Design and synthesis of polycyclic imidazole-containing N-heterocycles based on C-H activation/cyclization reactions

Article abstract of DOI:10.1002/adsc.201200221

A new strategy for the synthesis of polycyclic imidazole-containing N-heterocycles, based on the two general synthetic ways, namely the Pd(II)-catalyzed intramolecular arylation via CH/C-Hal and CH/CH coupling reactions, was developed. The method proposed here enables the synthesis of many fused N-heterocycles containing purine, 1-deazapurines and benzimidazole structural units. Copyright

Full text of DOI:10.1002/adsc.201200221

FULL PAPERS
DOI: 10.1002/adsc.201200221
Design and Synthesis of Polycyclic Imidazole-Containing N-
À
Heterocycles based on C H Activation/Cyclization Reactions
a,b,
a
a
a
Viktor O. Iaroshenko, * Dmytro Ostrovskyi, Mariia Miliutina, Aneela Maalik,
a
b,c
c,d
Alexander Villinger, Andrei Tolmachev, Dmitriy M. Volochnyuk,
a,e
and Peter Langer
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498 6412; e-mail: viktor.iaroshenko@uni-rostock.de
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
b
c
“Enamine Ltd.” 23 A. Matrosova st., 01103 Kyiv, Ukraine
d
e
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kiev-94, Ukraine
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received: March 17, 2012; Revised: June 2, 2012; Published online: August 23, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200221.
Abstract: A new strategy for the synthesis of poly- fused N-heterocycles containing purine, 1-deazapur-
cyclic imidazole-containing N-heterocycles, based on ines and benzimidazole structural units.
the two general synthetic ways, namely the Pd(II)-
catalyzed intramolecular arylation via CH/CÀHal
and CH/CH coupling reactions, was developed. The Keywords: CÀH activation; cyclization; fluorine; imi-
method proposed here enables the synthesis of many dazoles; palladium
Introduction
It is a well-known fact that azoles as well as fused
azoles represent attractive targets for combinatorial
Transition metal-catalyzed CÀH activation reactions library synthesis, due to their wide range of valuable
have recently found a tremendous number of novel biological activities. Many natural and synthetic
applications (ca. 1000 publications) after the discovery azoles have occupied an important place in drug re-
[
15]
and establishment of the methodology. In general, the search as so-called privileged drug scaffolds. More
CÀH activation can be efficiently catalyzed by than 30 of the 200 worldwide best-selling drugs con-
[
1]
[2]
a number of transition metals, such as Pd, Pt,
tain azole rings with two or more heteroatoms, both
[3]
[4]
[5]
[6]
[7]
[8]
Rh, Ru, Ir as well as Cu, Co, and Ni. The in the parent form as well as in the form of condensed
most efficient and economical methods are consid- systems or in a reduced state. About 20 of them con-
ered to be Pd-catalyzed reactions, which, by their tain an imidazole framework. Nevertheless, 6-tri-
virtue, have opened many new synthetic ways to vari-
ACHTUNGTRENNUNfG luoromethylated purines, which were recently regard-
ous heterocycles and carbocycles furnished with aro- ed as inhibitors of adenosine deaminase (ADA), are
matic or aliphatic substituents as well as functional novel prospective drug-like scaffolds finding applica-
groups. In the same time the other transition metals tions in the design and synthesis of pharmaceutically
[
16]
are gaining relevance regarding their usage as catalyt- interesting compounds.
ic systems for synthetic strategies related to CÀH acti- et al. have communicated the synthesis of 2- and 6-tri-
vation. fluoromethylated purines and 1-deazapurines as
Nowadays, functionalization of heterocycles by promising scaffolds for the design of adenosine deam-
Very recently, Iaroshenko
[9]
AHCTUNGTRENNUNG
[
17]
direct CÀH bond activation is an important strategy inase (ADA) inhibitors.
The relevance of imida-
for the derivatization of heterocyclic and carbocyclic zoles and imidazole-containing scaffolds in medicinal
[
10]
[1a,11]
compounds. Direct arylation, alkylation,
acyla- chemistry and life sciences leads the way to the devel-
reactions opment of new methods for the functionalization of
of aromatic molecules were performed most of all by azole heterocycles.
