The application of Stille cross-coupling reactions with multiple nitrogen containing heterocycles

Article abstract of DOI:10.1016/j.tet.2011.09.053

Substituted imidazoles and purine bioisosteres have been widely studied in the literature. We endeavored to combine these heterocyclic core structures into precursors, especially 7-azaindoles, of previously unknown pharmacologically relevant lead structur

Full text of DOI:10.1016/j.tet.2011.09.053

Tetrahedron 67 (2011) 9204e9213
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The application of Stille cross-coupling reactions with multiple nitrogen
containing heterocycles
,
,
Roland Selig a y, Dieter Schollmeyer b, Wolfgang Albrecht c, Stefan Laufer a
*
a Department of Medicinial Chemistry, University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
b Department of Organic Chemistry, University Mainz, Duesbergweg 10-14, 55099 Mainz, Germany
c c-a-i-r biosciences GmbH, Paul-Ehrlich-Strasse 15, 72076 Tuebingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2011
Received in revised form 4 September 2011
Accepted 13 September 2011
Available online 22 September 2011
Substituted imidazoles and purine bioisosteres have been widely studied in the literature. We endeav-
ored to combine these heterocyclic core structures into precursors, especially 7-azaindoles, of previously
unknown pharmacologically relevant lead structures. A highly flexible synthetic procedure was de-
veloped, derived from investigations of the influence of the substrates, solvents, ligand systems, and side
reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Purine
7-Azaindoles
Imidazoles
Stille cross-coupling
Destannylation
1. Introduction
pyrrolopyrimidines, and 7-azaindoles fulfill the specifications of
such a system. Therefore, we were in need to a robust and flexible
In recent years, purines and their bioisosteres have attracted
special interest in medicinal chemistry1e4 as inhibitors of kinase
activity or of phosphodiesterase 4 (PDE-4). Therefore, these het-
erocycles may be potentially useful for the treatment of rheumatoid
arthritis, COPD (chronic obstructive pulmonary disease), asthma,
and rhinitis. The rigid donoreacceptor systems of these compounds
constitute core subunits in many bioactive molecules and natural
products. In addition, imidazoles have been also widely studied as
potent p38 MAP kinase inhibitors.5 Many synthetic efforts have
been accomplished to introduce specific functionalizations to these
heterocycles. As part of our drug research discovery program, we
sought a robust method to functionalize the aforementioned het-
erocycles, faced with the difficulty of CeC bond formations be-
tween these core structures. In this study, we focussed on imidazole
synthesis, suitable to introduce various substituents at the C-5
position of the imidazole core.
Fig. 1. p38 MAP kinase inhibitors.
We considered palladium-catalyzed cross-coupling reactions to
introduce C-5 substituents to the central imidazole core as the most
promising synthetic strategy to fulfill this objective (Scheme 1).
structures as basic framework, derived from known p38a MAP ki-
nase inhibitors SB203580 and SKF86002 (Fig. 1). These inhibitors
have already been optimized by substituting the pyridinyl moiety
at the C-2 position by several alkyl- and arylamines 1 (Fig. 1). We
envisioned an exchange of the flexible amine moiety with seven-
membered heterocycles, which contain the essential hydrogen
bond donoreacceptor system. Heterocycles like purines,
* Corresponding author. Tel.: þ49 70712972459; fax: þ49 7071295037; e-mail
address: stefan.laufer@uni-tuebingen.de (S. Laufer).
Scheme 1. Retrosynthetic analysis of the target structures, based on the CeC cross-
coupling reaction.
y
Fax: þ49 7071295037.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.053

R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
9205
2. Results and discussion
2.1. Stannylation of imidazoles
Two possibilities appeared to be feasible for the cross-coupling
reaction, using either the halogenated imidazoles6 or the haloge-
nated heterocycles and the corresponding transmetallation part-
ners. We used the electron rich imidazoles as the transmetallating
agents and the electron poor heterocycles for the oxidative addition
(Scheme 1). Due to their electronic characters, CeC coupling should
be enforced. The halogenation of the desired heterocycles (Fig. 2)
can be achieved in good yields by literature known procedures.2,7e9
Scheme 2. Stannylation of the imidazole derivatives 2e8.
the electron donating effect is assisted by the þM-effect of the
bridged vinyl moiety. Then we tried to generate the more stable
CeSi bonding in the C-5 position (Scheme 3) of the two thio-
imidazole derivatives 8 and 9 from the brominated derivatives 10
and 12. The SeMe silylimidazole 11 could be synthesized while the
synthesis of the corresponding silylimidazothiazole 13 failed
(metalation of the thiazole 12 was proven by deuteration, see
Supplementary data). This outcome supports our hypothesis, that
the strengthened electron donating effect of sulfur is increased by
the enforced þM-stabilization, resulting in
a complete de-
stabilization of the CeSi bonding.
Fig. 2. Halogenated substrates for the cross-coupling reaction.
Scheme 3. Silylation of thioimidazoles.
The described methods of generating transmetallation coupling
centers on imidazoles led us to select the Stille-coupling reaction as
the most effective method.10
We attempted to synthesize stannylated imidazoles of the cor-
responding imidazoles 2e9 with a fixed substitution pattern in 2-
and 4-position (Fig. 3).
The same mechanism can be applied to the weaker CeSn
bonding (Scheme 4), which is now in a more unfavorable energetic
range than the CeSi bonding. The electronic character of the SeMe
bond of compound 8 is now sufficient to destabilize the CeSn
bonding. Similarly, this mechanism can also be observed by the
stannylation of the N-Me imidazole (Scheme 4).10 A destannylation
occurs in the 5- and 2-positions (14) and the most unstable
bonding, the C-2eSn bond, is hydrolyzed to compound 15. In the
case of the thioimidazole 16, the CeS bonding is the more stable
bonding, so that cleavage of the more labile 5-stannyl moiety is
favored.
Fig. 3. Imidazoles for stannylation.
Scheme 4. Electronic effect of C-2 substitution.
The C-5 stannylated derivatives of imidazoles 2e9 (Fig. 3) were
expected to be useful as broad synthetic platform for the variation
of the C-5 position of the central imidazole core. The synthesis of
the imidazole derivatives 2e9 (Fig. 3) was accomplished by litera-
ture known procedures.6,11e14 Stannylation of the diarylimidazoles
2e7 via C-5 lithiation yielded positive results (Scheme 2) and the
stannylated imidazoles were used for the subsequent cross-
coupling reaction without further purification, due to an observed
protodestannylation. In the course of the imidazole stannylations,
we could observe a strong dependency on the C-2 substitution of
the imidazole core. This was supposed to be the reason for the
failed stannylation of thioimidazole 8 (Scheme 2).
In conclusion, electron rich substituents at C-2 position of the
imidazole prevent stannylation in C-5-position. Therefore, we
changed the electron donating character of sulfur by its oxidation to
the corresponding sulfone 17 (Scheme 5). The sulfone could be
stannylated by the above mentioned procedure. The subsequent
Stille-coupling provided compound 19, further deprotection lead to
compound 20.
2.2. Reactivity of the stannylimidazoles with different purine
biosisosters
We assumed that the electron donating character of sulfur with
its þM-effect, affording high electron density at the C-5 position of
the imidazole, prevents the CeSn bond formation. To evaluate this
assumption, we synthesized the corresponding thiazole 9 where
The rare literature known Stille couplings of imidazoles and
halogenated heterocycles are confined to electron poor heterocy-
cles and therefore activated species like pyridine,15 pyrimidine16 or

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R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
Table 2
Cross-coupling with different Pd/ligand ratios
Entry
Conditions
Catalyst loading
Ratio
Pd/ligand (PPh3)
t (min)
Yieldb
TOF
1
2
3
4
5
6
79 ꢀCa
1/2
1/2
1/3
1/3
1/4
1/4
227
12%
13.2 mol %
0.21 hꢁ1
26%
79 ꢀCa
Overnight
227
13.2 mol %
79 ꢀCa
9%
15.3 mol %
0.14 hꢁ1
29%
79 ꢀCa
Overnight
227
Scheme 5. Stannylation and CeC cross coupling of the sulfone 17.
15.3 mol %
79 ꢀCa
5%
13.4 mol %
0.09 hꢁ1
8%
purine.17 The reactivity of these heterocycles is sufficient enough
for cross-coupling reactions without the problems we found in case
of electron rich and therefore deactivated heterocycles. In analogy
to the procedures of Liverton,16 we performed cross-coupling ex-
periments with several combinations of halogenated purines and
bioisosteric structures (Fig. 2), using PdCl2(PPh3)2 as pre-catalyst in
THF (Table 1, entries 1e4). The yields corresponded to our expec-
tations. The electron poor heterocycles, purines and pyrrolopyr-
imidines, excelled in providing high yields and high reaction rates
due to their electron poor character (Table 1, entries 1e3).
79 ꢀCa
Overnight
13.4 mol %
a
Dioxane (3 ml), stirring frequency 5r/s, 2 equiv of the stannylated imidazole 2
(0.068 mmol).
b
Quantified by HPLC.
The turn-over frequencies (TOFs) decreased with increasing Pd-
ligand ratio (Table 2, entries 1, 3, and 5). The overall yield was
shown to be equal to the 1/2 and 1/3 ratio (Table 2, entries 2 and 4),
whereas the 1/4 ratio was shown to be ineffective (Table 2, entries 5
and 6). The observed catalyst decomposition was inhibited by
raising the Pd/ligand ratio to 1/3. The decomposition could only be
observed after heating overnight, in contrast to the 1/2 ratio with
an observable decomposition after heating for 4 h.
