
O
N
N
N
4
5
6
NH2
F
F
(CH2NR2)3
70–86%
c
R1
R1
F
H
O–
N+
R3Hal
e
R3
N
N
N
d
S
S
80–82%
N
N
69–98%
R2
R2
R2
N
N
N
2
7
8
F
F
F
h
R3SCN
52%
82%
i
R1
R1
R1
Route B
R2NH2/HCl
g
O
*HBr
Br
O
O
f
*HCl
21–30%
89–96%
NH
R2
N
N
N
11
10
9
F
F
F
Scheme 3 Preparation of 2-fluoro-4-pyridyl imidazole scaffolds with fixed regiochemistry using different ethanone precursors: (a) NaNO2,
70% HF–pyridine (Olah’s reagent), –15 to –10 °C, then r.t.; (b) NaNO2, glacial AcOH, r.t.; (c) EtOH, reflux; (d) 2,2,4,4-tetramethylcyclobu-
tane-1,3-dithione, CH2Cl2, r.t.; (e) K2CO3, MeOH, r.t.; (f) Br2, glacial AcOH, r.t.; (g) initially CH2Cl2, –5 to 0 °C, then 1.25 M HCl in EtOH;
(h) KSCN, DMF, reflux, (i) DMF, reflux.
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

258
S. A. Laufer et al.
PAPER
Table 2 Substitution for Compounds 2, 7–11
Table 3 Substitution for Compounds 2b, 12–18
Compound R1
R2
R3
Compound R1
R2
R3
R4
2b
2c
4-F
Me
Me
12a, 13a
12b, 13
14a, 15a
14b, 15b
14c, 15c
14d, 15d
16a
H
–
4-F
(CH2)2OMe
Me
4-F
H
–
2d
4-F
(CH2)2OMe
Bn
(CH2)2OMe
Bn
2e
4-F
(CH2)2OMe
CH2CH(OH)CH2OH
H
7a
–
Me
–
–
–
–
–
–
–
–
–
–
–
–
4-F
4-F
H
Me
7b
–
(CH2)2OMe
(CH2)2OMe
(CH2)2OMe
Bn
8a
4-F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
–
8b
4-F
(CH2)2OMe
16b
H
–
8c
3-CF3
4-F
(CH2)2OMe
16c
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
Me
–
9a
–
16d
(CH2)2OMe
Me
–
9b
3-CF3
4-F
–
17a
–
10a
10b
11a
11b
11c
–
17b
(CH2)2OMe
Me
–
3-CF3
4-F
–
18a
3-Tol
4-Tol
4-pyridyl
Me
18b
(CH2)2OMe
Me
4-F
(CH2)2OMe
(CH2)2OMe
18c
3-CF3
2b
Me
2-fluoro-4-pyridyl
a catalyst. The coupling reactions were carried out either
in a biphasic toluene/water system or in N,N-dimethyl-
formamide. Alternatively sodium carbonate or potassium
acetate was used as the base. This access to 1,4,5-trisub-
stituted 2-sulfanylimidazoles combines the advantages of
rapid imidazole construction with the regioselective intro-
duction of different N1 residues in good yields. Further-
more, to complete the essential vicinal diaryl system, the
quantitatively. Compounds 17 were readily obtained by
bromination of 16 at the imidazole C5 position using N-
bromosuccinimide.45,46 Finally, the 5-(2-fluoro-4-py-
ridyl)imidazole 2 and analogous products 18 were ob-
tained from 17 in 10–77% yield by the Suzuki–Miyaura
coupling45,47 using different (hetero)aryl boronic acids
and
dichlorobis(triphenylphoshine)palladium/triphe-
nylphosphine or tetrakis(triphenylphosphine)palladium as
R1
R1
R1
R1
H
N
O
O
O
c
b
a
S
*HCl
Me
12
61–78%
42–76%
100%
N
R2
Br
NH
R2
H
15
13
14
d
43%
+14% (16)
OH
B
e
99–100%
R5
X
R1
R1
R1
OH
R3
R3
R3
N
N
N
N
f
g
S
S
S
N
R2
N
R2
R4
Br
H
83–97%
10–77%
R2
2, 18
17
16
R1 = H, halogen(alkyl), R2 = (substituted) alkyl/alkyl(hetero)aryl/(hetero)aryl, R3 = (substituted)
alkyl/alkyl(hetero)aryl, R4 = (substituted) (hetero)aryl, R5 = halogen/alkyl, X = C, N
Scheme 4 Synthesis of 1,4,5-trisubstituted 2-sulfanylimidazoles using the Suzuki–Miyaura coupling reaction: (a) Br2, glacial AcOH, r.t.; (b)
R2NH2, CH2Cl2 (+ MeOH), –5 to 0 °C, 1.25 M HCl in EtOH, acetone–Et2O (1:1); (c) KSCN, DMF, reflux; (d) MeSCN, DMF, reflux; (e) MeI,
K2CO3, MeOH, r.t.; (f) NBS, CCl4, 0 °C then r.t.; (g) Pd(PPh3)4, argon, 2 M Na2CO3, toluene, 120 °C.
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

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Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
259
relative chemical purity (%). The Agilent ChemStation software
(Version Rev. A.09.03) was used for the instrument control and data
analysis.
C5 position of the imidazole could be varied in a final
step, which is in contrast to most existing sulfanylimida-
zole syntheses.
The following compounds were prepared according to common lit-
erature procedures: 10a and 13b.43,44 The syntheses and analytical
properties of compounds 1a, 1b, 2a, 4, 9a, and 9b have been report-
ed elsewhere; commercially available 12a, 12b, and 13a were used.
The above regiospecific synthetic methodologies enabled
us to prepare highly diverse substituted imidazole deriva-
tives starting from regioisomeric ethanones. In contrast to
an already published multistep method (10 steps), our
novel and extremely flexible synthetic approaches to-
wards further substitutable pyridylimidazole intermedi-
ates ran with only three to six steps, dependant on the
starting ethanone, thereby notably increasing overall
yields. All kinds of relevant substituents were tolerated on
the defined positions and no protection group was needed
2-Fluoro-4-[4-(4-fluorophenyl)-1-methyl-2-(methylsulfanyl)-
1H-imidazol-5-yl]pyridine (2b)
Variant 1: To a cooled soln (0 °C) of 1a (1.73 g, 5.50 mmol) in 50%
HBF4 (6.0 mL) was carefully added NaNO2 (450 mg) in small por-
tions. A little N2 gas was released and a yellowish green precipitate
formed. The mixture was stirred for a short period at 0 °C and then
the thermal decomposition of the intermediate diazonium salt was
for the construction of the imidazole ring. Consequently accomplished by warming the mixture to 45 °C where it was aged
for 1 h. The mixture then was cooled to –10 °C (acetone and liq N2
the brief syntheses described here were more efficient and
bath) and made alkaline with Na2CO3 to pH 8; the precipitate agglu-
much less time consuming than earlier procedures. More-
tinated. CH2Cl2 (70 mL) and H2O (70 mL) were consecutively
over the fluorine atom at the pyridine moiety allowed the
poured to the suspension and the organic layer separated. The aque-
ous phase was extracted with CH2Cl2 (3 × 70 mL) and the combined
organic layers were washed with H2O (2 × 70 mL), dried (Na2SO4),
and the solvent removed in vacuo. The resulting crude material was
purified by column chromatography (silica gel 60, EtOAc) to give
2b (0.95 g, 54%) as a fine yellowish powder.
introduction of different (chiral) N-, O-, or S-nucleo-
philes. As a result both selective and highly potent p38
MAPK inhibitors could be prepared and selected for fur-
ther development.
Variant 2: Starting from 8a, the preparation of 2b was accomplished
as follows: 8a (0.3 g, 1.0 mmol) was suspended in MeOH (6 mL) in
a 25-mL round-bottomed flask. K2CO3 (0.11 g) was added to the
stirred suspension followed by the injection of a soln of MeI (0.23
g, 1.6 mmol) in a little MeOH. The flask was capped with a glass
plug and the mixture was stirred at r.t. for 19.5 h. During this time
(~1.5 h), the initial suspension changed to give a bright yellow soln.
The solvent as well as excess MeI were removed in vacuo and sub-
sequent the solid residue was combined with EtOAc–H2O (3:2, 12
mL). The organic phase was collected and the aqueous phase again
extracted with EtOAc. The combined organic layers were dried
(Na2SO4) and the filtrate was evaporated to dryness; yield: 255 mg
(81%). The resulting solid product 2b is of high analytical purity.
