Regioselective N-alkylation of imidazo[4,5-b]pyridine-4-oxide derivatives: an experimental and DFT study

Article abstract of DOI:10.1016/j.tetlet.2009.02.006

Regioselectivities were determined for N-alkylations of imidazo[4,5-b]pyridine-4-oxide and 2-methyl-imidazo[4,5-b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K₂CO₃ in DMF as a base. Experimental attempts have shown that N-1/N-3 ratios slightly varied according to the substitution on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has shown first that this N-benzylation reaction passed through a S_N2 mechanism. Moreover, regioselectivity of N-benzylation has appeared essentially governed by 'steric approach control'. It explained that opposite N-1/N-3 ratios were obtained with imidazo[4,5-b]pyridine-4-oxide and its 2-methyl-substituted analog. Finally, regioselectivities slightly varied with the nature of benzyl halide.

Full text of DOI:10.1016/j.tetlet.2009.02.006

Tetrahedron Letters 50 (2009) 1828–1833
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective N-alkylation of imidazo[4,5-b]pyridine-4-oxide derivatives:
an experimental and DFT study
a,
a
Wael Zeinyeh a, Julien Pilmé b,c, , Sylvie Radix , Nadia Walchshofer
*
*
a Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, INSERM U863, IFR 62, F-69373 Lyon cedex 08, France
b Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, F-69373 Lyon cedex 08, France
c Laboratoire de Chimie Théorique, Université Pierre et Marie Curie, Paris VI, UMR-CNRS 7616, 4 Place Jussieu, 75252, Paris cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselectivities were determined for N-alkylations of imidazo[4,5-b]pyridine-4-oxide and 2-methyl-
imidazo[4,5-b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K2CO3 in DMF as a
base. Experimental attempts have shown that N-1/N-3 ratios slightly varied according to the substitution
on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has
shown first that this N-benzylation reaction passed through a SN2 mechanism. Moreover, regioselectivity
of N-benzylation has appeared essentially governed by ‘steric approach control’. It explained that oppo-
site N-1/N-3 ratios were obtained with imidazo[4,5-b]pyridine-4-oxide and its 2-methyl-substituted ana-
log. Finally, regioselectivities slightly varied with the nature of benzyl halide.
Received 15 December 2008
Revised 29 January 2009
Accepted 3 February 2009
Available online 8 February 2009
Keywords:
N-alkylation
DFT calculations
Imidazo[4,5-b]pyridine
Regioselectivity
SN2 mechanism
Tautomerism
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
precursors 3 and 4. Actually, these compounds can exist in two
tautomeric forms like benzimidazole or purine systems,3 and
The multidrug resistance (MDR) phenotype remains a signifi-
cant impediment to successful chemotherapies used in particular
against cancer or parasitic infections. MDR transporters are in-
volved in the efflux of xenobiotics across biological membranes,
and among them, ABC (Adenosine triphosphate–Binding Cassette)
transporters couple the hydrolysis of ATP to substrate efflux.1
These proteins are therefore potential drug targets of great
interest.2 Imidazo[4,5-b]pyridine derivatives which are already
known to possess versatile biological activity3 (antiviral, cytostatic,
antimicrobial, fungicidal, cardiovascular, antisecretory, and other
functions) can be considered as 1-deazapurine analogs. So, we
decided to design new synthetic N-substituted imidazo[4,5-b]pyri-
din-7-one derivatives (Fig. 1) which could target the ATP-binding
site contained into ABC transporters. Moreover, it has been often
proved that enhancing the selectivity of ATP-binding inhibitors
could be achieved via the binding of these inhibitors in neighboring
pockets adjacent to the catalytic site.4 The position and the nature
of substituents on imidazopyridinone derivatives are therefore of
great importance. So, during the course of our investigations, we
decided to study the regioselectivity of N-benzylation of 4-oxide
therefore could lead to 1-benzyl- or 3-benzyl-imidazo[4,5-b]pyri-
dine-4-oxide a or b (Fig. 2).
R2
N1
O
O
N
R1
R1
N
3N
N
N
R2
R3
R3
Figure 1. Structures of N1- and N-3-substituted imidazo[4,5-b]pyridin-7-one
derivatives.
