A concise and optimized four-step approach toward 2-(aryl-)alkylsulfanyl-, 4(5)-aryl-, 5(4)-heteroaryl-substituted imidazoles using alkyl- or arylalkyl thiocyanates

Article abstract of DOI:10.1016/j.tetlet.2006.07.147

A convenient cyclization method leading to trisubstituted imidazoles in up to 84% yield is reported. Diverse 1-aryl-, 2-heteroaryl-substituted ethanones are converted into the corresponding α-oximino derivatives which are reduced under regioselective cond

Full text of DOI:10.1016/j.tetlet.2006.07.147

Tetrahedron Letters 47 (2006) 7199–7203
A concise and optimized four-step approach toward
2-(aryl-)alkylsulfanyl-, 4(5)-aryl-, 5(4)-heteroaryl-substituted
imidazoles using alkyl- or arylalkyl thiocyanates
Stefan A. Laufer* and Andy J. Liedtke
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tu¨bingen,
Auf der Morgenstelle 8, 72076 Tu¨bingen, Germany
Received 19 June 2006; revised 26 July 2006; accepted 28 July 2006
Available online 17 August 2006
Abstract—A convenient cyclization method leading to trisubstituted imidazoles in up to 84% yield is reported. Diverse 1-aryl-, 2-
heteroaryl-substituted ethanones are converted into the corresponding a-oximino derivatives which are reduced under regioselective
conditions. The obtained a-amino carbonyl intermediates are reacted with alkyl- or arylalkyl thiocyanates to directly yield C2–S-
substituted imidazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
to occur by normalizing cytokine levels to physiological
values by orally available drugs. In both in vitro and in
animal model studies, p38a MAP kinase activity was
significantly inhibited in a competitive manner by
synthetic compounds derived from the first generation
pyridin-4-yl imidazole SB 203580 (1) (Fig. 1); these inhi-
bitors were effective at nM–lM concentrations.5,6 Since
Lee and co-workers7 identified the serine/threonine
protein kinase involved in the regulation of inflamma-
tory cytokine biosynthesis as the target for 2,4-diaryl-
5-pyridin-4-yl-imidazoles,8 the structural requirements
for p38a MAP kinase inhibition have been extensively
discussed. Thus, MAP kinases have recently become
an attractive research objective for ‘small molecules’
that interrupt the inflammatory cascade at a very early
point. 2-Thioimidazoles are reported to have some
advantages over the prototype SB-like 2-arylimidazoles,
for example, fewer interactions with metabolic enzymes
like CYP-450.9 To provide a simple and rapid access
to a diversity of 2-(aryl-)alkylsulfanyl-, 4(5)-aryl-, 5(4)-
heteroaryl-substituted imidazoles, we developed an
optimized and easily handled general thioimidazole
synthesis based on the Marckwald’s10 process. Indeed,
several current references describe formation of imid-
azoles from KSCN, but only a few methods have been
described that function through regio-controlled
production of N-substituted imidazoles by the use of
substituted isothiocyanates. However, so far, no practi-
cal evidence exists for the one-step production of
Pyridinyl imidazoles are the preferred synthetic scaffolds
for compounds targeting protein kinases, for example,
p38 mitogen-activated protein (MAP) kinase.1,2 These
kinases are involved in signal transduction pathways
for pro-inflammatory cytokines. Potential indications
include the pathogenesis of chronic inflammatory
diseases like rheumatoid arthritis,3 osteoarthritis, or
Crohn’s disease accompanied with nonphysiologically
increased cytokine levels. The major pro-inflammatory
cytokines, interleukin-1b (IL-1b), and tumor necrosis
factor-a (TNF-a), can trigger autoimmune processes
that may destroy bone, cartilage, and tissue through
mechanisms beyond upholding chronic inflammation.
An augmented release of pro-inflammatory cytokines
can be promoted by the activation of MAP kinases,4
for example, the p38 family, in response to stimuli like
infection or cellular stress (osmotic shock, UV irradia-
tion). MAP kinases can modify the phosphorylation
status of transcription factors implicated in cell prolifer-
ation and differentiation processes. An advancement in
the therapy of chronic inflammatory diseases is believed
Keywords: Trisubstituted imidazoles; Alkyl-/arylalkyl thiocyanates;
p38 MAP kinase inhibitors.
Corresponding author. Tel.: +49 7071 2972459; fax: +49 7071
295037; e-mail: stefan.laufer@uni-tuebingen.de
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.147