[12]
[13]
[14]
tion,
sulfonation,
and halogenation
the application of Pd catalysts.
Recent advances in CÀH activation reactions of
[
18]
azoles implicate several general methods which
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Viktor O. Iaroshenko et al.
FULL PAPERS
Table 1. Yields of imidazo ACHUTNRGNENUG[ 4,5-b]pyridines 5 and 6.
1
2
3
No.
n
R
R
R
Yield [%]
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
a
b
c
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
2
3
3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
H
Me
Me
Ph
Ph
2-thienoyl
2-thienoyl
2-furyl
2-furyl
CF3
CF3
Me
Me
Me
Me
H
H
Me
Ph
Me
80
68
82
72
87
63
71
59
55
57
61
55
84
77
44
43
72
68
69
53
CO Me
2
CO Me
2
CF Cl
2
CF Cl
2
H
H
CF3
CF3
CF3
CF3
H
H
H
d
Ph
Scheme 1. Reaction conditions (i): DCM, reflux, 1 h 20 min;
(
ii): DCM, reflux, 6 h; (iii): DCM, reflux, 7 h.
Table 2. Yields of N-substituted purines 8.
give rise, depending on the degree of substitution of
the heterocyclic ring, to the possibility of selective in-
troduction of new substituents into one of the hydro-
No.
n
R
Yield [%]
8
a
2
1
2
1
CF3
CF3
H
68
gen-substituted positions of the azole ring. Directing 8b
groups were used for the specific orientation of CÀH 8c
69[
a]
36
[
19]
activation reactions. A number of methods for the 8d
H
39
[
20]
synthesis of fused heterocycles have been reported,
including intramolecular cyclizations of N-alkylated
[a]
[25]
Described in ref.
[21]
[22a,b]
imidazoles, and purines
tionalization protocol.
by a CÀH bond func-
Iaroshenkoꢃs group based on the regioselective formal
On the other hand, the arylation of azoles by oxida- [3+3]-cyclization of in situ generated imidazole-5-
tive CÀH bond activation can be also considered as amines 3 with a set of commercially available 1,3-di-
[17,24]
[
17,23]
a promising method for the synthesis of new azole de- carbonyl compounds 4
and 1,3,5-triazines 7
rivatives as well as for the functionalization of the (Table 1 and Table 2).
[22]
azole ring.
Our initial experiments were mainly focused on the
The subject of the current study is the intermolecu- cyclization reaction of 1-deazapurines 5 and 6 by two
lar Pd-catalyzed arylation of position 2 of benzimida- general protocols, namely the direct Pd-catalyzed CÀ
zoles and fused heterocycles containing the imidazole H arylation and oxidative CÀH arylation.
moiety, namely purines and 1-deazapurines. The latter
At the beginning of this study, we probed a variety
two systems were furnished with CF groups as well of bases and solvents for the desired direct intermo-
3
as other electron-withdrawing groups, since this in- lecular arylation of substrate 5a which was taken as
creases the acidity of proton 2-H of the imidazole a model compound. The reactions were carried out in
ring and thus ensures a high activity in CÀH activa- the absence of phosphine ligands (Table 3). We have
tion reactions. The main concept of our study is the found that the most effective transformations were
construction of new polyheterocyclic scaffolds con- accomplished using K CO as the base and using
2
3
taining an incorporated imidazole moiety.
DMF as the solvent (Scheme 1).
Treatment of 1-deazapurines 5a, containing an
ortho-halogenated aryl group attached by an alkyl-
linker to position 9 of the 1-deazapurine moiety, with
Results and Discussion
Pd ACHTUNGTENRUNG( OAc) (10 mol%) in DMF and K CO (2 equiv.)