H
7a N1
7
N
N
N
N
6
5
2 R
R
R
3a N
4N
O
N
O
N
O
3
a
3 R=H
4 R=CH3
b
* Corresponding authors. Tel.: +33 478785609; fax: +33 478785607 (J.P.), tel.:
+33 478777253; fax: +33 478777158 (S.R.).
E-mail addresses: julien.pilme@univ-lyon1.fr (J. Pilmé), sylvie.radix@univ-
lyon1.fr (S. Radix).
Figure 2. Structures of N-benzylated imidazo[4,5-b]pyridine-4-oxide derivatives a
and b and their precursors 3 and 4.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.006

W. Zeinyeh et al. / Tetrahedron Letters 50 (2009) 1828–1833
1829
11,5%
7,9%
2. Chemistry
H
N
N
Imidazo[4,5-b]pyridine-4-oxide derivatives 3 and 4 were pre-
pared by the two-step sequence that is outlined in Scheme 1.
The cyclization to the imidazo[4,5-b]pyridine ring system was ef-
fected by refluxing the commercially available 2,3-diaminopyri-
dine in triethyl orthoformate or triethyl orthoacetate followed by
chlorohydric acid treatment to obtain, respectively, 15 or 2.6 The
4-oxide derivatives 37 and 4 were prepared from 1 or 2 according
to the Ochiai procedure,8 namely by oxidation with meta-chloro-
perbenzoic acid in 75% and 79% yield, respectively.9
At this point, N-benzylation of imidazopyridine-4-oxides 3 and
4 was carried out under classical conditions of nucleophilic substi-
tution using anhydrous potassium carbonate in DMF solution as a
base to generate the corresponding anions 3’ and 40 (Scheme 2).10
Whatever the alkylating agent we used (either benzyl bromide or
benzyl iodide), the reaction produced a mixture of N-1 and N-3
regioisomers which were easily separated by flash chromatogra-
phy.12 It is worth noting that N-1 compounds (5a and 6a) are con-
sistently the more polar ones (silica gel t.l.c.),11 and have the
highest melting point, compared with N-3 isomers (5b and 6b).
1D Homonuclear nuclear Overhauser enhancement (nOe) dif-
ference spectroscopy was used to establish the structure of each
regioisomer synthesized from 3 (5a and 5b). As mentioned in Fig-
ure 3, irradiation of the N–CH2 resonance in each regioisomer re-
sulted in nOe effects, respectively, on C-7-proton signal for
compound 5a and on C-5-proton signal for compound 5b. Once
the regioselectivity of N-benzylation of 3 has been unambiguously
determined, it appeared that comparison of 1H NMR spectra al-
lowed to assign easily the structure of N-1 and N-3 regioisomers
(Table 1). Indeed, C-7 and N–CH2 proton signals of N-1 products
(5a and 6a) were significantly shielded compared with the corre-
H
5
H
3
H
N
O
7
1
N
H
H
N 2
N
O
H
1,5%
4,1%
δ(NCH2) = 5.54 ppm
δ(NCH2) = 5.72 ppm
5a
5b
Figure 3. Establishment of the regioselectivity of N-benzylation of 5 by 1D nOe
difference spectroscopy. 1H NMR spectra were registered in DMSO-d6.
Table 1
1H NMR assignments of regioisomers 5a,b and 6a,b produced via Scheme 2
H
5aa
5ba
D
d
6aa
6ba
Dd
H-2
CH3
H-5
H-6
H-7
N–CH2
8.64 (s)
—
8.37 (s)
—
—
—
2.55 (s)
8.12 (d)
6.98 (dd)
7.55 (d)
5.53 (s)
2.58 (s)
8.17 (d)
7.03 (dd)
8.04 (d)
5.67 (s)
8.20 (d)
7.21 (dd)
7.60 (d)
5.54 (s)
8.39 (d)
7.17 (dd)
8.32 (d)
5.72 (s)
ꢀ0.72
ꢀ0.18
ꢀ0.49
ꢀ0.14
1H spectra were recorded at 300 MHz in DMSO-d6 at 23 °C. Chemical shifts are
reported in part per million (ppm). In parentheses: multiplicity (coupling constants
[J] in hertz are mentioned in Ref. 12).