Table 1
Accomplished cross-coupling reactions with the different heterocycles
To optimize the synthetic procedure to a high yielding pro-
cedure, it was necessary to determine the rate determining steps of
the catalytic pathway. We performed several coupling experiments
with activated purine and deactivated azaindole halogen de-
rivatives with Pd(PPh3)Cl2 as the pre-catalyst (Table 3), using the
stannylated imidazole 2 for the transmetallation.
Entrya Stannylated imidazole Heterocycleb Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
3
4
6
a
c
b
e
d
a
e
f
g
h
i
g
g
g
THF
THF
THF
THF
62
63
55
10
Table 3
Cross-coupling of purine and azaindole derivatives with PdCl2(PPh2)3
Dioxane 52
Dioxane 80
Dioxane 27
Dioxane 40
Dioxane 21
Dioxane 39
Dioxane 31
Dioxane 31
Dioxane 35
Dioxane 48
9
10
11
12
13
14
Entrya
Catalyst loading
Heterocyclec
t (min)
Yieldd (TOF)
1a
2a
3a
4a
5a
6b
20 mol %
23 mol %
21 mol %
25 mol %
21 mol %
30 mol %
l
20/40
20
20/40
20/40
20/40
20
16/22 (1.1 hꢁ1/0.7 hꢁ1
)
m
a
j
k
a
35 (4.4 hꢁ1
)
23/33 (3.3 hꢁ1/2.4 hꢁ1
15/19 (1.8 hꢁ1/1.1 hꢁ1
)
)
a
Solvent (4 ml), stirring frequency 5r/s, 2 equiv of the stannylated imidazole 2,
reflux temperature.
9/11 (1.2 hꢁ1/0.8 hꢁ1
12 1.2 hꢁ1
)
b
w0.09 mmol.
a
Dioxane (1 ml), stirring frequency 5r/s, 2 equivof the stannylatedimidazole2,101 ꢀC.
b
c
Dioxane(1 ml), stirringfrequency5r/s, 2 equivofthestannylatedimidazole2, 72 ꢀC.
The yields and reaction rates with 7-azaindole were strongly
decreased (Table 1, entry 4) by virtue of the increased electron
density, which led to decreased reactivity in the oxidative addition
and the transmetallation. Therefore, we tried to develop a high
yielding synthetic procedure focusing on this problem. A first
modification of the reaction conditions was to change the solvent
from THF to dioxane with the intention of higher reaction tem-
peratures and thus higher reaction rates (Table 1, entries 5e14). The
improved, but moderate yields led us decide to further investigate
these coupling reactions.
w0.09 mmol.
Quantified by HPLC.
d
As expected, the reactivity profile inverted with the substrate.
The turn-over frequencies of the halogenated purines increased in
the following order Cl>Br>I (Table 3, entries 3e5). This ranking
corresponds to the transmetallation being the rate determining step
and to an associative mechanism.18 Two possible explanations for
the inverted reactivities of the corresponding halogenated azain-
doles (Table 3, entries 1 and 2) are feasible. The oxidative addition
may be rate determining and therefore the chlorinated species is
disfavored. On the other hand, a dissociative mechanism should
present the same reactivity profile as the azaindole due to
To exclude the observed catalyst decomposition as reason for
the lowered yields with the PdCl2(PPh3)2 system, we tried to sta-
bilize the catalyst by increasing the palladium/ligand ratio from 1/2
up to 1/4 (Table 2, entries 1e6).

R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
9207
a facilitated ligand dissociation in the case of the less electronegative
halogenides. To clarify the observed reactivities, we performed the
cross-coupling reactions with tri-2-furylphosphine (TFP) (Scheme
The observed destannylation is already described in litera-
ture.21,22 In order to surpress the destannylation, we made addi-
tional series of experiments. To investigate a possible thermal
decomposition of the stannyl substrate, we first heated the stan-
nylated compound 2 (Table 4, entry 6) in dioxane for 1 h at reflux
temperature. The decomposition of 1% is not corresponding to the
observed decomposition within the cross-coupling reaction. Traces
of water are a common assumed culprit for the destannylation via
a mechanism of protodestannylation. Therefore, we examined the
destannylation of the stannylated compound 2 under drastic water
concentrations (compared to traces of water) of 0.1 ml per ml under
reflux conditions and argon atmosphere. An enhanced de-
composition took place, but the decomposition rate of 11% per hour
(Table 4, entry 5) was also not in the range of the observed de-
composition in the coupling reaction. Examination of the destan-
nylation in combination with the catalyst resulted in strongly
increased decomposition rates. The marked increase in the de-
composition of the stannylated species by the catalyst indicates,
that the destannylation step is involved in a catalytic mechanism. A
further increase of catalyst decomposition was observed by the
addition of water (0.1 ml per ml), indicating a direct dependency of
the destannylation rates on the water concentration. Traces of
water can be expected in the pre-catalyst and in the stannyl com-
pound. We assumed, that traces of water are mainly originated
from the stannyl substrate. This is in accordance with the synthesis
of the stannylimidazoles, by using an excess of butyllithium and
tributylstannyl chloride with subsequent quenching by water.
Tributylstannyl hydroxide is formed as byproduct, which can fur-
ther react to the distannylether under release of water by heating.23
Thus, a water induced catalytic destannylation can take place. To
elucidate a possible influence of the various ligands, we quantified
the destannylation of the stannylated species 2 with different li-
gand systems of the catalyst by quantitative NMR (Table 4, entries
1e5).
6). The lower
s-donor activity should favor the transmetallation
reaction and decrease the rate of oxidative addition.19,20 If the
transmetallation is the rate determining step, an enhanced reaction
rate should be observed in contrast to the PPh3 ligand system. In the
case of the chlorinated purine a (Fig. 2), a 3.5fold increase of the
reaction rate was monitored at 72 ꢀC (Scheme 6/Table 3, entry 6),
whereas the chlorinated azaindole l showed no activity, even at
higher temperatures. This result is consistent with our assumption
that the transmetallation is the rate determining step in the cross-
coupling reaction of purines, whereas the cross-coupling reaction
of azaindoles seems to be determined by the oxidative addition,
hindered by the lower nucleophilicity of the PdeTFP-species.
Scheme 6. Coupling reaction of the chlorinated azaindole and purine with TFP as li-
gand system (catalyst loading 11 mol %, dioxane, 72 ꢀC).
The cross-coupling procedure for the purine substrates could be
optimized with the TFP-ligand system by facilitation of the trans-
metallation reaction. In case of the azaindole substrates, this
strategy is unfeasible, because of their supposed inversion of the
rate determining steps.
Table 4
2.3. Destannylation process
Effect of the catalyst on destannylation of the stannylated imidazole 2
The limiting factor in this reaction is the stability of the in-
dividual stannylated imidazoles, expressed in the monitored de-
composition of the stannyl derivatives as competitive reaction of
the cross-couplings (Scheme 7). Especially, the cross-coupling re-
action with the low reactive azaindoles is dominated by this side
reaction. A further detrimental effect is the strong catalyst de-
composition, indicated by Pd-black.
Entrya
1
Catalyst
t (h)
Additive
Decompositionb
PdCl2(PPh3)2
11 mol %
0.37
d
38.9%
1.8%/min
(TOF 9.6)
22.7%
2.8%/min
(TOF 16.5)
33.2%
1.5%/min
(TOF 6.82)
40.8%
5.1%/min
(TOF 18.7)
8.2%
0.1%/min
(TOF 0.27)
1.3%
0.02%/min
11.1%
2
3
4
5
PdCl2(PPh3)2
11 mol %
0.13
0.37
0.13
1.25
H2O
d
Pd(OAc)2/X-Phos
13 mol %
Pd(OAc)2/X-Phos
16 mol %
H2O
d
Pd(OAc)2/TFP
28 mol %
6
7
d
d
1.03
0.55
d
H2O
0.3%/min
a
Dioxane (2 ml), stirring frequency 5 r/s, 0.09 mmol of stannylated imidazole 2,
72 ꢀC.
b
Quantified by NMR.
The destannylation rates were in the range between 0.02%/min
(no catalyst, Table 4, entry 6) and 1.8%/min (PdCl2(PPh3)2/11 mol %,
Table 4, entry 1). The decomposition rates were further increased
by adding water to the reaction mixture (Table 4, entries 2 and 4).
Scheme 7. Stille-coupling and competitive destannylation.

9208
R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
Table 6
As shown, the destannylation process is strongly dependent on the
water concentration. On this account, the monitored TOFs of the
cross-coupling and the destannylation reactions should be evalu-
ated with care, since the concentration of water can vary with the
lot of the stannylated compounds. In comparison to PPh3, nearly
the same destannylation rates can be observed with X-Phos (2-
Dicyclohexylphosphino-20,40,60-triisopropylbiphenyl) as ligand
Cross-coupling with Pd(OAc)2/X-Phos (1/3) as pre-catalyst
Entry
Conditions
Catalyst loading
Heterocyclec
t (min)
Yieldd
TOF
1
2
3
4
5
6
101 ꢀCa
5 mol %
101 ꢀCb
7 mol %
101 ꢀCa
10 mol %
72 ꢀCa
l
20
5
34%
16.6 hꢁ1
70%
l
121 hꢁ1
18%
system, whereas the low
s-donor TFP (trifurylphosphine) is sig-
m
a
j
20
20
20
20
1.2 hꢁ1
34%
nificantly reducing the destannylation process. A high electron
density on the Pd-center seems to be crucial for the destannylation
process, exemplified by the PPh3 (Table 4, entry 1) as well as the X-
Phos system (Table 4, entry 3) with comparable reaction rates. In
conclusion, the destannylation process is involved in a catalyst
dependent reaction path. Regarding the overall cross-coupling
procedure, there is a competing effect of the destannylation and
the cross-coupling reaction on the catalyst. Therefore, the domi-
nating reaction is determined by the reaction rates of the two in-
dividual reaction pathways.