7200
S. A. Laufer, A. J. Liedtke / Tetrahedron Letters 47 (2006) 7199–7203
F
allowed to come slowly to room temperature to com-
plete the nucleophilic substitutions. In every case, the to-
tal reaction time was limited to 2.5 h. After quenching
the reactions with diluted aqueous HCl, the organic
layer was separated and almost pure and previously
reported halogenpyridine ketones9,13 7–9 and 11 could
be isolated from THF as white to yellowish solids or
viscous brownish oils in up to 87% yield (Table 1). While
1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (7)
as well as the analogous chloro- and bromopyridine
derivatives 8 and 9 could be obtained crystalline by sub-
merging the obtained residue in tert-BME followed by
filtration of the precipitate, the corresponding 3-trifluo-
romethylphenyl compound 11 remained gelatinous. In
contrast, the novel 1-(4-fluorophenyl)-2-quinolin-4-yl-
ethanone (10) slowly crystallized as a pure white fluffy
substance from the water phase (open beaker, a few
days, 100%). If necessary, purification of the ethanones
was conducted by extracting the crude material with
hot hexane. After cooling, the pure products separated
as voluminous needles. Preparation of the a-oximinoke-
tones 12–149 as well as 15 and 16 was derived from eth-
anones 7–11 by stirring with an excess (3 equiv) of
sodium nitrite in acetic acid at room temperature. Addi-
tion of water led to precipitation of the product as a fine
white powder. A positive reaction course was always
indicated by the release of nitrogen gas. In each case,
the preferred oxime regioisomer was formed as a single
product in line with reported data (TLC and 1H
NMR).9 Finally, the oximes exemplified by 4 were
reduced to amines 17–19,9 20, 21 by vigorous shaking
with Pd–C under hydrogen gas in HCl/2-propanol at
atmospheric pressure and room temperature. Comple-
tion of the reaction was monitored by TLC. 2-Halo-
genopyridines reacted with ethanol under acidic
conditions, but not with sterically more demanding iso-
propanol. Bromopyridine derivative 14,9 however,
underwent a hydrogenolytic cleavage yielding pure
unsubstituted pyridine 19. To our surprise, the potential
concomitant reduction of the vicinal carbonyl group was
never detected under these conditions. The desired prod-
ucts could be isolated quantitatively as fine powdered
hydrochlorides. Table 1 gives an overview of the
synthetic routes to these key intermediate a-amino etha-
nones 5. The final target compounds 6 as specified in
Table 2 were prepared from 5 using an extended
N
O
S
N
H
CH3
N
1
Figure 1. First generation prototype inhibitor SB203580 (1).
C2–S-substituted imidazoles 6 from diverse 1-aryl-2-
heteroaryl-substituted a-amino ethanones using alkyl-
or arylalkyl thiocyanates.
2. Results and discussion
Our general synthetic pathway is briefly shown in
Scheme 1 starting from a number of ketones 3 which
were produced by either deprotonating 2-halogeno-4-
methylpyridine or 4-methylquinoline, and consecutively
reacting them with different ethyl fluorobenzoates 2. The
main feature of the reactivity of alkylpyridines and anal-
ogous alkylquinolines is the deprotonation of the alkyl
group at the carbon adjacent to the hetero ring. In this
regard, it is common knowledge that alkyllithiums selec-
tively deprotonate a-methyl groups whereas amide bases
prefer to produce the more stable c-anion.11 The facility
of deprotonation of the a- and c-isomers is related to the
mesomeric stabilization of the anion involving the ring
nitrogen. Former methods characteristically realized
such c-deprotonation/substitution operations via LDA
at À78 °C, with the application of the expensive
Weinrebamides as the corresponding electrophiles.5,6
We performed this fundamental step according to
Thompson’s protocol12 using sodium bis(trimethyl-
silyl)amide (NaHMDS) in THF at moderate temperatures
using easily accessible fluoro-substituted benzoic acid
esters, thus avoiding the disadvantages of low reaction
temperature, the requirement for a strictly inert atmo-
sphere, and lengthy reaction time. Herein, ethyl esters
2 provided better results than methyl esters. After
deprotonation of 2-halogeno-4-methylpyridine or
4-methylquinoline at 0 °C and the addition of the
corresponding ethyl fluorobenzoates, the mixtures were
R1
R1
R1
R1
R1
i
ii
iii
iv
O
O
O
N
O
N
S
O
2
84-100%
62-91%
100%
11-84%
N
H
R3
H5C2
R2
3
R2
OH
R2
NH3+ Cl
,
R2
4
5
6
R1 = 4-Fluoro-, 3-trifluoromethyl-
R2 = (halogen-substituted) heteroaryl moiety
R3 = alkyl/arylalkyl moiety
halogen = F, Cl, Br
Scheme 1. Optimized synthesis of 2-thioimidazoles. Reagents and conditions: (i)12 NaHMDS 2.0 M in THF, 2-halogeno-4-methylpyridine or 4-
methylquinoline, THF, 0 °C then rt; (ii) NaNO2, glacial acetic acid; (iii) H2, Pd–C 10%, 1 atm, 2-propanolic hydrogen chloride, rt; (iv) DMF,
methyl-/ethyl-/benzylthiocyanate, reflux.