2
2
3
Purines 8 and 1-deazapurines 5, 6, were prepared fol- resulted in formation of 9a by intermolecular cycliza-
lowing the synthetic protocol recently developed by tion. However, the yields of the fused imidazole 9a
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Design and Synthesis of Polycyclic Imidazole-Containing N-Heterocycles
Table 3. Optimization of the CÀH activation, synthesis of compound 9a.
Entry
Reaction conditions
Yield [%]
1
2
3
4
5
Pd
Pd
Pd
Pd
Pd
A
T
N
T
E
N
G
8
5
56
93
83
2
2
2
2
2
2
3
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
were rather low (less than 9%). Optimization of the Table 4. Yields of fused imidazo
ACHTUNGTRENNUNG
conditions included mainly variation of ligands. The
1
2
3
No.
n
R
R
R
highest yields were obtained when P(Cy) was em-
3
Scheme 2 Scheme 3
ployed which can be used directly or by generation in
situ from the corresponding salt P(Cy) ·HBF . Under
[
a]
a]
a]
a]
a]
a]
a]
a]
[d]
3
4
9a
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
3
3
CF3
CF3
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO
Me
Me
Ph
93[
61
62
these optimal condition [Pd
A
H
U
G
R
N
N
(OAc)
(5 mol%), 9b
67[
95[
2
[d]
P(Cy) ·HBF4 (10 mol%), K CO3 (2.5 equiv.), DMF, 9c
3
2
1
408C], the reaction was completed within 7 h and af- 9d
CF
Ph
76
3
[
9
9
9
9
9
9
9
9
e
f
g
h
i
j
k
l
CF3
2-thienoyl 88[
forded the desired fused imidazole 9a in up to 93%
yield. (Table 3, entry 4).
CF3
2-thienoyl 69
[
CF3
CF3
CF3
CF3
2-furyl
2-furyl
CF3
CF3
Me
Me
Me
Me
H
79[
To study the scope and limitations of our synthetic
methodology, the influence of substituents R and the
length of the aliphatic linker were investigated. The
reactions of a set 1-deazapurines 5b–p were studied.
We have found that the type as well as the position of
the substituents R of the pyridine core had a dramatic 9m
influence on the yields. For instance, some illustrative 9n
trends in the chemical reactivity of adducts 5 are 9o
52
[a]
[b]
[c]
88
64
39
CO Me
2
[
[
[
a–c]
a–c]
a–c]
CO Me
0
0
0
2
CF Cl
2
CF
H
Cl
2
[
a]
69
[a–c]
2
9
9
9
p
q
r
H
CF3
CF3
NO2
H
Me
Ph
0
shown in Table 4. The reaction proceeded uneventful-
ly and in high yields for 1-deazapurines furnished
[d]
H
H
57[
48
d]
with a CF substituent located at position 6 (products
3
[
[
[
[
a]
9
a–j) (Scheme 2, Table 4).
At the same time, the reaction of substrates 5m and
Pd
A
T
N
T
E
N
N
(OAc) (5 mol%), P(Cy) ·HBF (10 mol%), K CO3
2
3
4
2
(2.5 equiv.), DMF, 1408C, 7 h.
b]
5
n, bearing a CF Cl group, failed under various condi-
Pd
2.5 equiv.), DMF, 1208C, 6 h.
Pd(OAc) (5 mol%), XPhoS (10 mol%), KOAc
2 equiv.), DMF, 1208C, 6 h.
Pd(OAc) (10 mol%), Cu(OAc) (2.5 equiv.), HOAc,
108C, air, 8 h.
A
H
U
G
R
N
U
G
2
(5 mol%), XPhoS (10 mol%),
K
CO
2
3
2
(
tions (Table 4). In the case of NO and CO Me substi-
2
2
c]
AHCTUNGTRENNUNG
tuted derivatives, the number n of CH groups be-
2
2
(
tween the aryl substituent and the N-atom of the imi-
dazole ring had an influence on the yields. We were
able only in the case of n=2 to isolate products 9k
and 9o in moderate yields. Moreover, in the case of 9j
and 9k, the use of a more sterically encumbered
ligand (XPhoS) was necessary. In general, the length
of the linker was essential in terms of yield: com-
pounds with n=2 show in all cases better yields than
those with n=1 (Scheme 3, Table 4).