6 mol %
17.1 hꢁ1
13%
72 ꢀCa
4 mol %
72 ꢀCa
5 mol %
9.7 hꢁ1
5%
k
2.6 hꢁ1
a
Dioxane (1 ml), stirring frequency 5 r/s.
Microwave 300 W, 101 ꢀC, 1 ml dioxane.
w0.09 mmol, 2 equiv stannylimidazole.
Quantified by HPLC.
b
c
d
The effect of X-Phos on the electron poor purine derivative was
2.4. Optimization of the cross-coupling reaction
positively influenced by the accelerating effect of X-Phos on the
transmetallation,27 resulting in a fourfold increased reaction rate
compared to TFP (Table 6, entry 4, Scheme 6). In the case of chlor-
azaindole l with X-Phos, the TOF is about 15-fold higher than in the
case of the PPh3 ligand system under the same conditions (Table 3,
entry 1 and Table 6, entry 1). Another benefit of this ligand system is
the stability in the course of the reaction. The TOFs with X-Phos were
nearly constant and the catalyst decomposition was also strongly
decreased, which allows a reliable product formation in contrast to
PdCl2(PPh3)2. To directly compare the effects of the PPh3 and X-Phos
ligand systems on the competing reaction of the cross-coupling, we
measured the product formation and the destannylation via quan-
titative NMR and HPLC (Scheme 8/Fig. 4) by reacting the stannylated
imidazole 2 and the chlorinated azaindole l.
Combining these gained results, we optimized the cross-
coupling of the deactivated 7-azaindoles. At first, we focussed on
a technical modification of the synthetic procedure by stepwise
addition of the stannylimidazoles. As shown above, the oxidative
addition was supposed to be the rate determining step in the case
of azaindole with PPh3 as ligand system. Consequently, the rate of
the reaction should be independent of the concentration of the
stannylated species. The rate of the destannylation proved to be
dependent on the water concentrations, resulting from the stan-
nylated compounds. By stepwise addition of the stannylimidazoles,
the water concentration is reduced to a minimum without affecting
the rates of the cross-coupling reactions. This strategy allowed us
a threefold increase of the yields from 21% (Table 1, entry 9) to 67%
(Table 5, entry 1), with PdCl2(PPh3)2 as pre-catalyst. Similar results
were obtained in further experiments with related stannylimida-
zoles (Table 5, entries 2e4).
Table 5
Improved cross-coupling procedure by stepwise addition of the stannyl compound
Scheme 8. Quantification of cross-coupling with l versus destannylation of the stan-
nylated imidazole 2.
Entry
Stannylated
imidazole
Heterocycle
Solvent
Isolated
yield (%)
1
2
3
4
2
3
5
7
g
g
g
g
Dioxane
Dioxane
Dioxane
Dioxane
67
65
60
71
The effects of the ligand sphere on the destannylation process
led us decide to use X-Phos in the following coupling experiments.
In general, the rate constant of the coupling reaction should sig-
nificantly exceed the rate constant of the competing destannyla-
tion. The inhibitory effect of 7-azaindoles in the coupling reaction is
due to their obstructed oxidative addition. Thus, the cross-coupling
reactions should be enhanced by using ligands with higher re-
activity toward the oxidative addition and without affecting the
rate of the destannylation. In our investigations of the destanny-
lation, X-Phos and PPh3 showed nearly the same reactivities (Table
4, entries 1 and 3). On the other hand, a markedly differing re-
activity toward the oxidative addition was expected. Based on the
bulkiness of X-Phos, an increase of the reactivity toward oxidative
addition with X-Phos can be expected.24e26 The rate constants of
the electronic contrary chlorinated purine and azaindole de-
rivatives with X-Phos as ligand system were determined by quan-
titative HPLC (Table 6), using the stannylated imidazole 2 as
representative substrate for the transmetallation.
Fig. 4. Destannylation and product formation in the cross-coupling experiment with
Cl-azaindole l.

R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
9209
The cross-coupling was performed with a stannyl overload of
4. Experimental section
2 equiv. The product to destannylation ratio of the cross-coupling
with PdCl2(PPh3)2 was 0.5 (Fig. 4), so the catalyst activity toward
the coupling reaction was reduced to about 30%. A theoretical
overload of 3 equiv of the stannylimidazole would be necessary to
achieve a full product conversion. The observed poor stability of the
catalyst is an additional factor to exclude a full product conversion.
The product to destannylation ratio of 3.8 in the case of X-Phos was
completely inverted (Fig. 4) with a catalyst activity of 80%. A the-
oretical overload of 1.2 equiv of the stannylimidazole would be
sufficient for quantitative conversion. The stability of the catalyst
with its constant turn-over frequencies (Table 3) guarantees a full
product conversion, which was observed in the ongoing performed
experiments.
In the case of the X-Phos ligand, a selective, nearly unidirec-
tional acceleration of the cross-coupling path was shown. The
cross-coupling reaction dominates the overall reaction. In con-
trast, the destannylation is the dominant factor in the cross-
coupling reaction with PPh3, reflected by the poor yields in the
coupling experiments with the azaindoles (Table 1, entries 4 and
7e13). To further accelerate the cross-coupling reaction, we also
used microwave irradiation and examined, in case of the chlori-
nated azaindole l, a strongly increased turn-over frequency (Table
6, entry 2). The TOF was raised up from 1.1 hꢁ1 (Table 3, entry 1),
16.6 hꢁ1 (Table 6, entry 1) to 120.9 hꢁ1 (101 ꢀC/microwave irra-
diation) (Table 6, entry 2). We transferred these gained results to
the substituted azaindoles f, g, i and to the purine a. The cross-
coupling experiments were performed under microwave irradia-
tion for 10e15 min with a catalyst loading of 8 mol % (Table 7).
The yields were comparable with the yields, which were obtained
within 1 h under reflux conditions. The up to nearly quantitative
yields were in accordance to our results of this optimization
study.
4.1. General experimental methods
All commercially available reagents and solvents were used
without further purification. NMR data were obtained on a Bruker
Spectrospin AC 200 instrument at ambient temperature. High-
resolution spectral mass data were obtained on a Thermo Fin-
nigan TSQ70 instrument. Melting points were measured on a Bue-
chi Melting Point B-545 instrument. IR-spectra were obtained by
a PerkineElmer Spectrum One (ATR) instrument. LCemass spec-
trometry (MS) spectra were recorded by a Finnigan TSQ Quantum
triple quadrupole mass spectrometer (Finnigan MAT). GCeMass
spectrometry was done by Hewlett Packard HP 6890 Series GC-
System (Hewlett Packard HP 5973 Mass Selective Detector).
Method used for GCeMS: starting 120 ꢀC, hold 2 min; heating rate
10e200 ꢀC, hold 1 min; heating rate 10e300 ꢀC, hold 5 min.
4.2. General procedure of stannylation of the imidazoles
The N-protected diarylimidazole was dissolved in THF and
cooled to ꢁ78 ꢀC. Then n-BuLi was added. The reaction mixture was
stirred for 60 min at ꢁ78 ꢀC, then ClSnBu3 was added and the re-
action mixture was stirred for 30 min at rt. The solvent was re-
moved under reduced pressure and the obtained oily product was
used for following coupling reactions without further purification.
4.3. General procedures of the cross-coupling procedures
4.3.1. General procedure of Stille-coupling (methods A and B). The
halogenated N-protected heterocycle, PdCl2(PPh3)2 (0.3 mol %) and
the stannylimidazole (2 equiv) was dissolved in 3e6 ml THF (pro-
cedure A) or dioxane (procedure B). The reaction mixture was
stirred at reflux temperature under argon atmosphere for up to 4 h.
After quenching with KF (40% in water) and extracting with EtOAc,
the crude product was purified by flash-chromatography.
Table 7
Cross-coupling procedure under microwave irradiation
Entry
Stannylated
imidazolea
Heterocycle
Solventb
Isolated
yield (%)
4.3.2. General procedure of Stille-coupling (method C). The haloge-
nated N-protected heterocycle, PdCl2(PPh3)2 (0.3 mol %) was dis-
solved in 3e6 ml dioxane the stannylimidazole (2 equiv) was added
stepwise (consumption of the stannyl derivative was monitored by
TLC) to the reaction mixture at reflux temperature under argon at-
mosphere, after complete consumption of the added stannylimi-
dazole. After quenching with KF (40% in water) and extracting with
EtOAc, the crude product was purified by flash-chromatography.
1
2
3
4
2
2
5
2
a
g
g
i
Dioxane
Dioxane
Dioxane
Dioxane
79
94
92
50
a
2 equiv.
1 ml.
b
3. Conclusion
4.3.3. General procedure of Stille-coupling (method D). A premilled
mixture (0.1 mol % Pd) of Pd(OAc)2 and X-Phos (1/3) was stirred in
dioxane for 30 min, the yellow solution turned to a dark purple
solution. The halogenated N-protected heterocycle and the stan-
nylimidazole (2 equiv) was added to the reaction mixture and
heated under microwave irradiation (300 W, 100 ꢀC, 10e15 min)
under nitrogen atmosphere. After quenching with KF (40% in wa-
ter) and extracting with EtOAc, the crude product was purified by
flash-chromatography.