All reagents and solvents were of commercial quality and used
without further purification. Melting points were determined on a
Büchi Melting Point B-545 apparatus and are thermodynamically
1
corrected. H and 13C NMR spectra were generally collected on a
1
Bruker Avance 200 at 200 and 50 MHz, respectively, except H
NMR spectra of 3a, 3b, 3d, 3h, 3j, and 7a, which were collected on
a Varian Mercury plus 400 at 400 MHz; TMS was used as internal
standard. IR spectra were recorded by ATR technique on a Perkin–
Elmer Spectrum One spectrophotometer. GC/MS analyses were
carried out on a HP 6890 series GC-system equipped with a
HP-5MS capillary column (0.25 mm film thickness, 30 m × 0.25 mm
i.d.) and a HP 5973 mass selective detector (70 eV); He was used as
carrier gas, and one of the following temperature programs was em-
ployed: (1) initial isothermal period of 1.0 min at 160 °C, then an
increase at 10.0 °C/min to 240 °C with an isothermal period of 5
min at 240 °C, then an increase at 10.0 °C/min to 270 °C with an
isothermal period of 15 min at 270 °C; or (2) initial isothermal pe-
riod of 1.0 min at 240 °C, then an increase at 10.0 °C/min to 290 °C
with an isothermal period of 20 min at 290 °C. GC data are present-
ed as tR (min) and MS results as m/z ratio and intensity (%) relative
to the base peak. MS spectra were recorded on a Thermo Finnigan
LCQ Duo Ion Trap System. Purity of compounds was either deter-
mined by LC on a GROM-SIL 120 ODS-5 ST column (3 mm,
150 × 2 mm) which was eluted isocratically with a H2O–MeCN–
HCO2H system at a flow rate of 0.2 mL/min (ESI-MS detection,
positive ion mode) or by HPLC (vide infra). LC results are given as
tR (min) and relative purity (%). TLC analyses were performed on
fluorescent silica gel 60 plates (Macherey-Nagel Art.-Nr. 805021).
Spots were visualized under UV illumination at 254 and 365 nm.
Purification via preparative TLC was performed on fluorescent sil-
ica gel 60 F254 plates, 2 mm (Merck Art.-Nr.1.05717.0001).
Variant 3: Using the Suzuki–Miyaura coupling, 2b (25 mg, 12%)
was obtained starting from 17a (0.2 g, 0.66 mmol), 2-fluoro-4-py-
ridylboronic acid (0.1 g, 0.73 mmol), a catalytical mixture of
PdCl2(PPh3)2 (0.14 g, 0.20 mmol) and Ph3P (0.03 g, 0.11 mmol),
and KOAc (0.1 g, 1.0 mmol) in DMF (2 mL). The soln was heated
to 80 °C for 23 h. Isolation of the product was accomplished by col-
umn chromatography (silica gel, EtOAc–hexane, 1:2); mp 147–149
°C.
IR (neat): 3050, 2924, 1612, 1538, 1508, 1477, 1400, 1262, 1222
(C–F), 1192, 1161, 984, 876, 847, 817, 654 cm–1.
1H NMR (CDCl3): d = 2.79 (s, 3 H, SCH3), 3.53 (s, 3 H, NCH3), 6.88
(s, 1 H, H3pyridyl), 6.93–7.03 (m, 2 H, H3/H5phenyl), 7.11 (d, J = 5.05
Hz, 1 H, H5pyridyl), 7.38–7.45 (m, 2 H, H2/H6phenyl), 8.29 (d, J = 5.00
Hz, 1 H, H6pyridyl).
13C NMR (CDCl3): d = 15.9 (s, SCH3), 32.0 (s, NCH3), 110.3 (d,
J = 37.6 Hz, C3pyridyl), 115.4 (d, J = 21.5 Hz, C3/C5phenyl), 122.4 (d,
J = 4.3 Hz, C5pyridyl), 126.2 (d, J = 3.6 Hz, C5imidazole), 128.9 (s,
C1phenyl), 129.2 (d, J = 8.0 Hz, C2/C6phenyl), 139.2 (s, C4imidazole),
143.4 (d, J = 8.5 Hz, C4pyridyl), 145.9 (s, C2imidazole), 148.5 (d,
J = 15.5 Hz, C6pyridyl), 162.2 (d, J = 245.6 Hz, C4phenyl), 164.1 (d,
J = 238.7 Hz, C2pyridyl).
HPLC apparatus and chromatographic procedure: a HPLC Hewlett-
Packard HP 1090 Series II liquid chromatograph equipped with a
UV diode array detector (DAD) was used (detection at 230 nm and
254 nm). The chromatographic separation was performed on a Be-
tasil C8 column (150 mm × 4.6 mm i.d., dp = 5 mm, Thermo Fisher
Scientific, Waltham, MA, USA) at 35 °C oven temperature. Injec-
tion volume was 5 mL. HPLC Gradient (flow: 1.5 mL/min): 0.01 M
KH2PO4, pH 2.3 (Solvent A),: MeOH (Solvent B): 40% B to 85%
B in 8 min, 85% B for 5 min, 85% B to 40% B in 1 min, 40% B for
2 min, stoptime 16 min. HPLC results are presented as tR (min) and
1H NMR (DMSO-d6): d = 2.65 (s, 3 H, SCH3), 3.44 (s, 3 H, NCH3),
7.07–7.16 (m, 2 H, H3/H5phenyl), 7.26–7.41 (m, 4 H, H3/H5pyridyl
,
H2/H6phenyl), 8.31 (d, J = 5.08 Hz, 1 H, H6pyridyl).
13C NMR (DMSO-d6): d = 15.4 (s, SCH3), 31.9 (s, NCH3), 110.6 (d,
J = 38.1 Hz, C3pyridyl)), 115.5 (d, J = 21.4 Hz, C3/C5phenyl), 123.4 (d,
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260
S. A. Laufer et al.
PAPER
J = 4.1 Hz, C5pyridyl), 126.8 (d, J = 3.7 Hz, C5imidazole), 128.9 (d,
J = 8.1 Hz, C2/C6phenyl), 130.3 (d, J = 3.1 Hz, C1phenyl), 138.3 (s,
C4imidazole), 143.8 (d, J = 8.8 Hz, C4pyridyl), 144.9 (s, C2imidazole),
148.6 (d, J = 15.8 Hz, C6pyridyl), 161.4 (d, J = 242.5 Hz, C4phenyl),
163.7 (d, J = 234.6 Hz, C2pyridyl).
1H NMR (DMSO-d6): d = 2.65 (s, 3 H, SCH3), 3.08 (s, 3 H, OCH3),
3.39 (t, J = 5.82 Hz, 2 H, CH2O), 4.01 (t, J = 5.34 Hz, 2 H, NCH2),
7.06–7.15 (m, 2 H, H3/H5phenyl), 7.31–7.38 (m, 4 H, H3/H5pyridyl
,
H2/H6phenyl), 8.33 (d, J = 4.88 Hz, 1 H, H6pyridyl).
13C NMR (DMSO-d6): d = 15.5 (s, SCH3), 44.0 (s, NCH2), 58.0 (s,
OCH3), 69.7 (s, CH2O), 111.0 (d, J = 37.9 Hz, C3pyridyl)), 115.2 (d,
J = 21.4 Hz, C3/C5phenyl), 123.7 (d, J = 4.1 Hz, C5pyridyl), 126.3 (d,
J = 4.4 Hz, C5imidazole), 128.5 (d, J = 8.0 Hz, C2/C6phenyl), 129.9 (d,
J = 3.2 Hz, C1phenyl), 137.8 (s, C4imidazole), 144.0 (d, J = 8.8 Hz,
C4pyridyl), 144.5 (s, C2imidazole), 148.3 (d, J = 15.8 Hz, C6pyridyl), 161.1
(d, J = 242.4 Hz, C4phenyl), 163.4 (d, J = 234.9 Hz, C2pyridyl).
GC (conditions 2): tR = 4.6 min; MS (EI, 70 eV): m/z (%) = 317
(100, M+), 302 (5, M+ – CH3), 284 (80), 270 (6), 244 (42), 215 (12),
202 (4), 137 (8), 121 (6), 96 (5, 2-fluoro-4-pyridyl).
LC: tR = 19.1 min (100.0%); MS: m/z = 318.2 [M + 1]+.
2-Fluoro-4-[4-(4-fluorophenyl)-1-(2-methoxyethyl)-2-(methyl-
sulfanyl)-1H-imidazol-5-yl]pyridine (2c)
GC (conditions 2): tR = 5.4 min; MS (EI, 70 eV): m/z (%) = 361
(100, M+), 346 (4, M+ – CH3), 330 (24), 316 (15), 303 (23), 288 (5),
270 (81), 243 (12), 230 (8), 215 (10), 182 (7), 167 (9), 121 (22), 101
(4), 59 (8, methoxyethylamino+).
Variant 1: A soln of 1b (1.6 g, 4.46 mmol) in 50% HBF4 (6 mL) un-
der argon was stirred in a 100-mL round-bottom flask. This soln
was cooled to 0 °C in an ice bath and NaNO2 (440 mg) were added
in small portions over 15 min (diazotization step). The flask was
closed each time the addition of a portion of the NaNO2 was com-
plete. The mixture became foamy and a white precipitate devel-
oped. Dediazotization was accomplished by stirring the mixture at
45 °C for 1 h. The suspension was cooled to –10 °C (liquid N2 in
acetone bath) and then made alkaline with Na2CO3 to pH 7–8; the
precipitate agglutinated. CH2Cl2 (50 mL) and H2O (50 mL) were
added sequentially, the organic layer was separated and the aqueous
phase extracted with CH2Cl2 (3 × 50 mL). The combined organic
phases were washed with H2O (50 mL) and then the solvent was re-
moved in vacuo. The yellowish orange semisolid residue was re-
peatedly concentrated with Et2O and combined with Et2O again at
4 °C resulting in a fine yellow precipitation that was filtered off.