a
Table 2
Results obtained for the N-benzylation of compounds 3 and 4 with benzyl bromide or
benzyl iodide mentioned in Scheme 2
Entry
R
PhCH2X
Time
N-1/N-3 ratioa
Yieldb (%)
1
2
3
4
H
H
CH3
CH3
PhCH2Br
PhCH2I
PhCH2Br
PhCH2I
20 h
4 h
20 h
4 h
(5a:5b) 60:40
(5a:5b) 70:30
(6a:6b) 40:60
(6a:6b) 30:70
86
84
60
100
NH2
NH2
N
N
a or b
c or d
a
R
R
N-1/N-3 ratios were determined after flash chromatography separation and 1H
N
H
N
H
NMR study.
N
N
N
O
b
Total isolated yields.
1 R=H
2 R=CH3
3 R=H
4 R=CH3
sponding protons in N-3 compounds (5b and 6b):
ꢀ0.49 (C7–H), ꢀ0.18 or ꢀ0.14 (N–CH2).
D
d = ꢀ0.72 or
Scheme 1. Reagents and conditions: (a) (i) HC(OEt)3, reflux, 3 h 30 (ii) HCl 37%,
reflux, 1 h (83%); (b) (i) MeC(OEt)3, reflux, 3 h 30 (ii) HCl 37%, reflux, 1 h (78%); (c)
(R = H) m-CPBA 90%, AcOH, 50 °C, 16 h (75%); (d) (R = CH3) m-CPBA 90%, CHCl3, rt,
4 h (79%).
Literature has shown that N-alkylation of imidazo[4,5-b]pyri-
dine derivatives mainly led to N-3 regioisomer.3,13 However, this
NMR study has clearly confirmed that, whatever the alkylating
agent we used and despite only a slight regioselectivity, 4-oxide
3 provided N-1 isomer as the major isomer under N-benzylation
conditions (Table 2, entries 1 and 2).7a,14 Meanwhile, opposite N-
1/N-3 ratio was obtained when C-2-methylated 4-oxide 4 was trea-
ted under the same conditions (Table 2, entries 3 and 4). In both
cases, benzyl iodide, used as alkylating agent, predictably provided
more rapid reaction with more satisfactory N-1/N-3 ratios than
benzyl bromide (Table 2, entries 2 and 4).
H
N
N
K2CO3, DMF, rt, 1h
R
R
N
H
N
N
O
N
O
3' R=H
4' R=CH3
3 R=H
4 R=CH3
PhCH2Br or PhCH2I
DMF, rt
3. Computational methods
Ph
N1
Calculations have been performed at the hybrid density func-
tional B3LYP level15 with GAUSSIAN 03 program.16 The geometries
were fully optimized without symmetry constraint. The standard
all-electron 6-311+G(d) basis set was used for the Br, I, N, and O
atoms while the basis set 6-311G(d, p) was used for the C and H
atoms. Transition state (TS) geometries were approached by a
linear-transit procedure, while optimizing all other degrees of
freedom. Full TS searches were started from the geometries
corresponding to maxima along the linear-transit curves. Each TS
N
N
R +
R
N
N
O
N
O
3
Ph
a
b
5a,b R=H
6a,b R=CH3
Scheme 2. N-Benzylation of 3H-imidazo[4,5-b]pyridine-4-oxide derivatives 3 and 4.

1830
W. Zeinyeh et al. / Tetrahedron Letters 50 (2009) 1828–1833
displayed only one negative eigenvalue according to a non-ambig-
uous saddle point. The solvent corrections were taken into account
by the Polarized Continuum Model (PCM)17 implemented in the
modified parameters for the PCM environment (THF, e = 7.58) led
us to confirm these results since N-1 isomer 5a (R = H) was found
1.8 kcal/mol more stable than N-3 isomer 5b (R = H). Let us exam-
ine geometries of isomers in order to provide a further understand-
ing of these results. In all cases, the plane of the benzyl group was
perpendicularly staggered to imidazopyridine plane (Table 4). Con-
sequently, steric hindrance between benzyl and imidazopyridine
fragments appeared to be weak. Thus, because steric factors could
not explain stability difference between N-1 and N-3 regioisomers,
electronic charges have been calculated for each anion 30 (R = H)
and 40 (R = CH3) (Scheme 2) in gas phase and solvent. For the anion
30, N-1 atomic charge value18 was found quite similar to N-3 charge
in gas phase (ꢀ0.90e). In contrast, the analysis of solvated anion 30
revealed that the N-1 site was more polarized than N-3 site ones.