The performed optimization study of cross-coupling experi-
ments with different activated and deactivated halogen derivatives
of purine and its bioisosteres showed a substrate- and catalyst-
dependent reactivity profile with respect to the cross-coupling
reaction. A ligand-based substrate specific optimization for the
cross-coupling of the electron poor halogen derivatives by using
TFP as the ligand system was accomplished. We achieved an
overall optimization for activated and deactivated halogenated
heterocycles with up to nearly quantitative yields (Table 7) by
using X-Phos as the ligand system, raising the turn-over frequen-
cies from 1.1 hꢁ1 to 120.9 hꢁ1. The competitive destannylation was
demonstrated as a catalyst dependent reaction path as well as
a ligand and substrate induced selectivity could be shown. The
destannylation reaction could be significantly surpressed by
a nearly unidirectional acceleration of the coupling reaction. The
destannylation reaction could also be lowered by a technical
modification, which can be generally applied to cross-coupling
reactions with the problem of sensitive transmetallating sub-
strates and deactivated halogenides.
4.3.4. General procedure of Stille-coupling (method E). A premilled
mixture of Pd(OAc)2 and X-Phos (1/3) was stirred in dioxane for
30 min, the yellow solution turned to a dark purple solution. The
halogenated N-protected heterocycle and the stannylimidazole
(2 equiv) was added to the reaction mixture and heated under ni-
trogen atmosphere until complete consumption of the starting
materials (monitored by TLC).
4.3.5. General procedure of Stille-coupling (method F). A premilled
mixture of Pd(OAc)2 and TFP (1/3) was stirred in dioxane for

9210
R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
30 min, the yellow solution turned to a dark purple solution. The
halogenated N-protected heterocycle and the stannylimidazole
(2 equiv) was added to the reaction mixture and heated under ni-
trogen atmosphere.
1H NMR (200 MHz, chloroform-d)
5.20 (s, 2H) 7.03 (m, 4H) 7.31 (s, 1H) 7.77 (m, 4H); 13C NMR
(50.33 MHz, chloroform-d) ppm 55.3, 56.3, 77.3, 114.1, 115.8 (d,
J¼21.6 Hz), 116.2, 122.4, 126.6 (d¼8.0 Hz), 130.1 (d, J¼3.0 Hz), 130.4,
140.2, 148.9, 160.36, 162.0 (d, J¼245.1 Hz); MS (GCeMS) tR; m/z:
19.9Min,312; mp. 71 ꢀC.
d ppm 3.38 (s, 3H) 3.84 (s, 3H)
d
4.3.5.1. 4-(4-Fluorophenyl)-1-methyl-2-(methylthio)-5-(trime-
thylsilyl)-1H-imidazole (11). 5-Bromo-4-(4-fluorophenyl)-1-methyl-
2-(methylthio)-1H-imidazole 200 mg (0.7 mmol) was dissolved in
5 ml dry THF, after addition of 78 mg (0.7 mmol) iso-
propylmagnesium chloride (2 M in THF), the reaction mixture was
stirred for 45 min. Then 70 mg (0.7 mmol) trimethylsilylchloride was
added and the reaction mixture was stirred for 1 h. The reaction was
quenched with water and extracted with ethylacetate. The organic
layer was separated and solvent was removed under reduced pres-
sure. The crude product was subjected to flash-chromatography (el-
uent ethylacetate/n-hexane 1/2) to yield 115 mg (59%) of the pure
product. TLC (ethylacetate/n-hexane 1/2): Rf¼0.81; IR (ATR) [cmꢁ1]:
2949,1534,1476,1303,1251,1218,1156,1122,1090, 837, 817, 765, 693;
4.3.5.7. 4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-1H-imidazole
(educt of 3). Yield 56% (0.814 g, 3 mmol); IR (ATR) [cmꢁ1]: 3003,
1614, 1570, 1502, 1435, 1254, 1216, 1175, 1134, 1027, 836, 814, 781,
740, 678, 634, 553, 530, 519; 1H NMR (200 MHz, chloroform-d)
d
ppm 3.75 (s, 3H) 6.81 (d, J¼8.34 Hz, 2H) 6.99 (m, 2H) 7.64 (m, 2H)
7.74 (d, J¼8.46 Hz, 2H) 9.58 (s, 1H); 13C NMR (50.33 MHz, chloro-
form-d)
d
ppm 55.2, 114.1, 115.4 (2C, d, J¼21.6 Hz), 122.6, 126.6 (d,
J¼7.9 Hz), 127.0, 129.1 (d, J¼3.3 Hz), 138.6, 147.4, 160.1, 161.9 (d,
J¼245.8 Hz); MS (GCeMS) tR, m/z:19.7, 268; mp: 145 ꢀC.
4.3.5.8. 4-(4-Fluorophenyl)-2-(3,4,5-trimethoxyphenyl)-1H-imid-
azole (educt of 6). Yield 72% (4.2 g, 15 mmol); IR (ATR) [cmꢁ1]:
2938, 1588, 1499, 1464, 1432, 1230, 1123, 999, 836, 813, 768, 729,
1H NMR (200 MHz, methanol-d4)
(s, 3H) 7.04 (m, 2H) 7.28 (m, 2H); 13C NMR (50.33 MHz, methanol-d4)
d ppm 0.07 (s, 9H) 2.47 (s, 3H) 3.68
d
ppm 0.48, 16.8, 34.9, 115.5 (2C, d, J¼22.1 Hz), 130.2, 133.1 (d,
665; 1H NMR (200 MHz, chloroform-d)
d
ppm 3.67 (s, 3H) 3.79 (s,
6H) 6.99 (m, 2H) 7.16 (s, 2H) 7.30 (s, 1H) 7.64 (m, 2H); 13C NMR
(50.33 MHz, chloroform-d) ppm 55.2, 59.7, 102.7, 114.9 (d,
J¼8.6 Hz), 134.1 (d, J¼3.5 Hz), 147.6, 152.0, 164.1 (d, J¼245.6 Hz); MS
(GCeMS) tR, m/z: 8.410 min (GCeMS) tR, m/z: 294, mp: 104 ꢀC.
d
J¼22.1 Hz), 125.5, 126.4 (d, J¼8.1 Hz), 129.1 (d, J¼3.0 Hz), 138.3,
147.2, 153.4, 161.9 (d, J¼244.6 Hz), MS (GCeMS) tR, m/z: 22.3 min,
328; mp: 118 ꢀC.
4.3.5.2. 4-(4-Fluorophenyl)-2-[4-(methylthio)phenyl]-1H-imidaz-
ole (educt of 5). Yield 59.5% (1.95 g, 6.9 mmol); IR (ATR) [cmꢁ1]:
3234, 2923, 1606, 1537, 1536, 1490, 1428, 1217, 1130, 1108, 948, 844,
838, 824, 813, 777, 727, 697, 657; 1H NMR (200 MHz, acetone-d6)
4.3.5.9. 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-(3,4,5-
trimethoxyphenyl)-1H-imidazole (6). Yield 74% (2.3 g, 6.2 mmol); IR
(ATR) [cmꢁ1]: 2932, 1590, 1562, 1500, 1473, 1464, 1381, 1323, 1240,
d
ppm 2.51 (s, 3H) 7.13 (m, 2H) 7.33 (d, J¼8.59 Hz, 2H) 7.58 (s, 1H)
7.91 (m, 2H) 7.99 (d, J¼8.59 Hz, 2H); 13C NMR (50.33 MHz, acetone-
1
d6)
d
ppm 14.3, 115.0 (d, J¼21.6 Hz), 125.4, 126.1, 126.3 (d, J¼7.9 Hz),
1135, 1075, 1000, 967, 956, 733; H NMR (200 MHz, chloroform-d)
127.5, 146.2, 161.5 (d, J¼242.9 Hz); MS (GCeMS) tR, m/z: 21.7 min,
d
ppm 3.38 (s, 3H) 3.90 (s, 3H) 3.92 (s, 6H) 7.15 (m, 5H) 7.55 (m, 2H);
284; mp: 179 ꢀC.
13C NMR (50.33 MHz, chloroform-d)
d
ppm 55.1, 56.1, 60.8, 75.0,
105.9, 115.9 (d, J¼21.5 Hz), 125.1, 125.6 (d, J¼3.2 Hz), 126.7, 130.4 (d,
J¼8.1 Hz), 134.6, 139.0, 150.0, 153.3, 162.73 (d, J¼248.6 Hz); MS
(GCeMS) tR, m/z: 22.3 min, 328; mp: 117 ꢀC.