From this crude product the pure 2c was either isolated by exhaus-
tive extraction (hot hexane) or by column chromatography (silica
gel–EtOAc); in each case a bright yellow and viscous residue of 2c
(0.76 g, 47%) was obtained. Crystallization of the product occurred
very slowly.
4-[2-(Benzylsulfanyl)-4-(4-fluorophenyl)-1-(2-methoxyethyl)-
1H-imidazol-5-yl]-2-fluoropyridine (2d)
To a suspension of 8b (0.3 g, 0.86 mmol) in MeOH (5 mL) in a 25
mL flask was added initially K2CO3 (0.09 g) and then BnBr (0.148
g, 0.86 mmol) in MeOH (1 mL) was added by injection and the mix-
ture stirred at r.t. for 22 h (monitored by GC/MS). During this time
the initial suspension changed to a brownish soln. The solvent was
removed in vacuo and the resulting viscous residue combined with
EtOAc–H2O (3:2). The aqueous phase was extracted with EtOAc.
The combined organic extracts were dried (Na2SO4) and the filtrate
was concentrated to dryness on a rotary evaporator leaving almost
pure 2d as a red to brownish viscous mass. Crystallization of the
residue was initiated by evaporating the product several times with
Et2O; yield: 0.37 g (98%); mp 61 °C.
IR (neat): 3063, 2932, 2893, 1609, 1542, 1507, 1453, 1400, 1259,
1220 (C–F), 1185, 1156, 1118, 1015, 879, 839, 815, 698 cm–1.
1H NMR (CDCl3): d = 3.17 (s, 3 H, OCH3), 3.36 (t, J = 5.51 Hz, 2
H, CH2O), 3.81 (t, J = 5.52 Hz, 2 H, NCH2), 4.49 (s, 2 H, CH2),
6.94–7.03 (m, 3 H, H3pyridyl, H3/H5phenyl), 7.09–7.13 (m, 1 H,
H5pyridyl), 7.29–7.47 (m, 7 H, Hbenzyl, H2/H6phenyl), 8.27 (d, J = 5.14
Hz, 1 H, H6pyridyl).
Variant 2: Following the typical procedure for 2b, variant 2, using
8b (2.3 g, 6.6 mmol) and MeI (1.55 g, 10.9 mmol) in MeOH (48
mL) gave 2c (2.31 g, 97%) as an oily residue, that crystallized sub-
sequent to freezing in liquid N2, seeding, and storing under vacuum.
Variant 3: A soln of 11b (0.5 g, 1.5 mmol) with methyl thiocyanate
(0.26 g, 3.6 mmol) in DMF (15 mL) was refluxed for 35 min. Addi-
tion of ice H2O to the cooled mixture followed by repeated extrac-
tion with EtOAc (3 × 30 mL) and separation of the concentrated
organic layer by column column chromatography (silica gel 60,
CH2Cl2–EtOAc, 1:2) gave 2c, which was initially isolated in one
fraction together with small amounts of the imidazole-2-thione 8b
(GC/MS). Upon treatment of the oily mixture with Et2O the side
product 8b quantitatively precipitated in white crystals that could be
filtered off (60 mg, 12%). Evaporation of the solvent (Et2O) left the
yellowish main product 2c (275 mg, 52%) as a semisolid, but in
good analytical quality that was dried in vacuo over CaCl2; mp 86–
88 °C.
13C NMR (CDCl3): d = 39.5 (s, SCH2Ph), 44.5 (s, NCH2), 58.8 (s,
OCH3), 70.6 (s, CH2O), 111.2 (d, J = 37.7 Hz, C3pyridyl)), 115.4 (d,
J = 21.5 Hz, C3/C5phenyl), 123.1 (d, J = 4.3 Hz, C5pyridyl), 126.6 (d,
J = 3.6 Hz, C5imidazole), 127.6 (s, C4benzyl), 128.5 (s, C2/C6benzyl),
128.9 (s, C3/C5benzyl), 129.1 (d, J = 8.1 Hz, C2/C6phenyl), 137.2 (s,
C1benzyl), 138.9 (s, C4imidazole), 143.0 (s, C2imidazole), 143.8 (d, J = 7.9
Hz, C4pyridyl), 148.3 (d, J = 15.4 Hz, C6pyridyl), 162.2 (d, J = 245.9
Hz, C4phenyl), 164.0 (d, J = 238.8 Hz, C2pyridyl).
GC (conditions 2): tR = 10.4 min; MS (EI, 70 eV): m/z (%) = 437
(41, M+), 404 (3), 379 (50), 346 (100, M+ – C7H7), 314 (9), 288 (13),
270 (9), 256 (6), 243 (19), 230 (6), 215 (2), 121 (6), 91 (81, tropyli-
um+), 65 (5).
LC: tR = 19.1 min (94.9%); MS: m/z = 438.3 [M + 1]+.
IR (neat): 3072, 2932, 2894, 1728, 1608, 1543, 1508, 1400, 1260,
1221 (C-F), 1186, 1157, 1117, 1095, 1015, 880, 840, 815 cm–1.
3-[4-(4-Fluorophenyl)-5-(2-fluoro-4-pyridyl)-1-(2-methoxyeth-
yl)-1H-imidazol-2-ylsulfanyl]propane-1,2-diol (2e)
1H NMR (CDCl3): d = 2.89 (s, 3 H, SCH3), 3.27 (s, 3 H, OCH3), 3.57
(t, J = 5.33 Hz, 2 H, CH2O), 4.09 (t, J = 5.35 Hz, 2 H, NCH2), 6.93–
7.06 (m, 3 H, H3/H5phenyl, H3pyridyl), 7.19 (dd, J = 1.58/5.00 Hz, 1 H,
H5pyridyl), 7.40–7.47 (m, 2 H, H2/H6phenyl), 8.30 (d, J = 4.98 Hz, 1 H,
H6pyridyl).
13C NMR (CDCl3): d = 17.1 (s, SCH3), 45.2 (s, NCH2), 59.0 (s,
OCH3), 70.0 (s, CH2O), 111.5 (d, J = 37, 9 Hz, C3pyridyl)), 115.6 (d,
J = 21.6 Hz, C3/C5phenyl), 123.2 (d, J = 4.3 Hz, C5pyridyl), 126.5 (s,
C5imidazole), 128.6 (d, C1phenyl), 129.7 (d, J = 8.2 Hz, C2/C6phenyl),
137 (s, C4imidazole), 142.4 (d, C4pyridyl), 145.4 (s, C2imidazole), 148.6 (d,
J = 15.3 Hz, C6pyridyl), 162.6 (d, J = 247.1 Hz, C4phenyl), 164.0 (d,
J = 239.3 Hz, C2pyridyl).
A stirred suspension of 8b (0.15 g, 0.43 mmol) in MeOH (5 mL) at
r.t. was combined with K2CO3 (0.01 g). At the same time color
changed rapidly from bright to dark yellow. A soln of 3-bromopro-
pane-1,2-diol (0.098 g, 0.63 mmol) in MeOH (1 mL) was immedi-
ately injected into the mixture. The initial suspension was aged at
r.t. for 20 h thereby changing into a soln. The solvent was evaporat-
ed and the residue was separated from unreacted substrate by pre-
parative TLC (silica gel 60 F254, 2 mm; EtOAc, separation from
silica gel by extraction with acetone) to give analytical 2e (125 mg,
69%). The highly viscous product was hygroscopic and therefore
could not be durable crystallized. While storing the product it took
a glass-like shape.
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Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
261
IR (neat): 3307 (OH), 2929, 2876, 1610, 1543, 1509, 1449, 1400
(OH), 1261 (C–F), 1221 (C–F), 1187, 1158, 1117, 1096, 1035,
1016, 881, 839, 816, 691 cm–1.
GC (conditions 2): tR = 11.6 min; MS: m/z (%) = 416 (29, M+), 401
(1, M+ – CH3), 385 (100), 357 (7, M+ – C3H7O), 341 (1), 327 (7),
311 (6), 293 (13), 192 (4), 146 (5), 121 (3), 59 (2).
1H NMR (CDCl3): d = 3.28 (s, 3 H, OCH3), 3.41 (d, J = 5.50 Hz, 2
H, SCH2), 3.57 (t, J = 5.35 Hz, 2 H, CH2O), 3.71–3.81 (m, 2 H,
CH2OH), 3.99–4.08 (m, 3 H, CHOH, NCH2), 6.91–7.00 (m, 2 H,
H3/H5phenyl), 7.05 (s, 1 H, H3pyridyl), 7.16–7.20 (m, 1 H, H5pyridyl),
7.25–7.32 (m, 2 H, H2/H6phenyl), 8.29 (d, J = 5.13 Hz, 1 H, C6pyridyl),
OH signals were not detected.