d]
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNG
2
2
1
Thereafter, we have turned to the synthesis of
structurally related fused purines 10 and have tested
a set of purines 8a–d. Using similar reaction condi-
tions with some slight optimization (trifluoromethyl-
containing purines were proven to be unstable in the
case of temperatures higher than 1008C and in pres-
ence of strong bases), it was possible to conduct the
desired ring cyclization which delivered the fused pu-
rines 10a–d in a yield range of 47–96%. In this case
we have also observed a strong dependence of the
yields on the length of the alkyl linker. The best Scheme 2. Reaction conditions: (i) CÀH activation, Table 4:
yields were observed for n=2. At the same time, for conditions a–c; Table 6: conditions a and b.
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Viktor O. Iaroshenko et al.
FULL PAPERS
n=1, the yields were considerably lower or the reac-
tion experienced failure.
We were also interested in the development of
more economical methods for the synthesis of scaf-
folds 9. We were aware of the possibility to use halo-
gen-free analogues of 5, which, in our opinion, should
give rise to the desired fused imidazoles by oxidative
CÀH activation. As a starting point, we have applied
[
25]
Scheme 3. Reaction conditions: (i) oxidative CÀH activation,
the pioneering work of Desarbre et al., who report-
ed a related methodology for the synthesis of novel
indole derivatives.
Table 4: conditions d.
After the optimization of the reaction conditions,
we have found that the best results were obtained
Table 5. Optimization of the oxidative C-H activation, synthesis of compound 9a.
Entry
Reaction conditions
Yield [%]
1
2
3
4
5
6
7
8
9
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
T
N
T
N
U
G
0
18
0
0
0
24
34
42
42
61
61
61
2
2
2
2
2
2
2
2
2
2
2
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (5 mol%)/Cu
A
H
U
G
R
N
U
G
2
10
11
12
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (10 mol%)/Cu
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (10 mol%)/Cu
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (10 mol%)/Cu
2
Scheme 4. Reaction conditions: (i): 1 equiv. of alkylating agent, 1,1 equiv. of NaH, DMF, 2 h; (ii): Pd
ACHTUNGTNERNU(GN OAc) (10 mol%),
2
Cu(OAc) (2,5 equiv.), HOAc, 1108C, air, 8 h; (iii): Pd(OAc) (5 mol%), XPhoS (10 mol%), KOAc (2 equiv.), DMF, 1208C.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
2
2
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Design and Synthesis of Polycyclic Imidazole-Containing N-Heterocycles
Table 6. Yields of fused purines 10.
No.
n
R
Yield [%]
[
b]
b]
a]
10a
10b
10c
10d
2
1
2
1
CF3
CF3
H
90[
47[
96
[
a,b]
H
0
[
a]
Pd
2.5 equiv.), DMF, 1408C, 14 h.
Pd(OAc) (5 mol%), XPhoS (10 mol%), KOAc
2 equiv.), DMF, 1008C, 6 h.
ACHTUNGTRENNUNG( OAc) (5 mol%), P(Cy) ·HBF (10 mol%), K CO
2 3 4 2 3
(
[
b]
ACHTUNGTRENNUNG
2
(
Scheme 6. Reaction conditions: (i): 1 equiv. of alkylating
agent, 4 equiv. of K CO DMF, 908C, air, 12 h; (ii):
2
3,
Pd
A
H
U
G
R
N
N
(OAc)
(10 mol%), Cu
A
T
N
T
E
N
N
(OAc)
(2,5 equiv.), K CO3
2
2
2
(
2 equiv.), PivOH, air, 1308C, 14 h.
Motivated by our success, we decided to change the
type of the linker. The direct base-mediated alkyla-
tion of 1-deazapurine 11 afforded compounds 12, 14
and 15 in good yields (Scheme 4, Table 6). Using
a subsequent CÀH bond functionalization, we intend-
ed to access the fused imidazoles 13 and 16. However,
only substrates 12 could be converted into the corre-
sponding products 13. In the case of 14 and 15, both
CÀH activation protocols mentioned above have ex-
perienced a failure.