4.3.5.3. 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-[4-(methyl-
thio)phenyl]-1H-imidazole (5). Yield 60% (1.04 g, 3.2 mmol); IR
(ATR) [cmꢁ1]: 1561, 1493, 1424, 1362, 1214, 1181, 1152, 1113, 1096,
916, 843, 812, 763, 729, 661; 1H NMR (200 MHz, chloroform-d)
4.3.5.10. 4-(4-Fluorophenyl)-2-{4-[(triisopropylsilyl)oxy]phenyl}-
1H-imidazole (educt of 7). Yield 46% (2.72 g, 6.62 mmol); IR (ATR)
[cmꢁ1]: 2943, 2867, 1609, 1499, 1481, 1439, 1265, 1234, 1123, 912,
883, 839, 771, 740, 687, 671; 1H NMR (200 MHz, chloroform-d)
d
ppm 2.50 (s, 3H) 3.39 (s, 3H) 5.20 (s, 2H) 7.06 (m, 2H) 7.32 (m, 3H)
7.77 (m, 4H); 13C NMR (50.33 MHz, chloroform-d)
d
ppm 15.3, 56.3,
76.1115.3 (2C, d, J¼21.5 Hz), 116.6, 126.0, 126.0, 126.6 (d, J¼8.0 Hz),
129.2, 129.8 (d, J¼3.1 Hz), 140.3, 148.5, 162.0 (d, J¼245.6 Hz); MS
(GCeMS) tR, m/z: 21.5, 328; mp: 80 ꢀC.
d
ppm 1.06 (s, 9H) 1.09 (s, 9H) 1.24 (m, 3H) 6.87 (d, J¼8.72 Hz, 2H)
7.01 (m, 2H) 7.20 (m, 1H) 7.65 (m, 2H) 7.74 (d, J¼8.72 Hz, 2H) 8.66
(m, 1H); 13C NMR (50.33 MHz, CHLOROFORM-D)
ppm 12.5, 115.5
d
4.3.5.4. 4-(4-Fluorophenyl)-2-[4-(methoxymethoxy)phenyl]-1-
(d, J¼21.6 Hz), 120.3, 122.8, 126.5 (d, J¼7.9 Hz), 126.8, 129.1 (d,
J¼3.1 Hz), 147.3, 156.9, 161.9 (d, J¼245.8 Hz); MS (LCeMS) tR, m/z:
7.38 min, 411 [MþHþ]; mp: 137 ꢀC.
(methoxymethyl)-1H-imidazole (4). Yield 92% (0.247 g; 0.7 mmol);
1H NMR (200 MHz, acetone-d6)
d
ppm 3.43 (s, 3H) 3.46 (s, 3H) 5.26
(s, 2H) 5.36 (s, 2H) 7.13 (m, 4H) 7.73 (s, 1H) 7.77 (d, J¼8.97 Hz, 2H)
7.91 (m, 2H); 13C NMR (50.33 MHz, acetone-d6)
ppm: 55.2, 55.4,
d
4.3.5.11. 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-{4-[(triisopro-
77.1, 94.0, 114.9 (2C, d, J¼21.7 Hz), 116.0, 117.7, 124.1, 126.3 (d,
pylsilyl)oxy]phenyl}-1H-imidazole
(7). Yield
54%
(0.800 g,
J¼7.8 Hz), 129.8, 145, 157.8, 161.4; mp. oily substance at rt.
1.76 mmol); IR (ATR) [cmꢁ1]: 2944, 2867, 1609, 1532, 1498, 1476,
1461, 1426, 1362, 1281, 1264, 1211, 1172, 1099, 909, 881, 842, 773,
4.3.5.5. 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-1H-im-
idazole (2). Yield 83% (0.850 g, 3 mmol); IR (ATR) [cmꢁ1]: 2939,
1563, 1495, 1364, 1213, 1174, 1154, 1101, 1072, 918, 843, 837, 772,
748, 732, 683; 1H NMR (200 MHz, acetone-d6)
d ppm 1.12 (s, 9H)
1.15 (s, 9H) 1.33 (m, 3H) 3.42 (s, 3H) 5.33 (s, 2H) 7.03 (d, J¼8.72 Hz,
2H) 7.12 (m, 2H) 7.73 (s, 1H) 7.79 (d, J¼8.72 Hz, 2H) 7.91 (m, 2H); 13C
754, 721, 700, 686; 1H NMR (200 MHz, methanol-d4)
d
ppm 3.22 (s,
3H) 5.09 (s, 2H) 6.96 (m, 2H) 7.35 (m, 3H) 7.51 (m, 1H) 7.64 (m, 4H);
13C NMR (50.33 MHz, methanol-d4)
ppm 56.3, 78.0, 115.9 (d,
NMR (50.33 MHz, acetone-d6) d ppm; 12.4, 17.3, 55.4, 77.1, 114.9 (d,
J¼21.5 Hz), 117.6, 119.7, 123.7, 126.3 (d, J¼8.0 Hz), 130.0, 131.1 (d,
J¼3.1 Hz), 139.3, 148.0, 156.6, 161.6 (d, J¼243 Hz); MS (LCeMS) tR,
m/z: 12.84 min, 455 [MþHþ]; mp: 79 ꢀC.
d
J¼21.6 Hz), 118.6, 127.5 (d, J¼21.6 Hz), 129.3, 129.8, 130.2, 130.4,
130.9 (d, J¼3.0 Hz), 140.67, 149.9, 162.5 (d, J¼244.6 Hz) MS
(GCeMS) tR, m/z:17.7 min,238; mp107 ꢀC.
4.3.5.12. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridine (educt of i). IR
(ATR) [cmꢁ1]: 3126, 3071, 2920, 2849, 1609, 1587, 1538, 1423, 1276,
892, 820, 797, 767, 760, 725, 661; 1H NMR (200 MHz, chloroform-d)
4.3.5.6. 4-(4-Fluorophenyl)-1-(methoxymethyl)-2-(4-
methoxyphenyl)-1H-imidazole (3). Yield 84% (0.732 g, 2.3 mmol); IR
(ATR) [cmꢁ1]: 2934, 1610, 1540, 1498, 1481, 1458, 1428, 1391, 1299,
1251, 1221, 1174, 1157, 1079, 1024, 976, 970, 843, 814, 764, 745, 667;
d
ppm 1.64 (m, 8H) 2.21 (m, 2H) 2.90 (m, 1H, ipso-ChH) 6.20 (s, 1H)
7.05 (m, 1H) 7.86 (dd, J¼7.71, 1.39 Hz, 1H) 8.24 (dd, J¼4.93, 1.52 Hz,
1H) 12.43 (s, 1H); 13C NMR (50.33 MHz, chloroform-d)
ppm 26.1,
d

R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
9211
26.3, 32.6, 37.8, 94.9, 115.2, 121.7, 127.7, 140.2, 147.0, 149.0; MS
(ATR) [cmꢁ1]: 2944, 2893, 1608, 1510, 1480, 1379, 1252, 1220, 1168,
1079, 921, 883, 840, 805, 758, 744, 682, 662; 1H NMR (200 MHz,
(GCeMS) tR, m/z: 13.2 min, 200; mp: 171 ꢀC; yield: 47%.
acetone-d6)
d ppm 1.12 (s, 9H) 1.16 (m, 9H) 1.34 (s, 3H) 3.09 (s, 3H)
4.3.5.13. 4-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridine (educt
of i). Yield 45% (0.789 g, 3.4 mmol) IR (ATR) [cmꢁ1]: 3126, 2927,
1607, 1577, 1534,1447, 1408, 1297, 1184, 1155, 961, 871, 849, 799, 789,
3.42 (m, 3H) 5.18 (m, 2H) 5.69 (m, 2H) 6.33 (s, 1H) 6.93 (m, 2H) 7.08
(d, J¼8.84 Hz, 2H) 7.46 (m, 6H) 7.65 (m, 2H) 7.87 (d, J¼8.84 Hz, 1H);
13C NMR (50.33 MHz, acetone-d6)
d ppm 12.42, 17.3, 57.8, 55.8, 72.5,
761, 669; 1H NMR (200 MHz, chloroform-d)
d
ppm 1.44 (m, 5H) 1.84
75.0, 100.4, 114.5 (d, J¼21.5 Hz), 118.7, 119.8, 120.0, 123.7, 125.9,
128.5 (d, J¼8.3 Hz), 128.9, 130.3, 131.2 (d, J¼3.1 Hz), 131.5, 137.7,
142.7, 143.2, 149.3, 150.4, 156.9, 161.6 (d, J¼243.9 Hz); HRMS (ESI):
calcd for C41H47FN4O3Si [MþH]þ 691.34742, found 691.34763 (error
0.09 ppm); mp: 105 ꢀC.
(m, 3H) 2.15 (m, 2H) 2.84 (m, 1H) 6.30 (s, 1H) 7.08 (d, J¼5.31 Hz, 1H)
8.09 (d, J¼5.18 Hz, 1H) 11.74 (s, 1H); 13C NMR (50.33 MHz, chloro-
form-d)
d ppm 27.0, 26.1, 37.6, 94.0, 115.6, 120.8, 134.9, 140.6, 147.4,
149.1; MS (GCeMS) tR, m/z:15.2 min, 234; mp: 191 ꢀC; yield: 61%.
4.3.5.14. 4-Chloro-2-cyclohexyl-1-(methoxymethyl)-1H-pyrrolo
[2,3-b]pyridine (i). Yield 36% (0.300 g, 1.08 mmol); IR (ATR) [cmꢁ1]:
2928, 2853, 1591, 1561, 1536, 1475, 1272, 1255, 1163, 1112, 1069, 912,
4.3.5.20. 4-{4-(4-Fluorophenyl)-1-(methoxymethyl)-2-[4-(meth-
ylthio)phenyl]-1H-imidazol-5-yl}-1-(methoxymethyl)-2-phenyl-1H-
pyrrolo[2,3-b]pyridine (5g). According to general procedures C and
D (Tables 5 and 7) TLC (ethylacetate/n-hexane 1/1): Rf¼0.58; IR
(ATR) [cmꢁ1]: 2928, 1599, 1507, 1478, 1370, 1247, 1219, 1156, 1080,
964, 908, 839, 776, 756, 742, 698; 1H NMR (200 MHz, chloroform-d)
808, 785, 757, 725; 1H NMR (200 MHz, chloroform-d)
d ppm 1.71
(m, 10H) 2.85 (m, 1H) 3.27 (s, 3H) 5.67 (s, 2H) 6.36 (s, 1H) 7.05 (d,
J¼5.31 Hz, 1H) 8.10 (d, J¼5.18 Hz, 1H); 13C NMR (50.33 MHz, chlo-
roform-d)
d
ppm 25.9, 26.4, 33.4, 35.6, 56.1, 72.1, 95.2, 116.4, 119.9;
d ppm 2.53 (s, 3H) 3.13 (s, 3H) 3.50 (s, 3H) 5.02 (m, 2H) 5.64 (m, 2H)
134.7, 141.8, 147.7; MS (GCeMS) tR, m/z: 15.0 min, 278; mp: color-
less oil at rt; yield: 42%.