13C NMR (CDCl3): d = 36.3 (s, SCH2), 44.9 (s, NCH2), 58.9 (s,
OCH3), 64.0 (s, CH2OH), 70.2 (s, CH2O), 72.0 (s, CHOH), 111.3 (d,
J = 37.7 Hz, C3pyridyl)), 115.6 (d, J = 21.5 Hz, C3/C5phenyl), 123.2 (d,
J = 4.4 Hz, C5pyridyl), 126.7 (s, C5imidazole), 128.4 (d, J = 3.3 Hz,
C1phenyl), 128.8 (d, J = 8.1 Hz, C2/C6phenyl), 138.4 (s, C4imidazole),
143.4 (d, J = 8.5 Hz, C4pyridyl), 145.6 (s, C2imidazole), 148.4 (d,
J = 15.5 Hz, C6pyridyl), 162.2 (d, J = 246.1 Hz, C4phenyl), 164.0
(J = 238.9 Hz, C2pyridyl).
{4-[4-(4-Fluorophenyl)-1-(2-methoxyethyl)-2-(methylsulfanyl)-
1H-imidazol-5-yl]-2-pyridyl}phenylamine (3h); Typical Proce-
dure
NaH (55–65%, 170 mg, 3.9 mmol) and aniline (280 mg, 3.0 mmol)
in diglyme (3 mL) were heated to 70 °C while stirring. When gas
evolution ceased a soln of 2c (361 mg, 1 mmol) in diglyme was add-
ed and the mixture was further stirred (monitored by TLC). The
mixture then was cooled to r.t. and CH2Cl2 (40 mL) added. The or-
ganic phase was washed with H2O (6 × 25 mL), dried (Na2SO4, and
rotary evaporated. The oily residue was purified by column chroma-
tography (silica gel, EtOAc–hexane, 3:7); yield: 275 mg (65%); mp
107.6 °C.
HPLC: tR = 7.79 min; purity: 99.9% (l = 254 nm).
IR (neat): 1219 (C–F) cm–1.
1H NMR (CDCl3): d = 2.71 (s, 3 H, SCH3), 3.20 (s, 3 H, OCH3), 3.51
(t, J = 6.0 Hz, 2 H, CH2O), 4.04 (t, J = 6.0 Hz, 2 H, 2 H, NCH2),
6.76–7.47 (m, 11 H, H3/H5pyridyl, Hphenyl), 8.23 (d, J = 6.0 Hz, 1 H,
H6pyridyl).
LC: tR = 15.9 min (98.5%); MS: m/z = 422.2 [M + 1]+.
{4-[4-(4-Fluorophenyl)-1-methyl-2-(methylsulfanyl)-1H-imida-
zol-5-yl]-2-pyridyl}[(R)-1-phenylethyl]amine (3a); Typical Pro-
cedure
A mixture of 2b (500 mg, 1.6 mmol) and (+)-(R)-a-methylbenzyl-
amine (1.7 g, 14.0 mmol) was stirred at 165 °C for 17 h. The amine
was removed in vacuum and residue taken up in a mixture of H2O,
sat. NaHCO3, and EtOAc. The phases were separated and the organ-
ic phase washed with H2O and brine, dried, and evaporated; yield:
520 mg (80%).
4-{4-[4-(4-Fluorophenyl)-1-(2-methoxyethyl)-2-(methylsulfa-
nyl)-1H-imidazol-5-yl]-2-pyridylamino}cyclohexanol (3j); Typ-
ical Procedure
Compound 2c (1.45 g, 4.0 mmol) and trans-4-aminocyclohexanol
(2.32 g, 19.8 mmol) were combined and stirred at 140 °C in a sealed
tube for 14 h. After cooling the mixture was taken up in a mixture
of H2O and EtOAc. The organic layer was separated and washed
with H2O (4 ×), dried (anhyd Na2SO4), and evaporated in vacuo;
yield: 1.75 g (97%).
HPLC: tR = 6.67 min; purity: 99.8% (l = 254 nm).
IR (neat): 1219 (C–F) cm–1.
1H NMR (DMSO-d6): d = 1.41 (d, J = 6.8 Hz, 3 H, CH3), 2.62 (s, 3
H, SCH3), 3.30 (s, 3 H, NCH3), 4.99 (q, J = 6.8 Hz, 1 H, CH), 6.40
(s, 1 H, H3pyridyl), 6.42 (d, J = 5.2 Hz, 1 H, H5pyridyl), 7.05–7.42 (m,
9 H, Hphenyl), 8.01 (d, J = 5.2 Hz, 1 H, H6pyridyl).
HPLC: tR = 4.33 min; purity: 98.1% (l = 254 nm).
IR (ATR): 3319 (OH), 2928, 2856, 1604, 1546, 1501, 1448, 1219
(C–F), 1117, 839, 812 cm–1.
2-{4-[4-(4-Fluorophenyl)-1-(2-methoxyethyl)-2-(methylsulfa-
nyl)-1H-imidazol-5-yl]-2-pyridylamino}propan-1-ol (3e); Typi-
cal Procedure
1H NMR (CDCl3): d = 1.26–1.39 (m, 4 H, Hcyclohexyl), 1.98–2.07 (m,
4 H, Hcyclohexyl), 2.73 (s, 3 H, SCH3), 3.28 (s, 3 H, OCH3), 3.38–3.46
(m, 1 H, H1cyclohexyl), 3.56 (t, J = 5.80 Hz, 2 H, NCH2CH2OCH3),
3.65–3.72 (m, 1 H, H4cyclohexyl), 4.05 (t, J = 5.60 Hz, 2 H,
NCH2CH2OCH3), 6.42 (s, 1 H, H3pyridyl), 6.56 (dd, J = 1.4/5.40 Hz,
1 H, H5pyridyl), 6.92–6.96 (m, 2 H, H3/H5phenyl), 7.44–7.47 (m, 2 H,
H2/H6phenyl), 8.05 (d, J = 6.40 Hz, 1 H, H6pyridyl).
1H NMR (DMSO-d6): d =1.13–1.28 (m, 4 H, Hcyclohexyl), 1.80–1.93
(m, 4 H, Hcyclohexyl), 2.63 (s, 3 H, SCH3), 3.12 (s, 3 H, OCH3), 3.47–
3.42 (t, J = 5.62 Hz, 3 H, NCH2CH2OCH3, H1cyclohexyl), 3.57 (s, 1 H,
H4cyclohexyl), 3.95 (t, J = 5.60 Hz, 1 H, NCH2CH2OCH3), 4.52 (d,
Compound 2c (0.25 g, 0.7 mmol) and 2-aminopropan-1-ol (0.52 g,
6.9 mmol) were combined and stirred under argon at 155 °C for 19
h (monitored by TLC). The mixture was allowed to cool to r.t. and
EtOAc (60 mL) was added. The organic soln was washed with H2O
(6 × 20 mL) to quantitatively separate excess amino alcohol and
then it was dried (Na2SO4). After removal of the solvent, the result-
ing yellow, viscous residue was repeatedly evaporated with Et2O to
yield pure 3e (287 mg, 100%) as an amorphous product that, how-
ever, was hygroscopic and, therefore, shortly merged into a glass-
like consistence; mp 87 °C.
J = 4.40 Hz, 1 H, OH), 6.37 (s, 1 H, H3pyridyl), 6.45 (m, 2 H, H5pyridyl
,
NH), 7.07–7.12 (m, 2 H, H3/H5phenyl), 7.40–7.44 (m, 2 H, H2/
IR (neat): 3307 (OH), 2928, 1606, 1547, 1503, 1480, 1445, 1354
(OH), 1220 (C–F), 1157, 1118, 1094, 1050, 975, 840, 812 cm–1.
H6phenyl), 8.06 (d, J = 5.20 Hz, 1 H, H6pyridyl).
{4-[4-(4-Fluorophenyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]-
2-pyridyl}(tetrahydro-2H-pyran-4-yl)amine (3o); Typical Pro-
cedure
1H NMR (CDCl3): d = 1.23 (d, J = 6.72 Hz, 3 H, CH3), 2.71 (s, 3 H,
SCH3), 3.28 (s, 3 H, OCH3), 3.46–3.78 (m, 4 H, CH2O, CH2OH),
3.96–4.06 (m, 3 H, CH, NCH2), 4.74 (d, exchangeable, J = 5.68 Hz,
1 H, NH), 6.45 (s, 1 H, H3pyridyl), 6.55 (dd, J = 1.37/5.32 Hz, 1 H,
H5pyridyl), 6.89–6.98 (m, 2 H, H3/H5phenyl), 7.42–7.49 (m, 2 H, H2/
H6phenyl), 8.06 (dd, J = 0.61/5.31 Hz, 1 H, H6pyridyl).
13C NMR (CDCl3): d = 16.3 (s, SCH3), 17.7 (s, CH3), 44.1 (s,
NCH2), 50.3 (s, CH), 58.9 (s, OCH3), 68.4 (s, CH2OH), 70.6 (s,
CH2O), 109.8 (s, C3pyridyl), 114.7 (s, C5pyridyl), 115.0 (d, J = 21.3 Hz,
C3/C5phenyl), 127.8 (s, C5imidazole), 128.6 (d, J = 8.0 Hz, C2/C6phenyl),
129.9 (d, J = 3.2 Hz, C1phenyl), 138.3 (s, C4pyridyl), 140.5 (s,
C4imidazole), 144.3 (s, C2imidazole), 147.7 (s, C6pyridyl), 158.7 (s,
C2pyridyl), 161.8 (d, J = 244.5 Hz, C4phenyl).