In the same time, to obtain a complete profile of
Scheme 5. Reaction conditions: (i): 1 equiv. of alkylating the reaction studied, we were interested in the behav-
agent, 4 equiv. of K CO DMF, 908C, air, 12 h; (ii): ior of the simple benzimidazole derivatives 18. Indeed
2
3,
Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc)
(10 mol%), Cu
A
H
U
G
R
N
U
G
(2.5 equiv.), K CO
3
the oxidative CÀH bond functionalization developed
2
2
2
(
2 equiv.), PivOH, air, 1308C, 14 h. For X, see Table 7.
here can be also applied for the construction of the
condensed benzimidazole scaffolds 19 (Scheme 5,
Table 7), however some restrictions are present. In
the case of benzimidazoles only methods with pivalic
acid were efficient. Compound 19c was partially
formed after prolonged heating (40 h), but could not
be isolated pure, and compound 19d did not form at
all.
Table 7. Yields of benzimidazole derivatives 18 and 19.
No.
n
R
X
Yield [%]
18a
18b
18c
18d
19a
19b
19c
19d
2
2
3
3
2
2
3
3
H
Me
H
H
H
Me
H
H
CH2
CH2
CH2
–
CH2
CH2
CH2
–
79
64
77
69
58
50
0
After the general reaction conditions for both CÀH
bond activation strategies had been established and
investigated in detail, we then switched to the direct
intermolecular oxidative arylation of scaffolds con-
taining two azole subunits which are linked by
a spacer attached to both N-atoms. As model sub-
strates for this study, we have chosen the benzimida-
0
using Pd ACHTUNGTRENNUNG( OAc) in the presence of Cu ACHTUNGTERNN(GNU OAc) as a sac- zole derivatives 20 which were obtained by direct al-
2
2
rificial oxidant and air as co-oxidant; this transforma- kylation of benzimidazole 21 (Scheme 6). At the same
tion progressed under acidic conditions using acetic time, we planned to investigate the influence of the
acid. Nevertheless, acetic acid as solvent has demon- length of the linker on the arylation reaction. Our at-
strated the best yields for the reaction (Table 4, tempt to use the same reaction conditions, as in the
entry 10). Usage of pivalic acid as a solvent or pure case of imidazo
oxygen as co-oxidant does not affect product outcome spite the fact that simple benzimidazoles constitute
Table 4, entries 11 and 12). As we have found, the a class of more electron-enriched heterocycles. In the
quality of the Cu(OAc) played a crucial role. The use current case, implementation of pivalic acid as a sol-
of the hydrated form of the salt decreases drastically vent and base is obligatory. It should be also noted
ACHTUNGTRENNUNG[ 4,5-b]pyridines surprisingly failed, de-
(
ACHTUNGTRENNUNG
2
the overall yields (Table 5, entry 2).
that the reaction could be monitored by TLC and
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Viktor O. Iaroshenko et al.
FULL PAPERS
Table 8. Yields of benzimidazole derivatives 20 and 21.
No.
X
Yield [%]
20a
20b
20c
20d
20e
20f
21a
21b
21c
21d
21e
21f
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(-CH -)
60
76
69
67
76
83
52
58
39
31
28
42
2
2
3
4
5
ACHTUNGTRENNUNG( -CH -)
ACHTUNGTRENNUNG( -CH -)
2
ACHTUNGTRENNUNG( -CH -)
-(CH ) O ACHTUGNTRNEUNG( CH ) -
2 2
1,2-phenylenedi(methylene)
ACHTUNGTRENNUNG( -CH -)
ACHTUNGTRENNUNG( -CH -)
2
ACHTUNGTRENNUNG( -CH -)
2
2
2
2
2
2
3
4
5
2
ACHTUNGTRENNUNG( -CH -)
2
-(CH ) O ACHTUGNTRNEUNG( CH ) -
1,2-phenylenedi(methylene)
2
2
2 2
Figure 1. ORTEP plot of the structure 10b.