6.22 (s, 1H) 6.87 (m, 2H) 7.45 (m, 10H) 7.85 (d, J¼8.72 Hz, 2H) 8.47
(d, J¼4.93 Hz,1H); 13C NMR (50.33 MHz, chloroform-d)
d ppm: 15.2,
55.5, 56.5, 100.5, 114.97 (d, J¼21.4 Hz), 118.7, 120.3, 126.0, 126.1,
128.6, 128.7, 128.8, 129.1, 129.3, 129.9, 131.3, 138.3, 140.6, 143.1 (d,
J¼8.1 Hz), 149.5, 150.2, 161.9 (d, J¼246.2 Hz); HRMS (ESI): calcd for
C33H29FN4O2S [MþH]þ 565.2068, found 565.2066 (error
0.39 ppm); mp: 159 ꢀC.
4.3.5.15. 4-Chloro-9-(methoxymethyl)-9H-pyrido[2,3-b]indole
(f). Yield 62.8%; IR (ATR) [cmꢁ1]: 2934, 2828, 1588, 1557, 1464,
1454, 1412, 1367, 1292, 1221, 1119, 1070, 1056, 903, 810, 784, 749,
737, 675; 1H NMR (200 MHz, acetone-d6)
d ppm 3.29 (s, 3H) 5.92 (s,
2H) 7.34 (d, J¼5.43 Hz, 1H) 7.41 (td, J¼8.08, 1.01 Hz, 1H) 7.63 (td,
J¼7.20, 1.14 Hz, 1H) 7.76 (d, J¼8.34 Hz, 1H) 8.44 (m, 2H); 13C NMR
4.3.5.21. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-1-(methoxymethyl)-2-phenyl-1H-pyrrolo[2,3-b]
pyridine (2g). According to general procedures B, C, and D (Tables 1,
5, and 7) TLC (ethylacetate/n-hexane 2/1): Rf¼0.58, TLC (ethyl-
acetate/n-hexane 1/1): Rf¼0.51, IR (ATR) [cmꢁ1]: 3061, 2929, 1590,
1511, 1475, 1379, 1357, 1325, 1250, 1222, 1189, 1076, 958, 843, 761,
(50.33 MHz, chloroform-d)
d ppm 56.4, 72.6, 110.1, 114.0, 116.9,
119.9, 121.2, 123.2, 127.5, 138.1, 139.2, 145.8, 152.4; MS (GCeMS) tR,
m/z: 13.8 min, 246; mp: 94 ꢀC.
4.3.5.16. 2-(4-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin (educt
of h). Yield 80.4% (6.97 g, 31.1 mmol); IR (ATR) [cmꢁ1]: 3147, 2837,
1613, 1490, 1441, 1277, 1245, 1182, 1114, 1029, 013, 827, 799, 761,
698; 1H NMR (200 MHz, acetone-d6)
d ppm 3.10 (s, 3H, ImMOMCH3)
3.43 (s, 3H) 5.22 (m, 2H) 5.70 (m, 2H) 6.34 (s, 1H) 6.95 (m, 2H) 7.49
725; 1H NMR (200 MHz, DMSO-d6)
d
ppm 3.78 (s, 3H) 6.74 (m, 1H)
7.01 (m, 3H) 7.86 (m, 3H) 8.17 (dd, J¼4.67, 1.52 Hz, 1H) 12.05 (s, 1H);
13C NMR (50.33 MHz, DMSO-d6)
ppm 55.5, 96.0, 114.7, 116.2, 121.5,
(m, 9H) 7.67 (m, 2H) 7.95 (m, 2H) 8.49 (d, J¼4.93 Hz, 1H); 13C NMR
(50.33 MHz, chloroform-d)
d ppm 55.5, 56.5, 72.8, 75.0, 100.5, 115.0
d
(d, J¼21.5 Hz), 118.7, 120.3, 126.0, 126.1, 128.6, 128.7, 128.8, 129.1,
129.4, 129.9, 131.3, 138.3, 143.0, 143.2, 149.8, 150.2, 161.9 (d,
J¼246.7 Hz); HRMS (ESI): calcd for C32H27FN4O2 [MþH]þ 519.21908,
found 519.219057 (error 0.04 ppm); mp: 137 ꢀC.
124.6, 127.1, 127.6, 138.8, 140.5, 150.0, 159.6, MS (GCeMS) tR, m/z:
17.1, 224; mp: 211 ꢀC.
4.3.5.17. 4-Chloro-1-(methoxymethyl)-2-(4-methoxyphenyl)-1H-
pyrrolo[2,3-b]pyridine (h). Yield 33%; IR (ATR) [cmꢁ1]: 2939, 2833,
1616, 1591, 1499, 1474, 1376, 1300, 1289, 1250, 1180, 1156, 1072,
1032, 996, 906, 826, 794, 770, 758, 697; 1H NMR (200 MHz, ace-
4.3.5.22. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-(4-
methoxyphenyl)-1H-imidazol-5-yl]-1-(methoxymethyl)-2-phenyl-
1H-pyrrolo[2,3-b]pyridine (3g). According to general procedures B
and C (Tables 1 and 5) IR (ATR) [cmꢁ1]: 2939, 1590, 1512, 1482, 1378,
1251, 1173, 1070, 1031, 955, 843, 831, 762, 700; 1H NMR (200 MHz,
tone-d6) d ppm 3.41 (s, 3H) 3.87 (s, 3H) 5.61 (s, 2H) 6.64 (s, 1H) 7.08
(d, J¼8.84 Hz, 2H) 7.22 (d, J¼5.18 Hz, 1H) 7.75 (d, J¼8.97 Hz, 2H)
8.23 (d, J¼5.18 Hz, 1H); 13C NMR (50.33 MHz, acetone-d6)
d
ppm
chloroform-d) d ppm 3.13 (s, 3H) 3.50 (s, 3H) 3.87 (s, 3H) 5.02 (m, 2H)
56.4, 57.6, 74.3, 99.2, 115.7, 118.3, 121.0, 125.1, 129.4, 129.4, 130.7,
132.1, 134.7, 135.6, 144.6, 152.0, 162.0, 206.70; MS (GCeMS) tR, m/z:
18.0 min, 302; mp: 98 ꢀC.
5.63 (m, 2H) 6.21 (s,1H) 6.89 (m, 2H) 7.04 (d, J¼9.10 Hz, 2H) 7.50 (m,
7H) 7.90 (d, J¼8.84 Hz, 2H) 8.48 (d, J¼5.18 Hz, 1H); 13C NMR
(50.33 MHz, chloroform-d) d ppm 55.3, 55.8, 56.6, 72.8, 75.2, 100.2,
114.3, 115.2 (d, J¼22.2 Hz), 115.5, 118.7, 120.2, 120.2, 128.7, 128.8,
129.1, 130.5, 131.1, 143.2, 150.1; HRMS (ESI): calcd for C33H29FN4O3
[MþH]þ 549.2297, found 549.2300 (error 0.70 ppm).
4.3.5.18. 4-Chloro-2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyri-
dine (educt of h). Yield 48% (0.650 g, 2.5 mmol); IR (ATR) [cmꢁ1]:
2839, 1766, 1614, 1575, 1500, 1349, 1291, 1281, 1247, 1177, 1024, 859,
832, 782, 748, 623, 567, 527; 1H NMR (200 MHz, DMSO-d6)
d
ppm
4.3.5.23. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-(3,4,5-
trimethoxyphenyl)-1H-imidazol-5-yl]-1-(methoxymethyl)-2-phenyl-
1H-pyrrolo[2,3-b]pyridine (6g). According to general procedure B
(Table 1) TLC (ethylacetate/n-hexane 1/1): Rf¼0.32; IR (ATR)
[cmꢁ1]: 2937, 1587, 1510, 1486, 1422, 1374, 1321, 1238, 1133, 1076,
3.80 (s, 3H) 6.85 (s, 1H) 7.03 (d, J¼8.84 Hz, 2H) 7.16 (d, J¼5.18 Hz,
1H) 7.93 (d, J¼8.97 Hz, 2H) 8.11 (d, J¼5.18 Hz, 1H) 12.39 (s, 1H); 13C
NMR (50.33 MHz, DMSO-d6)
d ppm 55.3, 93.6, 114.4, 115.7, 120.1,
123.4, 127.1, 132.9, 139.5, 142.7, 150.1, 159.6; MS (GCeMS) tR, m/z:
18.7 min, 260; mp:251 ꢀC.