Compound 2a (0.3 g, 1 mmol) and tetrahydropyran-4-ylamine (0.9
g, 8.9 mmol) were combined and stirred under argon at 155 °C for
18 h (monitored by TLC). The brown mixture was allowed to cool
to r.t. and was taken up in 10% citric acid (adjusted to pH 4–5 with
NaOH, 15 mL). The resulting suspension was extracted with EtOAc
(4 × 40–50 mL) and the aqueous phase was discarded. Upon con-
centrating the combined organic layers pure 3o was obtained after
twofold preparative TLC [(1) silica gel 60 F254, 2 mm, acetone; (2)
silica gel 60, F254, 2 mm, EtOAc; relevant fractions were extracted
with acetone]. After filtration from silica gel and removal of the sol-
vent, the oily residue was solidified by evaporation with Et2O to
give amorphous 3o; yield: 85 mg (22%); mp 99 °C.
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

262
S. A. Laufer et al.
PAPER
IR (neat): 2927, 2847, 1606, 1548, 1519, 1502, 1433, 1366, 1292,
1220 (C–F), 1157, 1137, 1086, 980, 839, 814 cm–1.
IR (neat): 3052 (aryl-H), 2926 (CH3), 1586, 1515, 1503, 1475,
1439, 1386, 1221 (C–F), 1158, 1132, 991, 837, 783, 748, 690 cm–1.
1H NMR (CD3OD): d = 1.38–1.57 (m, 2 H, H3/H5tetrahydropyranyl),
1.86–1.93 (m, 2 H, H3/H5tetrahydropyranyl), 2.62 (s, 3 H, SCH3), 3.42–
3.53 (m, 2 H, H2/H4tetrahydropyranyl), 3.65–3.76 (m, 1 H, CH), 3.91–
3.97 (m, 2 H, H2/H6tetrahydropyranyl), 6.55–6.57 (m, 2 H, H3/H5pyridyl),
7.10–7.19 (m, 2 H, H3/H5phenyl), 7.43–7.49 (m, 2 H, H2/H6phenyl),
7.83 (d, J = 5.83 Hz, 1 H, H6pyridyl).
13C NMR (CD3OD): d = 16.9 (s, SCH3), 34.3 (s, C3/C5tetrahydropyranyl),
48.4 (s, CH), 68.0 (s, C2/C6tetrahydropyranyl), 107.4 (s, C3pyridyl), 111.8
(s, C5pyridyl), 116.7 (d, J = 21.8 Hz, C3/C5phenyl), 131.8 (d, J = 8.2
Hz, C2/C6phenyl), 144.6, 148.3 (s, C6pyridyl), 159.7 (s, C2pyridyl), 164.1
(d, J = 244.8 Hz, C4phenyl).
1H NMR (CD3OD): d = 2.58 (s, 3 H, SCH3), 6.77 (br s, 1 H,
H3pyridyl), 7.06–7.41 (m, 10 H, Hphenyl, H5pyridyl), 8.28 (d, J = 5.26 Hz,
1 H, H6pyridyl).
GC (conditions 2): tR = 18.9 min; MS: m/z (%) = 392 (100, [M –
1]+), 376 (11), 360 (3), 344 (5), 319 (8), 211 (7), 179 (12), 121 (3),
109 [1 (!), PhS+], 95 (2, 4-fluorophenyl+), 77 (2), 51 (1).
2-(4-Fluorophenyl)-1-(2-fluoro-4-pyridyl)ethanone (5); Typical
Procedure
In a 100-mL flask p. f. FEP (perfluoroethylenepropylene) with a
screw cap was provided Olah’s reagent (70% HF in pyridine, 39 g).
The stirred soln was cooled to –15 °C in an ice/NaCl bath and sub-
sequently combined in some portions with 4 (10.0 g, 43.4 mmol).
After 45 min, anhyd NaNO2 (4.89 g, 0.07 mol) was added portion-
wise to the orange mixture; the flask was closed after each addition
of NaNO2. N2 as well as little amounts of NOx were released when-
ever the flask was opened again. After complete addition of NaNO2
the initial cloudy mixture gradually changed to a soln that was
stirred at –15 to 0 °C for 1 h and at r.t. for 1 h. The mixture was then
rapidly poured into ice H2O (150 mL) immediately followed by the
addition of CH2Cl2 (90 mL). The organic layer was separated and
the aqueous phase extracted with CH2Cl2 (4 × 50 mL). The com-
bined organic phases were washed with 5% Na2CO3 (1 × 100 mL)
and H2O (1 × 100 mL), dried (Na2SO4), and the solvent removed in
vacuo. Purification could be afforded by repeatedly extracting the
oily residue with hot hexane (7 × 30 mL). Pure 5 crystallized from
the cooled hexane extracts in fluffy needles and could be filtered
and dried in an evacuated desiccator; yield: 5.90 g (58%); mp 58–
66 °C.
GC: tR = 16.4 min; MS m/z (%) = 384 (76, M+), 369 (10, M+ – CH3),
355 (10), 339 (19), 327 (79), 312 (20), 299 (100, M+ – tetrahydro-
pyranyl), 285 (16), 267 (32), 252 (9), 227 (9), 207 (7), 170 (8), 146
(19), 121 (7), 100 (5, tetrahydropyran-4-ylamino+), 55 (7).
4-[4-(4-Fluorophenyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]-2-
(2-thienylmethoxy)pyridine (3r); Typical Procedure
For the initial deprotonation step, a suspension of NaH (55–65%,
0.3 g, 6.9 mmol) in DMF (3 mL) was treated dropwise with
thiophene-2-methanol (0.75 g, 6.6 mmol) and the mixture stirred at
r.t. until H2 evolution ceased (~1 h). Compound 2a (0.2 g, 0.7
mmol) was added in 1 portion and the mixture was stirred at 155–
160 °C for 5.5 h under argon. The mixture was allowed to cool to
r.t. and was combined with H2O (30 mL) and extracted with EtOAc
(5 × 30 mL). The combined organic extracts were washed with 10%
citric acid (pH 4–5), 10% Na2CO3, and brine; the solvent was evap-
orated and the oily residue purified by flash chromatography (Com-
bi Flash Retrieve: silica gel, CH2Cl2–EtOAc gradient). The isolated
product fraction was concentrated and the residue evaporated with
Et2O to yield crystalline 3r (0.1 g, 38%); mp 124 °C.
IR (neat): 3067, 1702 (C=O), 1607, 1564, 1512, 1480, 1403, 1338,
1268 (C–F), 1221 (C–F), 1160, 1016, 866, 846, 825, 791, 662 cm–1.
IR (neat): 2927, 2855, 1606, 1542, 1505, 1412, 1364, 1308, 1220
(C–F), 1157, 1021, 971, 834, 814, 699 cm–1.
1H NMR (DMSO-d6): d = 4.49 (s, 2 H, CH2), 7.12–7.21 (m, 2 H,
H3/H5phenyl), 7.27–7.34 (m, 2 H, H2/H6phenyl), 7.72–7.74 (m, 1 H,
H3pyridyl), 7.84–7.87 (m, 1 H, H5pyridyl), 8.47–8.50 (m, 1 H, H6pyridyl).
13C NMR (DMSO-d6): d = 44.1 (s, CH2), 108.1 (d, J = 38.6 Hz,
C3pyridyl)), 115.0 (d, J = 21.1 Hz, C3/C5phenyl), 119.8 (d, J = 4.4 Hz,
C5pyridyl), 130.1 (d, J = 3.1 Hz, C1phenyl), 131.8 (d, J = 8.1 Hz, C2/
C6phenyl), 148.4 (d, J = 6.9 Hz, C4pyridyl), 148.9 (d, J = 14.5 Hz,
C6pyridyl), 161.1 (d, J = 241.0 Hz, C4phenyl), 163.7 (d, J = 235.5 Hz,
C2pyridyl), 196.3 (dd, J = 1.1/3.1 Hz, C=O).
1H NMR (DMSO-d6): d = 2.61 (s, 3 H, atropisomers ‘A’ + ‘B’,
SCH3), 5.49 (s, 1 H ‘A’, OCH2), 5.52 (s, 1 H ‘B’, OCH2), 6.83 (s, 1
H ‘A’, H3pyridyl), 6.83 (s, 1 H ‘B’, H3pyridyl), 6.91 (dd, J = 1.33/5.49
Hz, 1 H ‘B’, H5pyridyl), 6.99–7.03 (m, 2 H ‘A’ + 1 H ‘B’, H5pyridyl ‘A’,
H4thienyl ‘A’ + ‘B’), 7.17–7.36 (m, 3 H, ‘A’ + ‘B’, H3thienyl, H3/
H5phenyl), 7.45–7.55 (m, 3 H, ‘A’ + ‘B’, H5thienyl, H2/H6phenyl), 8.06
(d, J = 5.38 Hz, 1 H ‘A’, H6pyridyl), 8.12 (d, J = 5.26 Hz, 1 H ‘B’,
H6pyridyl), 12.73 (br s, 1 H ‘A’ + ‘B’, exchangeable, NHimidazole).