Figure 2. ORTEP plot of the structure 13a.
Scheme 7. Reaction conditions: (i): 1 equiv. of alkylating
agent, 1,1 equiv. of NaH, DMF, 2 h; (ii): Pd(OAc)
AHCTUNGTRENNUNG
2
(
10 mol%), Cu
ACHTUNGTRENNUNG( OAc) (2,5 equiv.), AcOH, air, 1108C, 8 h
2
(
a); or Pd(OAc) (10 mol%), AgOAc (2,5 equiv.)/AcOH,
ACHTUNGTRENNUNG
2
air, 1108C, 8 h (b).
worked up only with preliminary treatment with
NH Cl, possibly, due to the formation of stable com-
4
plexes of benzimidazole-derived substrates with
copper. As it is seen in Table 8, the length of the
linker X has a great impact on the overall yields. The
best yields were observed for imidazoles having
a length of n=2 or 3. An increase of the length re-
sulted in a decrease of the yields.
The next logical step was the synthesis of 1-deaza- Figure 3. ORTEP plot of the structure 23a.
purines 22 and their cyclization to furnish the fused 1-
deazapurines 23 (Scheme 7). In the case of the highly
electron-poor bis-trifluoromethyl derivative (22b), ox- single crystal analysis (Figure 1, Figure 2 and
[
26]
idation with copper acetate does not take place. How- Figure 3).
ever, reaction proceeds smoothly when the stronger
oxidant AgOAc is used.
The constitution of the synthesized fused imida- Conclusions
zoles was mainly established by 1D and 2D NMR
methods. Moreover, the structures of compounds 10b, In summary, we have developed a straightforward Pd-
13a, and 23a were independently established by X-ray catalyzed reaction for the synthesis of fused purines
2500
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2495 – 2503

Design and Synthesis of Polycyclic Imidazole-Containing N-Heterocycles
and 1-desazapurines furnished with a CF group as 20 mL of chloroform, and liquid residues were evaporated
3
under vacuum. The crude product was isolated via column
chromatography.
well as of condensed benzimidazoles. An optimization
study which implicated the development of many new
reaction conditions, by the scanning of different type
of ligands, catalyst systems, additives and bases was General Procedure for Preparation of Alkylated
conducted. In the same time the nature of the alkyl Derivatives 12, 14, 15, 20a and 22
linkers regarding the overall yields were studied.
To the solution of -NH-containing heterocycle (300 mg,
1
equiv.) in dry DMF (4 mL) sodium hydride (1.1 equiv.)
was added portionwise. After hydrogen evolution was over,
corresponding alkylating agent (1 equiv.) was added. The
mixture was stirred at room temperature during 2 h, and
then was poured into water. The mixture was extracted with
EtOAc (3ꢄ100 mL), organic layers were washed with water
and dried over sodium sulfate. After evaporation of solvent,
the residue was purified by column chromatography (in the
case of 18a, product was recrystallized from 60% aqueous
ethanol).
Experimental Section
All solvents were purified and dried by standard methods.
NMR spectra were recorded on a Bruker AVANCE 250 II
and Bruker DPX 300. The following abbreviations were
used to designate chemical shift multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.
IR spectra were recorded on a Perkin–Elmer FT IR 1600
spectrometer (ATR). Mass spectra were obtained on a Hew-
lett–Packard HP GC/MS 5890/5972 instrument (EI, 70 eV)
by GC inlet or on an MX-1321 instrument (EI, 70 eV) by
direct inlet. Column chromatography was performed on
silica gel (63–200 mesh, Merck). Silica gel Merck 60F254
plates were used for TLC.