848, 837, 762, 701; 1H NMR (200 MHz, acetone-d6)
d ppm 3.19 (s,
3H) 3.43 (s, 3H) 3.80 (s, 3H) 3.91 (m, 6H) 5.20 (m, 2H) 5.70 (m, 2H)
6.30 (s, 1H) 6.95 (m, 2H) 7.29 (s, 2H) 7.48 (m, 6H) 7.66 (m, 2H) 8.49
4.3.5.19. 4-(4-(4-Fluorophenyl)-1-(methoxymethyl)-2-{4-[(triiso-
propylsilyl)oxy]phenyl}-1H-imidazol-5-yl)-1-(methoxymethyl)-2-
phenyl-1H-pyrrolo[2,3-b]pyridine (7g). According to general pro-
cedure C (Table 5) TLC (ethylacetate/n-hexane 1/4): Rf¼0.22; IR
(d, J¼4.93 Hz, 1H); 13C NMR (50.33 MHz, chloroform-d)
d ppm 55.6,
56.2, 56.5, 72.8, 75.0, 100.4, 106.6, 115.1 (d, J¼21.5 Hz), 118.6, 120.3,
126.2, 128.6, 128.8, 128.9, 129.1, 131.2, 131.2, 143.2, 149.5, 150.2,

9212
R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
153.3; HRMS (ESI): calcd for C35H33FN4O5 [MþH]þ 609.2508, found
4.3.5.28. 2-Cyclohexyl-4-[4-(4-fluorophenyl)-1-(methox-
ymethyl)-2-phenyl-1H-imidazol-5-yl]-1-(methoxymethyl)-1H-pyr-
rolo[2,3-b]pyridine (2i). According to general procedures B and D
(Tables 1 and 7) TLC (ethylacetate/n-hexane 1/2): 0.38, TLC (ethyl-
acetate/n-hexane 1/1): Rf¼0.65; IR (ATR) [cmꢁ1]: 2927, 2853, 1736,
1599, 1538, 1447, 1380, 1364, 1321, 1221, 1156, 1077, 911, 838, 772,
609.2506 (error 0.30 ppm); mp: 175 ꢀC.
4.3.5.24. 7-Benzyl-4-[4-(4-fluorophenyl)-1-(methoxymethyl)-2-
phenyl-1H-imidazol-5-yl]-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine
(2d). According to general procedure B (Table 1) TLC (ethylacetate/
n-hexane 1/1): Rf¼0.47; IR (ATR) [cmꢁ1]: 2956, 2920, 1555, 1505,
1466, 1448, 1376, 1349, 1216, 1156, 1094, 1042, 840, 809, 774, 698;
699; 1H NMR (200 MHz, chloroform-d)
d ppm 1.26 (m, 6H) 1.73 (m,
4H) 2.74 (m, 1H) 3.10 (s, 3H) 3.31 (s, 3H) 4.97 (m, 2H) 5.67 (m, 2H)
5.83 (s, 1H) 6.81 (m, 2H) 7.23 (m, 1H) 7.45 (m, 5H) 7.90 (m, 2H) 8.32
1H NMR (200 MHz, chloroform-d)
d ppm 1.71 (s, 3H) 2.16 (s, 3H)
2.95 (s, 3H) 5.30 (m, 2H) 5.52 (m, 2H) 6.83 (m, 2H) 7.01 (m, 2H), 7.28
(d, J¼4.93 Hz, 1H); 13C NMR (50.33 MHz, chloroform-d)
d ppm 25.9,
(m, 2H) 7.46 (m, 6H) 7.87 (m, 2H) 8.97 (s, 1H); 13C NMR (50.33 MHz,
26.3, 33.3, 35.5, 55.4, 56.1, 71.8, 74.9, 96.8, 114.8 (d, J¼21.4 Hz), 117.9,
120.2, 126.5, 128.6, 128.7 (d, J¼8.1 Hz), 129.0, 129.1, 129.2, 130.2,
130.3 (d, J¼3.1 Hz), 138.4, 141.9, 148.7, 149.5, 149.7, 161.8 (d,
J¼245.7 Hz); HRMS (ESI): calcd for C32H33FN4O2 [MþH]þ 525.2660,
found 525.2658 (error 0.35 ppm); mp: 127 ꢀC.
chloroform-d)
d ppm 8.09, 10.0, 45.1, 55.8, 75.1, 106.3, 114.9 (d,
J¼21.44 Hz), 119.1, 125.1,126.3126.4 (d, J¼7.6 Hz),127.5, 128.4, 128.6,
128.7, 129.3, 129.4, 130.1, 130.2 (d, J¼3.2 Hz), 135.8, 137.0, 139.8,
147.8, 149.8, 150.5, 151.9, 161.9 (d, J¼246.0 Hz); HRMS (ESI): calcd
for C32H28FN5O [MþH]þ 518.2351, found 518.2354 (error
0.58 ppm); mp: 168 ꢀC.
4.3.5.29. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]
pyrimidine (2b). According to general procedure A (Table 1) TLC
(ethylacetate/n-hexane 1/2): Rf¼0.33; TLC (ethylacetate/n-hexane
1/1): Rf¼0.58; IR [cmꢁ1]: 2927, 1596, 1564, 1504, 1440, 1378, 1358,
1222, 1191, 1177, 1140, 1090, 1008, 972, 910, 841, 813, 776, 702, 682,
4.3.5.25. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-1-(methoxymethyl)-2-(4-methoxyphenyl)-1H-
pyrrolo[2,3-b]pyridine (2h). According to general procedure
B
(Table 1) TLC (ethylacetate/n-hexane 1/1): Rf¼0.48; IR (ATR)
[cmꢁ1]: 2923, 2853, 1609, 1587, 1589, 1477, 1443, 1376, 1356, 1326,
1295, 1246, 1088, 1070, 1039,957, 839, 803, 810, 771, 700; 1H NMR
660; 1H NMR (200 MHz, chloroform-d)
d ppm 2.43 (m, 3H) 2.96 (m,
3H) 5.58 (s, 2H) 5.91 (d, J¼4.04 Hz, 1H) 6.85 (m, 2H) 7.35 (m, 4H)
(200 MHz, DMSO-d6)
d ppm 3.36 (s, 3H) 3.79 (s, 3H) 5.62 (m, 2H)
7.49 (m, 4H) 7.81 (m, 2H) 8.09 (d, J¼8.34 Hz, 2H) 9.12 (s, 1H); 13C
6.27 (m,1H) 7.05 (m, 3H) 7.40 (m, 5H) 7.57 (m, 4H) 7.89 (m, 2H) 8.44
NMR (50.33 MHz, chloroform-d) d ppm 21.6, 55.6, 75.3, 104.5, 115.3
(d, J¼4.80 Hz, 1H); 13C NMR (50.33 MHz, DMSO-d6)
d
ppm 55.6,
(d, J¼21.49 Hz), 119.1, 126.6, 128.2, 128.6, 129.4, 129.6, 129.7, 129.8,
134.6, 142.7, 145.9, 150.8, 151.7, 151.9, 153.0, 162.3 (d, J¼247.4 Hz);
HRMS (ESI): calcd for C30H24FN5O3S [MþH]þ 554.1657, found
554.1658 (error 0.27 ppm); mp: 86 ꢀC.
55.6, 56.5, 72.8, 75.4, 99.6115.4 (d, J¼21.4 Hz), 119.1, 120.0, 123.6,
126.6, 128.7 (d, J¼8.3 Hz), 129.1, 129.6, 130.4, 130.5, 130.9, 131.0,
137.7, 142.7, 143.2, 149.3, 150.2, 160.1; HRMS (ESI): calcd for
C33H29FN4O3 [MþH]þ 549.2297, found 549.2230 (error 0.61 ppm);
mp: 156 ꢀC.
4.3.5.30. 4-[4-(4-Fluorophenyl)-2-[4-(methoxymethoxy)phenyl]-
1-(methoxymethyl)-1H-imidazol-5-yl]-1-(methoxymethyl)-2-
phenyl-1H-pyrrolo[2,3-b]pyridine (4g). According to general pro-
cedure B (Table 1) TLC (ethylacetate/n-hexane 1/1): Rf¼0.47; IR (ATR)
[cmꢁ1]: 2900, 1589, 1512, 1481, 1376, 1326, 1231, 1192, 1150, 1079,
1005, 959, 922, 841, 812, 762, 700; 1H NMR (200 MHz, methanol-d)
4.3.5.26. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-7-(methoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine
(2c). According to general procedure A (Table 1) TLC (ethylacetate/
n-hexane 1/1): Rf¼0.44; IR (ATR) [cmꢁ1]: 2929, 1569, 1502, 1469,
1448, 1403, 1338, 1284, 1219, 1181, 1163, 1095, 1079, 1061, 906, 842,
d
ppm 3.11 (s, 3H)3.38(s, 3H)3.48 (s, 3H)5.10 (m, 2H)5.27 (s, 2H)5.61
775, 755, 740, 708, 699; 1H NMR (200 MHz, DMSO-d6)
d
ppm 2.82
(m, 2H) 6.16 (s, 1H) 6.94 (m, 2H) 7.22 (d, J¼8.97 Hz, 2H) 7.41 (m, 6H)
(s, 3H) 3.21 (s, 3H) 5.58 (s, 4H) 5.95 (d, J¼3.41 Hz, 1H) 7.05 (m, 2H)
7.53 (m, 2H) 7.81 (d, J¼8.84 Hz, 2H) 8.43 (d, J¼5.05 Hz,1H); 13C NMR
7.38 (m, 2H) 7.55 (m, 4H) 7.62 (d, J¼3.92 Hz,1H) 7.86 (m, 2H) 9.04 (s,
(50.33 MHz, methanol-d) ppm
d 54.5, 54.8, 55.2, 72.3, 75.0, 93.9,
1H); 13C NMR (50.33 MHz, DMSO-d6)
d
ppm 55.7, 56.5, 74.7, 75.4,
100.2,114.6 (d, J¼21.8 Hz),116.0,118.3,120.2,122.7,126.1,128.3,128.4,
128.8, 129.1 (d, J¼8.15 Hz), 129.9, 130.4, 131.2, 138.1, 142.5, 143.0,
149.9, 158.6; HRMS (ESI): calcd for C34H31FN4O4 [MþH]þ 579.2402,
found 579.2398 (error 0.76 ppm); mp: 137 ꢀC.