1H NMR (CD3OD): d = 2.62 (s, 3 H, SCH3), 5.48 (s, 2 H, OCH2),
6.85 (br s, 1 H, H3pyridyl), 6.95–6.99 (m, 2 H, H5pyridyl, H4thienyl),
7.10–7.15 (m, 3 H, H3thienyl, H3/H5phenyl), 7.35–7.45 (m, 3 H,
H5thienyl, H2/H6phenyl), 8.02 (d, J = 5.38 Hz, 1 H, H6pyridyl).
GC (conditions 1): tR = 5.2 min; MS (EI, 70 eV): m/z (%) = 233 (26,
M+), 205 (66), 124 (69, M+ – fluorobenzyl), 109 (100, 4-fluoroben-
zyl+), 96 (33, 2-fluoro-4-pyridyl+), 83 (31), 69 (12), 57 (8).
1-(4-Fluorophenyl)-2-(2-fluoro-4-pyridyl)ethane-1,2-dione 1-
Oxime (6); Typical Procedure
GC (conditions 2): tR = 10.8 min; MS: m/z (%) = 397 (66, M+), 382
[1 (!), M+ – CH3], 300 (7, M+ – 2-thienylmethyl), 285 (51), 207 (3),
172 (4), 121 (2), 97 (100, 2-thienylmethyl+), 53 (4).
A soln of NaNO2 (4.72 g, 68.4 mmol) in H2O (15 mL) was added
dropwise over 8 min to a cooled (10 °C) soln of 5 (5.5 g, 23.6 mmol)
in glacial AcOH (110 mL). The visible release of N2 gas thereby ini-
tiated the reaction. After complete addition, cooling was removed
and the mixture stirred at r.t. for 1.5 h. Subsequently as much cold
H2O (~140 mL) as necessary to produce a fine growing suspension
was added. The mixture was stirred at r.t. for 5 h to quantify the pre-
cipitation and then the white solid product was gathered by filtration
and dried in vacuo over CaCl2 to give analytically pure 6; yield: 4.1
g (66%); mp 168 °C.
4-[4-(4-Fluorophenyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]-2-
(phenylsulfanyl)pyridine (3s); Typical Procedure
Following the typical procedure for 3r using NaH (55–65%, 0.6 g,
13.8 mmol), thiophenol (1.45 g, 13.2 mmol), and 2a (0.4 g, 1.3
mmol) in abs DMF (5 mL) the product formed after 7 h at 155–160
°C. Ice H2O (100 mL) was added to the cold mixture followed by
acidification with 20% HCl to pH 3–4. Extraction with EtOAc
(4 × 50 mL), evaporation of the organic solvent in vacuo, and re-
peated separation on preparative TLC led to the desired product
that, however, could not be isolated absolutely pure. Solidification
of the resulting oily residue was achieved by treatment with Et2O to
give 3s (0.3 g, 58%) as an amorphous foam; mp 215 °C.
IR (neat): 3156, 3006, 2843, 1673 (C=O), 1615, 1510, 1462, 1399,
1321, 1263 (C–F), 1225 (C–F), 1163, 1030, 1004, 820, 805, 678
cm–1.
1H NMR (DMSO-d6): d = 7.27–7.36 (m, 2 H, H3/H5phenyl), 7.53–
7.60 (m, 3 H, H2/H6phenyl, H3pyridyl), 7.67–7.70 (m, 1 H, H5pyridyl),
8.41 (d, J = 5.04 Hz, 1 H, H6pyridyl), 13.12 (s, 1 H, NOH).
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

PAPER
Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
263
13C NMR (DMSO-d6): d = 109.4 (d, J = 39.3 Hz, C3pyridyl)), 114.7
(d, J = 21.5 Hz, C3/C5phenyl), 121.3 (d, J = 4.2 Hz, C5pyridyl), 125.1
(d, J = 3.4 Hz, C1phenyl), 132.0 (d, J = 8.4 Hz, C2/C6phenyl), 147.7 (d,
J = 14.6 Hz, C6pyridyl), 151.1 (d, J = 7.4 Hz, C4pyridyl), 153.7 (s,
C=NOH), 162.2 (d, J = 25.9 Hz, C4phenyl), 162.6 (d, J = 234.6 Hz,
C2pyridyl), 190.0 (d, J = 3.3 Hz, C=O).
J = 15.4 Hz, C6pyridyl), 161.6 (s, C2imidazole), 162.8 (d, J = 249.1 Hz,
C4phenyl), 163.9 (d, J = 234.0 Hz, C2pyridyl).
GC (conditions 2): tR = 7.7 min; MS (EI, 70 eV): m/z (%) = 347 (24,
M+), 315 (4), 289 (100), 255 (5), 230 (6), 202 (4), 122 (6), 95 (3, 4-
fluorophenyl+), 58 (2).
2-Bromo-2-(2-fluoro-4-pyridyl)-1-[3-(trifluoromethyl)phe-
nyl]ethanone Hydrobromide (10b); Typical Procedure
Compound 9b (5.0 g, 17.7 mmol) was dissolved in glacial AcOH
(90 mL) and treated dropwise with Br2 (2.83 g, 17.7 mmol) in
AcOH (14 mL) at r.t.. The mixture was aged at r.t. for 1 h and then
the light brown soln was rotary evaporated to dryness. The crude
oily product 10b was used without further purification in the fol-
lowing reaction step; yield: 7.24 g (93%).
2-Fluoro-4-[4-(4-fluorophenyl)-1-(2-methoxyethyl)-3-oxido-
1H-imidazol-5-yl]pyridine (7b); Typical Procedure
Compound 6 (3.94 g, 15.0 mmol) was suspended in EtOH (68 mL)
at r.t. To the stirred suspension, a soln of 1,3,5-tris(2-methoxyeth-
yl)-1,3,5-triazinane (1.92 g, 7.3 mmol) in EtOH (8 mL) was added
under argon and the mixture was refluxed for 20 h. The solvent was
removed in vacuo and the resulting oily residue cooled in an ice bath
and taken up in Et2O (40 mL). The mixture was stored in a refriger-
ator overnight, and the crystalline product was filtered off and
washed (Et2O); yield: 3.46 g (70%); mp 167 °C.
IR (neat): 3073, 1698 (C=O), 1611, 1412, 1328, 1203, 1168, 1126
(CF3), 1072, 1001, 818, 760, 691 cm–1.
1H NMR (DMSO-d6): d = 7.23 (s, 1 H, CH), 7.37 (s, 1 H, H3pyridyl),
7.51–7.58 (m, 1 H, H5pyridyl), 7.84 (t, J = 7.92 Hz, 1 H, H5phenyl),
8.07 (d, J = 8.33 Hz, 1 H, H4phenyl), 8.29–8.39 (m, 3 H, H6pyridyl, H2/
H6phenyl).
IR (neat): 3056, 2894, 2828, 1607, 1547, 1514, 1436, 1379, 1352,
1241 (C–F), 1202, 1161, 1124, 1093, 1058, 898, 867, 827, 807, 690
cm–1.
1H NMR (DMSO-d6): d = 3.17 (s, 3 H, OCH3), 3.50 (t, J = 4.96 Hz,
2 H, CH2O), 4.06 (t, J = 4.92 Hz, 2 H, NCH2), 7.12–7.21 (m, 2 H,
H3/H5phenyl), 7.26–7.31 (m, 2 H, H3/H5pyridyl), 7.46–7.53 (m, 2 H,
H2/H6phenyl), 8.31 (d, J = 5.13 Hz, 1 H, H6pyridyl), 8.59 (s, 1 H, CH).
13C NMR (DMSO-d6): d = 45.5 (s, NCH2), 58.0 (s, OCH3), 70.0 (s,
CH2O), 111.2 (d, J = 38.7 Hz, C3pyridyl)), 114.9 (d, J = 21.5 Hz, C3/
C5phenyl), 122.7 (d, J = 3.8 Hz, C5imidazole), 123.1 (d, J = 3.3 Hz,
C1phenyl), 123.6 (d, J = 4.3 Hz, C5pyridyl), 127.1 (s, C2imidazole), 128.9
(s, C4imidazole), 131.6 (d, J = 8.3 Hz, C2/C6phenyl), 141.1 (d, J = 8.9
Hz, C4pyridyl), 148.4 (d, J = 15.6 Hz, C6pyridyl), 161.6 (d, J = 244.4
Hz, C4phenyl), 163.1 (d, J = 234.8 Hz, C2pyridyl).
1-(4-Fluorophenyl)-2-(2-fluoro-4-pyridyl)-2-[(2-methoxyeth-
yl)amino]ethanone Hydrochloride (11b); Typical Procedure
To a cooled soln of 2-methoxyethylamine (6.64 g, 88.4 mmol) in
CH2Cl2 (15 mL) was added dropwise over 45 min under argon a
soln of 10a (6.95 g, 17.7 mmol) in CH2Cl2 (20 mL). The yellow to
brownish mixture was stirred at –5 to 0 °C for 50 min and it was
then poured into ice H2O (80 mL). The phases were separated and
the organic layer was washed with ice H2O (2 × 70–80 mL). Subse-
quently the aqueous layers were extracted with CH2Cl2 (2 × 25 mL)
and finally all organic phases were combined and dried (Na2SO4).