Indeed, charges of N-1 and N-3 atoms are, respectively, determined
to be ꢀ0.94e and ꢀ0.90e and local dipolar polarizations17 were,
respectively, calculated to be 0.45 a.u. and 0.40 a.u. These calcula-
tions have led to find out the preferred site (N-1 vs N-3) for a SN2
mechanism in a polar solvent. Similar tendencies were found out in
the case of anion 40. Moreover, the charge of the oxygen atom was
found stronger for the ions in solvent phase (ꢀ0.70e) than in gas
phase (ꢀ0.48e). So, a nucleophilic attack on N-3 site appeared elec-
trostatically unfavorable in the solvated environment due to the
strong repulsive interaction Oꢀꢁ ꢁ ꢁXꢀ. All these electronic factors
led us to conclude that nucleophilic attack was a slightly more
favorable on N-1 site. Therefore, they allowed to easily grasp
why the N-1 regioisomers were always more stable than N-3 ones
in solvent phase. Nevertheless, observed N-1/N-3 ratios essentially
depended on the relative stabilities of TS involved in the SN2 pro-
cess which has appeared to be the energetically preferred
mechanism.
Gaussian program (e = 38, DMF). All the energies were corrected
of the basis set superposition error (BSSE) and the TS barriers have
been corrected of the zero-point energy correction (ZPE). Atomic
charges and atomic dipolar polarizations were calculated in the
framework of the QTAIM theory18 using the TopMoD package.19
Ball-and-stick models of the TS structures have been displayed
with the Molekel software.20
4. Density functional theory calculations
Starting from our experimental results, Density Functional The-
ory (DFT) calculations were next performed in order to provide a
further understanding of the observed N-1/N-3 ratios and their
relationship with alkylating agents. It seems likely that this slight
N-1/N-3 regioselectivity variation may be due to non-bonded steric
interactions governed by the geometries of the transition states
(TS) involved in the N-alkylation mechanism. To determine the
reaction pathway, SN2-TS energies were compared to TS energies
calculated for a hypothetical first stepꢀof dissociation of benzyl ha-
þ
lide in a SN1 mechanism (PhCH2 + X ). Actually, our calculations
have clearly shown an energetic stabilization above 30 kcal/mol
in favor of the SN2 barriers in both gas and solvent phases.21
4.1. Regioisomers
The SN2 regioisomers were optimized in both gas and solvent
phases. All the relative energies are reported in Table 3. The main
structural parameters of optimized structures are listed in Table 4.
Whatever the alkylating agent we used, N-3 isomers were lower in
energy than N-1 isomers in gas phase (Table 3). Conversely, N-1
isomers were found 3 kcal/mol lower in energy than N-3 isomers
in solvent phase (Table 3). Thus, these results led us to conclude
4.2. Transition state barriers
Relative energies of optimized SN2 TS, in gas phase and solvent,
are reported in Table 3. Single points were also calculated in sol-
vent from the optimized gas phase geometries. They were found
in reasonable agreement with the full optimized calculations. Main
structural parameters of TS geometries are listed in Table 4. As
displayed in Figure 4, TS-a structures (5 or 6) correspond to N-1-
benzylated derivatives while TS-b structures (5 or 6) correspond
to N-3-benzylated ones. As already observed for the final products
(see previous section), N-3 barriers were widely stabilized in gas
phase with respect to N-1 barriers (1.5–3.5 kcal/mol, see Table 3).