100.8, 115.5 (d, J¼21.4 Hz), 117.7, 125.2, 125.5, 126.5 (d, J¼7.85 Hz),
128.5, 129.1, 129.4, 129.5, 129.7, 129.8, 130.2, 130.8 (d, J¼3.2 Hz),
131.4, 140.5, 149.4, 150.4, 151.8, 152.0, 161.8 (d, J¼244.5 Hz); HRMS
(ESI): calcd for C25H22FN5O2 [MþH]þ 444.1830, found 444.1832
(error 0.29 ppm); mp: 177 ꢀC.
4.3.5.31. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-9-(methoxymethyl)-9H-pyrido[2,3-b]indole
(2f). According to general procedure B (Table 1) TLC (ethylacetate/n-
hexane 1/1): Rf¼0.52; IR (ATR) [cmꢁ1]: 2930, 1563, 1507, 1462, 1413,
1364,1324,1288,1212,1156,1112,1085, 998, 973, 914, 839, 774, 752,
4.3.5.27. 6-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purine
(2a). According to general procedures A, B, and D (Tables 1 and 7)
TLC (ethylacetate/n-hexane 1/1): Rf¼0.15; IR (ATR) [cmꢁ1]: 2925,
2854, 1580, 1507, 1439, 1439, 1325, 1210, 1159, 1084, 1043, 907, 839,
739, 699; 1HNMR (200 MHz, methanol-d4)
d ppm2.80 (s, 3H) 3.26(s,
3H) 5.85 (s, 2H) 6.73 (m, 2H) 7.01 (m,1H) 7.22 (d, J¼7.96 Hz,1H) 7.35
775, 744, 695; 1H NMR (200 MHz, methanol-d4)
d ppm 1.67 (m, 5H,
(m, 5H) 7.49 (m, 3H) 7.58 (d, J¼8.21 Hz, 1H) 7.81 (m, 2H) 8.52 (d,
THP) 2.10 (m, 3H, THP) 2.80 (s, 3H, MOMCH3) 3.74 (m, 1H, THP) 4.06
(m, 1H, THP) 5.46 (s, 2H, MOMCH2) 5.81 (m, 1H, THP) 6.87 (m, 2H,
meta-4F-PhH) 7.33 (m, 2H, ortho-4FPhH) 7.51 (m, 3H, meta-, para-
PhH) 7.75 (m, 2H, ortho-PhH) 8.51 (s, 1H, Pur.8-H) 8.97 (m, 1H,
Pur.2-H); 1H NMR (200 MHz, chloroform-d) ppm 1.88 (m, 6H) 2.94
(s, 3H) 3.80 (m, 1H) 4.18 (m, 1H) 5.57 (s, 2H) 5.81 (m, 1H) 6.86 (m,
2H) 7.48 (m, 5H) 7.81 (m, 2H) 8.13 (s, 1H) 9.07 (m, 1H); 13C NMR
J¼5.18 Hz,1H); 13C NMR (50.33 MHz, methanol-d4)
d ppm 55.7, 55.3,
72.0, 75.1, 110.0, 114.8 (d, J¼21.6 Hz), 115.0, 118.6, 119.5, 120.8, 121.5,
125.4, 127.3, 128.2 (d, J¼21.6 Hz), 128.5, 129.1, 129.1, 129.5 (d,
J¼4.4 Hz),129.6,132.3,137.7,139.6,145.6,146.6,150.3,152.0,162.0 (d,
J¼245.8 Hz); HRMS (ESI): calcd for C30H25FN4O2 [MþH]þ 493.2034,
found 493.2036 (error 0.27 ppm); mp: 63 ꢀC.
(50.33 MHz, chloroform-d)
d
ppm 26.7, 24.7, 31.5, 55.7, 64.8, 75.8,
4.3.5.32. 4-[4-(4-Fluorophenyl)-1-methyl-2-(methylsulfonyl)-1H-
imidazol-5-yl]-2-phenyl-1H-pyrrolo[2,3-b]pyridine (20). The cou-
pling reaction was performed according to method B. The crude
product was purified by flash-chromatography, the obtained
product was further refluxed in HClconcd./MeOH for 3 h. After
81.9, 114.8 (d, J¼21.4 Hz), 122.9, 128.3, 128.6, 129.6, 129.6, 130.0,
130.4 (d, J¼3.2 Hz), 132.1, 142.5, 143.2, 149.2, 151.3, 151.5, 151.8, 162.1
(d, J¼246.1 Hz); HRMS (ESI): calcd for C27H25FN6O2 [MþH]þ
485.2096, found 485.2095 (error 0.16 ppm); mp: 98 ꢀC.

R. Selig et al. / Tetrahedron 67 (2011) 9204e9213
9213
evaporation of the solvent, the crude product was purified by flash-
References and notes
chromatography, to obtain 17 mg (18%) of the pure product. IR
(ATR) [cmꢁ1]: 3031, 1609, 1517, 1306, 1253, 1222, 1159, 1128, 963,
1. Gibson, C. L.; Huggan, J. K.; Kennedy, A.; Kiefer, L.; Lee, J. H.; Suckling, C. J.;
Clements, C.; Harvey, A. L.; Hunter, W. N.; Tulloch, L. B. Org. Biomol. Chem. 2009,
7, 1829e1842.
844, 768, 749, 743, 685, 661; 1H NMR (200 MHz, acetone-d6)
d ppm
3.52 (s, 3H) 3.80 (s, 3H) 6.70 (s, 1H) 6.96 (m, 2H) 7.17 (d, J¼4.67 Hz,
2. Layek, M.; Gajare, V.; Kalita, D.; Islam, A.; Mukkanti, K.; Pal, M. Tetrahedron
2009, 65, 4814e4819.
3. Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987e4006.
1H) 7.44 (m, 5H) 7.92 (m, 2H) 8.38 (d, J¼5.31 Hz, 1H) 11.47; 13C NMR
(50.33 MHz, DMSO-d6)
d ppm 33.4 (CH3), 43.6 (CH3), 96.5 (CH),
4. Legraverend, M. Tetrahedron 2008, 64, 8585e8603.
115.7 (d, J¼21.4 Hz), 118.2 (Cq), 121.0 (CH), 126.0, 127.6, 128.6 (d,
J¼8.1 Hz), 128.8, 129.2, 129.8 (d, J¼3.1 Hz), 130.2, 131.3, 137.2, 140.4,
143.5, 150.5, 161.7 (d, J¼244.6 Hz); HRMS (ESI): calcd for
C24H19FN4O2S [MþNa]þ 469.1105, found 469.1103 (error 0.47 ppm).
5. Peifer, C.; Wagner, G.; Laufer, S. Curr. Top. Med. Chem. 2006, 6, 113e149.
6. Laufer, S. A.; Hauser, D. R. J.; Liedtke, A. J. Synthesis 2008, 253e266.
7. Benoit, S.; Gingras, S.; Soundararajan, N. PCT Int. Appl 2003, WO
2005082367.
8. Jain, M. L.; Tsao, Y. P.; Ho, N. L.; Cheng, J. W. J. Org. Chem. 2001, 66,
6472e6475.
9. Leysen, D. C. M.; Defert, O. R.; De Kerpel, J. O. A.; Fourmaintraux, E. P. P. R.; Arzel,
P.; De Wilde, G. J. H. PCT Int. Appl 2005, WO 2005082367.
10. Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof,
M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Process Res.
Dev. 2003, 7, 676e683.
11. Aggarwal, R.; Sumran, G. Synth. Commun. 2006, 36, 875e879.
12. Bhella, S. S.; Pannu, A. P. S.; Elango, M.; Kapoor, A.; Hundal, M. S.; Ishar, M. P.
Tetrahedron 2009, 65, 5928e5935.
4.3.5.33. 4-[4-(4-Fluorophenyl)-1-(methoxymethyl)-2-phenyl-
1H-imidazol-5-yl]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]
pyridine (2e). According to general procedures A and B (Table 1) IR
(ATR) [cmꢁ1]: 1596, 1506, 1362, 1176, 1155, 1089, 840, 775, 702, 680,
657; 1H NMR (200 MHz, acetone-d6)
d ppm 2.41 (s, 3H) 3.05 (s, 3H)
5.09 (m, 2H) 6.31 (d, J¼4.04 Hz, 1H) 6.90 (m, 2H) 7.48 (m, 9H) 7.77
13. Li, B.; Chiu, C. K. F.; Hank, R. F.; Murry, J.; Roth, J.; Tobiassen, H. Org. Process Res.
(d, J¼4.04 Hz, 1H) 7.92 (m, 2H) 8.09 (d, J¼8.72 Hz, 2H) 8.54 (d,
Dev. 2002, 6, 682e683.
14. Zuliani, V.; Cocconcelli, G.; Fantini, M.; Ghiron, C.; Rivara, M. J. Org. Chem. 2007,
72, 4551e4553.
J¼4.93 Hz,1H); 13C NMR (50.33 MHz, acetone-d6)
d ppm: 20.5, 54.6,
75.0, 104.8, 114.7 (d, J¼21.6 Hz), 120.4, 122.4, 125.1, 127.1, 128.5,
128.5, 128.8, 129.1, 129.7, 130.6 (d, J¼3.2 Hz), 131.9, 135.4, 144.9,
145.6, 149.7; HRMS (ESI): calcd for C31H25FN4O3S [MþH]þ
553.17042, found 553.170227 (error 0.35 ppm); mp: 82 ꢀC.
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Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.09.053.