1.25 M HCl in EtOH (15 mL) was added rapidly to the still cold or-
ganic soln; the solvent was removed in vacuo at 40 °C. The resulting
(viscous) residue was stirred with Et2O–acetone (1:1) and a fine
bright beige product salt separated. The product salt was filtered off
and dried in vacuo over CaCl2. From the mother liquor further prod-
uct precipitated; yield: 1.79 g (30%); mp 160–173 °C.
4-(4-Fluorophenyl)-5-(2-fluoro-4-pyridyl)-1-(2-methoxyethyl)-
1,3-dihydro-2H-imidazole-2-thione (8b); Typical Procedure
Variant 1: A soln of 7b (3.2 g, 9.7 mmol) in CH2Cl2 (40 mL) was
slowly combined with an equimolar amount of 2,2,4,4-tetramethyl-
cyclobutane-1,3-dithione in a small amount of pyridine. The mix-
ture was stirred at r.t. for 2 h, after which the fine white to yellowish
product 8b began to precipitate. To quantify precipitation, the sus-
pension was stirred for a further 30 min and finally the solid phase
was filtered off and dried on the air. From the orange filtrate further
8b could be obtained by evaporating to half its volume followed by
addition of an equivalent volume of Et2O; yield: 2.76 g (82%).
+
IR (neat): 2944, 2641 (NH2 ), 1687 (C=O), 1611, 1596, 1568, 1531,
1509, 1457, 1413, 1274 (C–F), 1234 (C–F), 1162, 1129, 1100, 931,
859, 848, 802, 725 cm–1.
1H NMR (DMSO-d6): d = 2.92–3.05 (m, 2 H, NCH2), 3.21 (s, 3 H,
OCH3), 3.66 (t, J = 4.82 Hz, 2 H, CH2O), 6.67 (br s, 1 H, CH), 7.37–
7.46 (m, 2 H, H3/H5phenyl), 7.58–7.61 (m, 2 H, H3/H5pyridyl), 8.15–
8.22 (m, 2 H, H2/H6phenyl), 8.36 (d, J = 5.10 Hz, 1 H, H6pyridyl),
Variant 2: The title compound could be also obtained by refluxing
11b (1.48 g, 4.3 mmol) and KSCN (0.78 g, 8.0 mmol) in DMF (38
mL) for 40 min under argon. Precipitation and isolation of the prod-
uct from the cold organic soln was conducted by stepwise addition
of ice cold H2O (75 mL) and subsequent filtration. The sandy raw
product was washed with a small volume of H2O and Et2O (2 ×) to
give very pure 8b; yield: 1.23 g (82%).
+
9.94–10.31 (br d, exchangeable, J = 43.02 Hz, 2 H, NH2 ).
13C NMR (DMSO-d6): d = 45.2 (s, NCH2), 57.9 (s, OCH3), 62.7 (s,
CH), 66.9 (s, CH2O), 110.5 (d, J = 38.4 Hz, C3pyridyl)), 116.4 (d,
J = 22.1 Hz, C3/C5phenyl), 122.1 (s, C5pyridyl), 129.4 (s, C1phenyl),
132.2 (d, J = 9.6 Hz, C2/C6phenyl), 144.8 (d, J = 8.8 Hz, C4pyridyl),
149.1 (d, J = 14.9 Hz, C6pyridyl), 163.3, 165.4, 190.0 (s, C=O).
Variant 3: Compound 8b could also be isolated via column chroma-
tography as a single side product in the synthesis of 2c from the re-
action of 11b with MeSCN; yield: 60 mg (12%); mp 229 °C.
LC: tR = 9.9 (10.7) min, 87.4%; MS: m/z = 307.0 [M + 1]+ (base).
2-(2-Fluoro-4-pyridyl)-2-(2-methoxyethylamino)-1-[3-(trifluo-
romethyl)phenyl]ethanone Hydrochloride (11c); Typical Proce-
dure
Following the typical procedure for 11b reacting 10b (7.0 g, 15.8
mmol) and 2-methoxyethylamine (5.9 g, 78.6 mmol) in CH2Cl2 (35
mL) for 45 min, gave 11c; yield: 1.33 g (21%); mp 168 °C.
IR (neat): 3070, 2902, 1609, 1548, 1494, 1474, 1408, 1395, 1254,
1224 (C–F), 1186, 1165, 1120, 1098, 982, 882, 845, 815 cm–1.
1H NMR (CDCl3): d = 3.26 (s, 3 H, SCH3), 3.79 (t, J = 4.95 Hz, 2
H, CH2O), 4.18 (t, J = 4.99 Hz, 2 H, NCH2), 6.97–7.16 (m, 3 H, H3/
H5phenyl, H3pyridyl), 7.21–7.28 (m, 3 H, H2/H6phenyl, H5pyridyl; signal
group superposed by the CHCl3 peak), 8.30 (d, J = 5.14 Hz, 1 H,
H6pyridyl), 12.22 (br s, 1 H, exchangeable, NH).
13C NMR (CDCl3): d = 45.4 (s, NCH2), 58.7 (s, OCH3), 69.0 (s,
CH2O), 111.8 (d, J = 38.2 Hz, C3pyridyl)), 116.3 (d, J = 21.9 Hz, C3/
C5phenyl), 117.8, 123.3 (d, J = 4.3 Hz, C5pyridyl), 124.4, 125.0, 129.3
(d, J = 8.3 Hz, C2/C6phenyl), 141.8 (d, J = 9.1 Hz C4pyridyl), 148.5 (d,
+
IR (neat): 2920, 2741, 2498 (NH2 ), 1698 (C=O), 1609, 1451, 1415,
1331, 1242, 1205, 1160, 1128 (CF3), 1100, 1072, 1044, 931, 798,
678 cm–1.
1H NMR (DMSO-d6): d = 2.90–3.05 (m, 2 H, NCH2), 3.19 (s, 3 H,
OCH3), 3.66 (t, J = 4.73 Hz, 2 H, CH2O), 6.80 (s, 1 H, CH), 7.57–
7.62 (m, 2 H, H3/H5pyridyl), 7.80 (t, J = 8.15 Hz, 1 H, H5phenyl), 8.06
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

264
S. A. Laufer et al.
PAPER
(d, J = 7.72 Hz, 1 H, H4phenyl), 8.32–8.35 (m, 3 H, H6pyridyl, H2/
H6phenyl), 10.22 (br s, 2 H, exchangeable, NH2 ).
4-(4-Fluorophenyl)-1-methyl-2-(methylsulfanyl)-1H-imidazole
(16c)
+
Compound 15c (1.0 g, 4.8 mmol) was dissolved in MeOH (28 mL)
and K2CO3 (0.52 g, 3.8 mmol) and MeI (1.11 g, 7.8 mmol) in MeOH
(5 mL) were added successively. The mixture was stirred at r.t. for
36 h and afterwards poured into EtOAc–H2O (3:2, 90 mL). The
aqueous phase was washed with EtOAc (30 mL) and finally the
combined organic layers were dried (Na2SO4). The organic soln was
concentrated in vacuo to give pure 16c as an oily residue that com-
pletely crystallized after seeding and cooling (bright yellow solid
product); yield: 1.07 g (100%); mp 71 °C.
13C NMR (DMSO-d6): d = 45.2 (s, NCH2), 57.8 (s, OCH3), 62.8 (s,
CH), 66.9 (s, CH2O), 110.6 (d, J = 39.1 Hz, C3pyridyl)), 122.3 (d,
J = 4.1 Hz, C5pyridyl), 123.4 (q, J = 270.8 Hz, CF3), 125.3 (s,
C2phenyl), 129.8 (q, J = 32.5 Hz, C3phenyl), 130.2, 130.5, 131.1, 132.9,
133.6, 144.7 (d, J = 9.9 Hz, C4pyridyl), 149.1 (d, J = 15.2 Hz,
C6pyridyl), 163.1 (d, J = 238.8 Hz, C2pyridyl), 190.6 (s, C=O).
LC: tR = 12.8 min, 96.5%; MS: m/z = 357.1 [M + 1]+ (base).
1-(4-Fluorophenyl)-2-(methylamino)ethanone Hydrochloride
(14c)
IR (neat): 2935, 1665, 1560, 1497, 1457, 1431, 1386, 1310, 1213
(C–F), 1199, 1153, 1136, 1091, 943, 842, 813, 757, 730, 691 cm–1.