However, it is worth noting that the relative gap between N-1
and N-3 barriers was apparently related to the nature of the group
on C-2 position (H or CH3). Indeed, the energetic gap between
TS-5a (N-1 isomer, R = H) and TS-5b (N-3 isomer, R = H) was
1.44 kcal/mol, whereas the gap between TS-6a (N-1 isomer,
R = CH3) and TS-5b (N-3 isomer, R = CH3) was greater than 2 kcal/
mol (Table 3). Although these results in gas phase did not explain
the experimental N-1/N-3 ratio variations, they confirmed that the
gap N-1/N-3 was influenced by the steric hindrance of the methyl
group on C-2 position. In contrast, the optimized calculations in
solvent phase have appeared in fairly good agreement with exper-
imentally observed ratios (Table 2) and have revealed a slight ener-
getic difference (0.2–0.9 kcal/mol, Table 3) between N-1 and N-3
barriers. Indeed, TS-5a (N-1 isomer, R = H) was found slightly lower
than TS-5b (N-3 isomer, R = H) in solvent. Conversely, in the pres-
ence of a methyl group on C-2 position (Fig. 4, bottom structures),
TS-6b (N-3 isomer, R = CH3) was found lower than TS-6a (N-1 iso-
mer, R = CH3). Consequently, TS-6a seemed to be less accessible
than TS-6b in agreement with the observed experimental ratio
6a:6b (Table 2, entries 3 and 4). Contrary to a hydrogen atom,
the methyl group on C-2 position caused an additional steric inter-
action with the benzyl group. This can be understood by the geom-
that a polar environment (DMF,
regioisomers better than N-3 ones. Tests of PCM calculations with
e = 38) was able to stabilize N-1
Table 3
Relative energies (kcal/mol) of products and transition states in gas and solvent
phases, B3LYP optimized calculations
b
c
e
Transition states/products
Egas+BSSE
Esolv+BSSE
ZPEd
Esol+BSSE+ZPE
TS-5-Bromide (R = H)
TS-5a
TS-5b
1.44
0.0
0.0
0.34 (0.56)
0.11 (0.12)
0.0
0.0
0.23 (0.44)
TS-6-Bromide (R = CH3)
TS-6a
2.32
2.45
0.0
0.38 (0.55)
0.95 (0.84)
0.0
0.0
0.06 (0.13)
0.15 (0.20)
0.23 (0.35)
0.86 (0.67)
0.0
TS-6a (2)a
TS-6b
TS-5-Iodide (R = H)
TS-5a
TS-5b
2.17
0.0
0.0
0.0
0.0
0.19
0.22
0.41
TS-6-Iodide (R = CH3)
TS-6a
TS-6b
3.21
0.0
0.41
0.0
0.0
0.22
0.20
0.0
Regioisomers
5a
5b
6a
6b
4.00
0.00
3.35
0.0
0.0
3.01 (3.18)
0.0
3.26 (3.20)
a
See Figure 4.
Optimized energy in the gas phase.
Single point and optimized (given in parentheses) solvent energy.
Zero point energy correction in the gas phase. Values in parentheses correspond
b
c
d
to the optimized geometries in the solvent phase.
e
Relative electronic single point and optimized (given in parentheses) energies
in the solvent phase including the BSSE and the ZPE corrections.

W. Zeinyeh et al. / Tetrahedron Letters 50 (2009) 1828–1833
1831
Table 4
Structural parameters of TS and regioisomers optimized for both gas and solvent phases (given in parentheses) with respect to the numbering in Figure 4
CxNxa
CxXb
N4O
CxNxCqa
CoCxH1H2
CoCxNxC2a
TS-Bromide
TS-5a
TS-5b
TS-6b
TS-6a
2.219 (2.374)
2.146 (2.357)
2.220 (2.400)
2.154 (2.382)
2.515 (2.552)
2.615 (2.619)
2.541 (2.583)
2.629 (2.618)
1.289 (1.316)
1.299 (1.317)
1.290 (1.318)
1.302 (1.320)
124.9 (118.5)
130.8 (118.6)
115.2 (118.8)
128.5 (119.5)
175.5 (171.4)
176.6 (173.1)
178.5 (172.8)
175.6 (172.6)
0.0 (2.8)
85.6 (60.9)
4.1 (4.1)
85.7 (54.4)
TS-Iodide
TS-5a
TS-5b
TS-6b
TS-6a
2.277
2.192
2.273
2.199
2.726
2.840
2.755
2.856
1.289
1.300
1.291
1.302
125.2
129.8
115.3
127.7
172.7
178.5
175.8
177.5
0.0
85.4
0.1
85.0
Products
5a
5b
6a
6b
1.478
1.482
1.469
1.475
1.302
1.309
1.304
1.313
126.0
130.5
126.2
129.0
120.5
122.0
120.0
121.1
38.1
81.7
74.6
73.1
Distances are in Å and angles are in °.
a
Nx = N1 or N3.