General Procedure for Preparation of Fused
Imidazo
ACHTUNGTRENUNNG[ 4,5-b]pyridines 9a, 9c, 9q, 9r and 23 via
Oxidative Arylation
2
00 mg (1 equiv.) of corresponding imidazo
was dissolved in 4 mL of acetic acid. Afterwards Pd
(10 mol%) and anhydrous Cu(OAc) (2.5 equiv.) or AgOAc
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
2
General Procedure for the Synthesis of Imidazo
A
H
N
T
E
N
N
[4,5-
ACHTUNGTRENNUNG
2
b]pyridines 5 and 6
(2.5 equiv.) (in the case of 21b) were added and reaction
mixture was heated up to 1108C under air athmosphere
during 8 h. As reaction is completed, the solvent was evapo-
rated under vacuum, the residue was treated with water
To a Schlenk flask, set with reflux, CH Cl (3 mL), corre-
2
2
sponding amine (0.0055 mol), and methyl N-(cyanomethyl)-
formimidate (0.005 mol) were added under an argon atmos-
phere at room temperature. The reaction mixture was re-
fluxed during 1 h 20 min and after that, the mixture was
cooled down to room temperature. 1,3-Dicarbonyl com-
pound was added, and the mixture was further stirred at the
same temperature for 15–20 min and then refluxed for 6 h.
(
1
30 mL). Organic residues were extracted with EtOAc (3ꢄ
00 mL), washed with water and dried over sodium sul-
phate. After evaporation of solvent, the desired product was
isolated by column chromatography.
The solvent was evaporated to dryness and the residue was General Procedure for Preparation of Alkylated
purified by column chromatography to give the desired com- Benzimidazole Derivatives 18 and 20b–f
pound.
To the solution of corresponding benzimidazole (300 mg,
1
equiv.) in 4 mL of DMF, K CO (4 equiv.) and alkylating
2 3
General Procedure for the Synthesis of Purines 8
agent (1 equiv.) were added. Reaction mixture was stirred
during 12 h at 908C, then poured into water. The mixture
was extracted with EtOAc (3ꢄ100 mL), the organic layers
were washed with water and dried over sodium sulfate.
After evaporation of solvent, the residue was purified by
column chromatography.
To a Schlenk flask, set with reflux, CH Cl (3 mL), corre-
2
2
sponding amine (0.0055 mol), and methyl N-(cyanomethyl)-
formimidate (0.005 mol) were added under an argon atmos-
phere at room temperature. The reaction mixture was re-
fluxed during 1 h 20 min and after that, the mixture was
cooled down to room temperature, and then to 08C on an
ice bath. Afterwards, corresponding 1,3,5-triazine was
added, and the mixture was further stiredr at the same tem-
perature for 15–20 min and then refluxed for 7 h. The sol-
vent was evaporated to dryness and the residue was purified
by column chromatography to give the desired compound.
General Procedure for Preparation of Fused
Benzimidazoles 19 and 21 via Oxidative Arylation
200 mg (1 equiv.) of corresponding benzimidazole was dis-
solved in 4 mL of pivalic acid. Afterwards Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc)
2
(
(
10 mol%), anhydrous Cu
2 equiv.) were added and reaction mixture was heated up
ACHTUNGTREN(NUGN OAc) (2,5 equiv.), K CO3
2
2
General Procedure for Preparation of Fused
Imidazo ACHTUNGTRENNUNG[ 4,5-b]pyridines and Purines 9a–p and 10
to 1408C under air atmosphere during 14 h. When the reac-
tion was completed, the crude mixture was threated with
20% aqueous NaOH, till the full neutralization of acid and
To an argon-purged pressure tube, filled with 200 mg of cor-
responding substrates 5 or 8, Pd(OAc) (5 mol%), ligand
10 mol%), and base (2 or 2.5 equiv.), 3,5 mL of dry DMF
A
H
U
G
R
N
U
G
then with concentrated aqueous NH Cl (50 mL) and left to
2
4
(
stand for 1 hour (treatment with ammonium chloride is not
necessary in the case of compounds 19). Organic residues
were extracted with EtOAc (3ꢄ150 mL), washed with water
and dried over sodium sulfate. After evaporation of solvent,
were added. Pressure tube was capped and reaction mixture
was heated at the required temperature (mentioned in text).
After the reaction is complete, the solution was diluted with
Adv. Synth. Catal. 2012, 354, 2495 – 2503
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2501

Viktor O. Iaroshenko et al.
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2503