A soln of 13b (5.0 g, 23.0 mmol) in CH2Cl2 (15 mL) was added
dropwise over 45 min to a stirred soln of ethanolic MeNH2 (5.37 g,
corresponding to 57.1 mmol MeNH2) in CH2Cl2 (10 mL) at –5 °C
and under argon. A slight white precipitate was formed after 10 min
that was slowly intensified during the reaction. The mixture was
stirred at 0 °C for a further 95 min and then poured into ice H2O (50
mL). The phases were separated and the organic layer was again
washed with ice H2O (50 mL). The aqueous phases were extracted
with CH2Cl2 (2 × 20 mL) and all organic phases were combined and
dried (Na2SO4). Finally the still cold organic soln was treated with
1.25 M HCl in EtOH (20 mL) and the color changed to intensive
red. The solvent was evaporated in vacuo to give a viscous dark
green product, this was repeatedly stirred with acetone to separate
14c as pure white crystals. The product salt was filtered off and
dried in an evacuated desiccator over CaCl2. From the mother liquor
further product precipitated upon storage overnight; yield: 1.98 g
(42%); mp 222 °C.
1H NMR (CDCl3): d = 2.65 (s, 3 H, SCH3), 3.64 (s, 3 H, NCH3),
6.98–7.13 (m, 3 H, H3/H5phenyl, CH), 7.67–7.75 (m, 2 H, H2/
H6phenyl).
13C NMR (CDCl3): d = 16.6 (s, SCH3), 33.1 (s, NCH3), 115.3 (d,
J = 21.4 Hz, C3/C5phenyl), 117.3 (s, C5imidazole, CH), 126.2 (d, J = 7.9
Hz, C2/C6phenyl), 129.9 (d, J = 3.4 Hz, C1phenyl), 140.7 (s, C4imidazole),
143.3 (s, C2imidazole), 161.8 (d, J = 243.7 Hz, C4phenyl).
LC: tR = 11.0 min, 100.0%; MS: m/z = 323.1 [M + 1]+.
5-Bromo-4-(4-fluorophenyl)-1-methyl-2-(methylsulfanyl)-1H-
imidazole (17a)
To a cooled soln (ice bath) of 16c (0.9 g, 4.0 mmol) in CCl4 (15 mL)
was added NBS (0.79 g, 4.4 mmol). The cloudy, yellowish mixture
was stirred at 0 °C for 10 min and was then allowed to come up to
r.t. where it was stirred for 18 h (TLC monitoring). Undiluted com-
ponents were separated by filtration (glass frit por. 3) and the puri-
fied filtrate was concentrated to dryness by rotary evaporation.
Upon treatment with liquid N2 the resulting oily residue was ob-
tained as a crystalline solid; yield: 1.18 g (97%); mp 63 °C.
IR (neat): 2932, 2771, 2703, 2419, 1680 (C=O), 1600, 1510, 1470,
1417, 1401, 1364, 1251, 1237 (C–F), 1167, 1012, 942, 837 cm–1.
1H NMR (DMSO-d6): d = 2.60 (s, 3 H, CH3), 4.74 (s, 2 H, CH2),
7.38–7.50 (m, 2 H, H3/H5phenyl), 8.03–8.13 (m, 2 H, H2/H6phenyl),
IR (neat): 2926, 1713, 1542, 1489, 1460, 1434, 1372, 1310, 1216
(C–F), 1158, 1126, 1076, 953, 833, 813, 744, 720, 685 cm–1.
1H NMR (CDCl3): d = 2.67 (s, 3 H, SCH3), 3.63 (s, 3 H, NCH3),
7.04–7.14 (m, 2 H, H3/H5phenyl), 7.88–7.97 (m, 2 H, H2/H6phenyl).
13C NMR (CDCl3): d = 16.5 (s, SCH3), 32.7 (s, NCH3), 101.0 (s,
C5imidazole (CH)), 115.2 (d, J = 21.5 Hz, C3/C5phenyl), 128.0 (d,
C1phenyl), 128.5 (d, J = 8.1 Hz, C2/C6phenyl), 137.4 (s, C4imidazole),
143.7 (s, C2imidazole), 162.2 (d, J = 245.5 Hz, C4phenyl).
+
9.40 (br s, 2 H, exchangeable, NH2 ).
13C NMR (DMSO-d6): d = 32.6 (s, NCH3), 53.4 (s, CH2), 116.1 (d,
J = 22.0 Hz, C3/C5phenyl), 130.4 (d, J = 2.9 Hz, C1phenyl), 131.2 (d,
J = 9.8 Hz, C2/C6phenyl), 165.6 (d, J = 252.2 Hz, C4phenyl), 190.9 (s,
C=O).
LC: tR = 3.4 min, 99.9%; MS: m/z = 168.0 [M + 1]+ (base).
4-(4-Fluorophenyl)-1-methyl-1,3-dihydro-2H-imidazole-2-
thione (15c)
LC: tR = 22.7 min, 100.0%; MS: m/z = 301.1 [M]+, 303.1 [M + 2]+.
A soln of 14c (1.8 g, 8.8 mmol) and KSCN (1.71 g, 17.6 mmol) in
DMF (75 mL) was refluxed for 45 min under argon and then was
allowed to cool to r.t. Precipitation of the product was initiated by
the addition of ice-cold H2O (160 mL) to the cold organic mixture.
The fine sandy-like (orange to red) crystals were filtered off,
washed with H2O and dried in vacuo over CaCl2. Further purifica-
tion was not necessary; yield: 1.12 g (61%); mp 234 °C.
4-(4-Fluorophenyl)-1-methyl-2-(methylsulfanyl)-5-(3-tolyl)-
1H-imidazole (18a)
To a stirred soln of 17a (0.2 g, 0.66 mmol), 3-tolylboronic acid
(0.14 g, 1.03 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in toluene
(4 mL) was added 2 M Na2CO3 (0.7 mL). The mixture was heated
to 120 °C under argon and stirred for 6 h (monitored by TLC and
GC/MS). After complete conversion of the starting material the soln
was cooled to r.t. and combined with H2O (5 mL). The phases were
separated and the organic layer was dried (Na2SO4). The solvent
was rotary evaporated and the resulting organic residue purified by
preparative TLC (silica gel 60 F254, CH2Cl2, isolation from silica gel
by extraction with acetone, 3 × 40 mL). Upon removing the solvent,
a yellow oil was obtained that slowly crystallized after treatment
with liquid N2; yield: 0.16 g (77%); mp 87 °C.
IR (neat): 3069, 2915, 1588, 1508, 1474, 1387, 1231 (C–F), 1204,
1159, 1134, 946, 837, 813, 756, 725, 677 cm–1.
1H NMR (DMSO-d6): d = 3.47 (s, 3 H, NCH3), 7.18–7.30 (m, 2 H,
H3/H5phenyl), 7.55 (d, J = 2.26 Hz, 1 H, CH), 7.63–7.71 (m, 2 H, H2/
H6phenyl), 12.64 (br s, 1 H, exchangeable, NH).
13C NMR (DMSO-d6): d = 33.5 (s, NCH3), 115.8 (d, J = 21.7 Hz,
C3/C5phenyl), 115.8 (d, J = 1.5 Hz, C5imidazole), 124.7 (d, J = 3.1 Hz,
C1phenyl), 125.9 (d, J = 8.1 Hz, C2/C6phenyl), 126.3 (s, C4imidazole),
161.3 (d, J = 243.4 Hz, C4phenyl), 162.2 (s, C2imidazole).
IR (neat): 2928, 1608, 1561, 1507, 1456, 1376, 1316, 1218 (C–F),
1156, 1130, 969, 837, 793, 701 cm–1.
LC: tR = 14.8 min, 100.0%; MS: m/z = 209.2 [M + 1]+.
1H NMR (CDCl3): d = 2.39 (s, 3 H, C6H4CH3), 2.76 (s, 3 H, SCH3),
3.43 (s, 3 H, NCH3), 6.85–6.94 (m, 2 H, H3/H5phenyl), 7.09–7.13 (m,
2 H, H2/H43-tolyl), 7.24–7.40 (m, 2 H, H5/H63-tolyl; superposed by
CD3OD signal), 7.44–7.51 (m, 2 H, H2/H6phenyl).
Synthesis 2008, No. 2, 253–266 © Thieme Stuttgart · New York

PAPER
Highly Substituted Pyridinylimidazole-Based p38 MAP Kinase Inhibitors
265
13C NMR (CDCl3): d = 16.3 (s, SCH3), 21.3 (s, CH3), 31.5 (s,
NCH3), 114.8 (d, J = 21.3 Hz, C3/C5phenyl), 126.3, 127.6 (s,
C63-tolyl), 128.2 (d, J = 7.9 Hz, C2/C6phenyl), 128.9 (s, C3-tolyl), 129.5
(s, C3-tolyl), 130.1, 130.4 (d, J = 4.1 Hz, C1phenyl), 131.0 (s, C3-tolyl),
136.8 (s, C13-tolyl), 138.8 (s, C33-tolyl), 142.7 (s, C2imidazole), 161.6 (d,
J = 243.7 Hz, C4phenyl).
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Supporting information for this article is available from the corre-
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Acknowledgment
This work was financially supported by the ratiopharm group and
Fonds der Chemischen Industrie. We thank Dr. S. Linsenmaier, S.
Luik and K. Bauer for the assistance in biological testing. Dr. H.
Scheible is friendly acknowledged for generating LC/MS data. We
are also thankful to R. Selig for arranging the Suzuki-coupling con-
ditions for the preparation of compound 2b according to the synthe-
sis described in Scheme 4.
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