S. A. Laufer, A. J. Liedtke / Tetrahedron Letters 47 (2006) 7199–7203
7201
Table 1. Summarization of the synthetic route to key intermediate amino ethanone hydrogen chloridesa
R1
4-Fluoro-
4-Fluoro-
3-Trifluoromethyl-
N
N
N
R1
R1
R1
R2
X
X
O
R2
R2
R2
X
F
Cl
Br
F
Code
(Yield)
7 (86%)
8 (84%)
9 (87%)
10 (100%)
a
11
Cond.
R2
a
a
a
a
N
N
N
O
N
X
X
OH
X
F
Cl
Br
F
16 (82%)b
Code
(Yield)
12 (84%)
13 (91%)
14 (82%)
15 (62%)
b
Cond.
b
b
b
b
N
N
N
R2
X
O
X
X
NH3+ , Cl
F
Cl
H
F
Code
(Yield) 17 (100%) 18 (100%) 19 (100%)
20 (100%)
21 (100%)
a Reagents and conditions: (a) NaNO2, glacial acetic acid; (b) H2, Pd–C 10%, 1 atm, 2-propanolic hydrogen chloride, rt.
b Yield over 2 steps.
procedure of the Marckwald synthesis. Herein, a-amino
ketones were originally condensed with KSCN to give
imidazole-2-thiols. We have already reported using such
4,5-diaryl-imidazole-2-thiols for probing substituents in
the 2 position of the imidazole.14 Our idea was now to
directly constitute 2-(aryl-)alkylsulfanyl-4,5-diaryl-
imidazoles in a single step following the Asinger
procedure,15 reported for cyclization reactions of a-mer-
capto ketones. Moreover, we increased the overall yield
compared to our former multi-step procedure. Initially
we selected methyl, ethyl, and benzyl thiocyanate, to
couple with the a-amino carbonyl salts. The resulting
C2–S-methyl- or benzyl-substituted imidazoles (Table
2) were already known to be good pharmacophores
for p38 MAP kinase inhibition.1,9,14 Additionally, the
protocol of Ando16 that permits a simple thiocyanate
reagent preparation using inorganic-solid-supported
potassium thiocyanate attracted our interest. All cycliza-
tions were performed in DMF. In general, the a-amino
ethanones were dissolved at room temperature in abso-
lute DMF under argon and to this solution a 2- to 2.5-
fold excess of the liquid or solid thiocyanate was directly
added in one portion by rapid injection (22a,9 22b, 23a,9
23b, 24,9 25, 26a, and 26b) or per hopper, respectively
(22c,9 23c,9 26c). Typically the primary bright orange
mixtures turned to intensive red when warming to reflux
temperature (160 °C, 45 min). Completion of the reac-
tions was indicated by the color change of the refluxed
solutions to orange from the initial red. The mixtures
were allowed to cool slowly to room temperature and
ice cold water was added. In many cases, a fine yellow
to orange product precipitated (22a, 24, 26a) or an or-
ange to brownish viscous mass (22c, 23a) dropped out
of the solution and was gathered (Table 2, variant A)
and dried in vacuo over CaCl2. Contrary to our expec-
tation, the isolated residues of 22a, 24, and 26a showed
satisfactory analytical results and required no further
purification. The raw products 22c and 23a could be
solidified and obtained pure by washing with a little cold
diethyl ether. Alternatively, the DMF/H2O mixture was
extracted with ethyl acetate and after evaporation of the
solvents, the resulting oily crude residue was purified by
column chromatography (22b, 23b,c, and 26b,c) (variant
B) or preparative TLC (25) (variant C). As summarized
in Table 2, isolated yields ranged from modest to excel-
lent, and were dependent on the inserted thiocyanates as
well as the provided aminoethanone hydrogen chlorides.
For the resultant 2-methylsulfanylimidazoles, the yield

7202
S. A. Laufer, A. J. Liedtke / Tetrahedron Letters 47 (2006) 7199–7203
Table 2. Synthesis of 2-(aryl-)alkylsulfanyl imidazoles
a-Aminoketone
Product
Code
R3
Varianta
Yieldb (%)
GC–MSc (m/z)
F
F
O
22a
22b
22c
–CH3
–C2H5
–Bnd
A
B
A
77
35
56e
303 (M+)
317 (M+)
379 (M+)
N
S
NH3+
R3
N
H
, Cl
N
N
F
F
17
22
F
F
23a
23b
23c
–CH3
–C2H5
–Bn
A
B
B
68e
32
320 (M+)
333 (M+)
395 (M+)
O
N
49
S
NH3+
,
Cl
N
H
R
3
N
N
Cl
18
Cl
23
F
F
O
N
24
–CH3
A
30
285 (M+)
S
NH3+
19
,
Cl
N
H
R
3
N
N
24
F
F
O
N
S
335 (M+)
NH3+
N
H
25
–CH3
C
25
, Cl
R3
N
N
20
25
CF3
CF3
O
N
353 (M+)
367 (M+)
429 (M+)
S
26a
26b
26c
–CH3
–C2H5
–Bn
A
B
B
84
11
42
NH3+
N
H
R3
,
Cl
N
N
F
F
21
26
a Variant A: Precipitation with H2O and if required, washing the crude product with a little cold diethyl ether; Variant B: Extracting with ethyl
acetate, then column chromatography (SiO2 60, dichloromethane/ethyl acetate, 1/1); Variant C: Extracting with ethyl acetate followed by
preparative TLC (RP-18 F254, methanol/H2O, 9/1).
b Conditions: DMF, 160 °C, 45 min.
c GC/MS analyses were carried out on a HP 6890 series GC-system equipped with a HP-5MS capillary column and a HP 5973 mass selective detector
(70 eV).
d Bn = Benzyl = –CH2Ph.
e Contains traces of side products (GC).

S. A. Laufer, A. J. Liedtke / Tetrahedron Letters 47 (2006) 7199–7203
R1
7203
R1
Supplementary data
Selected experimental procedures and spectroscopic
data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.07.147.
N
i or ii
N
S
S
N
H
N
H
R3
R3
N
N
27
28
Y
F
References and notes
R4
R1 = e.g. 4-fluoro-, 3-trifluoromethyl-
R3 = alkyl/arylalkyl moiety, preferably -CH3
R4 = (substituted) alkyl/(hetero)arylalkyl/(hetero)aryl moiety
Y = HN, O, S
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was generally high when the pyridine moiety was halo-
gen substituted. The fluoropyridylimidazole compounds
22a–c and 26a–c can be used for further substitutions
with various aromatic, heteroaromatic or aliphatic
amines, alcohols, or thioalcohols to optimize p38 inhibi-
tion activity or to decrease CYP interaction as described
elsewhere9,17,18 (Scheme 2).
3. Conclusions
In summary, two major synthetic achievements were
realized. First, the construction of fundamental etha-
nones 2 was simplified by conducting the reaction at
moderate temperature and with less strictly inert condi-
tions. Reaction time was drastically minimized while
yields were constantly high (84–100%) as compared to
our already reported method that suffered from irregu-
lar yields (5–99 %). The procedure could be applied to
diverse starting compounds (Table 1). Moreover, we
demonstrated that a series of alkyl- or arylalkyl thio-
cyanates are convenient cyclization reagents for the
direct production of 2-(aryl-)alkylsulfanyl imidazoles
in moderate to excellent yields (up to 84%) from several
amino ethanone hydrogen chlorides. Preparation of the
analogous 2-thioimidazoles by former multi-step proce-
dures only afforded, at maximum, 39% yield (last step).
Fluoro- and chloropyridine moieties are compatible
with the process. Only in the bromopyridine derivative
14, was bromine hydrogenolytically cleaved during the
reduction step. The optimized thioimidazole synthesis
also afforded the production of some new derivatives
(22b, 23b, 25, 26a–c) which can be used either as test
candidates or as intermediates for further synthetic
optimizations. In most cases, when applying methylthi-
ocyanate as the cyclization reagent, the desired, almost
pure products could be directly precipitated from
DMF. In using ethyl- or benzylrhodanide, a subsequent
extraction and purification was casually necessary. In
contrast to former thioimidazole syntheses and in
comparison to already available data, this new
cyclization reaction accelerates and improves imidazole
building while increasing total yields.
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