X = Br or I.
b
Figure 4. B3LYP optimized transition state structures for N-benzylation of imidazo[4,5-b]pyridine-4-oxide derivatives (ball-and-sticks models): N1-benzylation: TS-5a
(top,left), TS-6a (bottom,left) and TS-6a(2) (bottom, middle). N3-benzylation: TS-5b (top, right), TS-6b (bottom, right).
etries of TS as displayed in Figure 5. As anticipated in SN2 process,
carbon Cx showed a typical strong sp2 character (Table 4). TS-6a
structure displayed a benzyl group directly orientated in front of
the methyl (Fig. 5, left) whereas TS-6b structure exhibited a stag-
gered benzyl group with respect to the plane of the imidazopyri-
dine moiety (Fig. 5, right). Thus, the methyl group induced a
probable additional steric hindrance in the N-1 transition state
(TS-6a structure) which was only partially balanced by the stabiliz-
ing solvent effects. Therefore, TS-6b became slightly more stable
than TS-6a. Another structure TS-6a(2) ( Fig. 4, bottom middle)
was also determined but, this transition state appeared to be desta-
bilized since its energy was 0.3 kcal/mol higher than TS-6a one
(Fig. 4, bottom left). This higher destabilization of TS-6a(2) could
be probably explained by electrostatic repulsive effects between
benzyl group and imidazopyridine moiety.
Thus, solvent effects strongly stabilized N-1 barrier (vs N-3 bar-
rier) when a hydrogen atom is bonded to the C-2 position. On the
other hand, in the presence of a methyl group on C-2 position, N-3
barrier remained lower than N-1 one in gas phase and solvent
highlighting that, in this case, the regioselectivity of N-alkylation
was mainly controlled by steric factor. So, our calculations have
confirmed what literature has conveyed so far, that is, that regiose-
lectivity in N-alkylation of azaheterocycle systems appeared essen-
tially governed by ‘steric approach control’.21

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W. Zeinyeh et al. / Tetrahedron Letters 50 (2009) 1828–1833
Figure 5. Comparative orientation of the benzyl plane in the TS-6a and TS-6b structures.
5. Antonini, I.; Cristalli, G.; Franchetti, P.; Grifantini, M.; Martelli, S.; Petrelli, F. J.
4.3. Alkylating agent effect
Pharm. Sci. 1984, 73, 367–369.
6. (a) Dubey, R. Indian J. Chem., Sect. B 1978, 16, 531; (b) Meravi, M. M.; Montazeri,
N.; Rahmizadeh, M.; Bakavoli, M.; Ghassemzadeh, M. J. Chem. Res. S 2000, 12,
584–585.
7. (a) Itoh, T.; Ono, K.; Sugawara, T.; Mizuno, Y. J. Heterocycl. Chem. 1982, 19, 513–
517; (b) Mizuno, Y.; Ikekawa, N.; Itoh, T.; Saito, K. J. Org. Chem. 1965, 30, 4066–
4071.
8. Ochiai, E. J. Org. Chem. 1953, 18, 534–551.
9. Synthesis of 2-methyl-3H-imidazo[4,5-b]pyridine-4-oxide 4: m-Chloroperbenzoic
acid (90%, 5.690 g, 30 mmol) was added to a suspension of 2-methyl-3H-
Both experimental and computational results have shown that
the nature of benzyl halide slightly influenced N-1/N-3 ratios. In-
deed, calculated relative energetic orders of the TS barriers in sol-
vent were quite similar whatever the alkylating agent was used.
However, optimized TS structures calculated with benzyl iodide
(TS-5b structure) led to a more important steric hindrance between
halide atom and the N-oxide group than with benzyl bromide. Con-
sequently, the energetic gap between TS-5b and TS-5a has ap-
peared slightly larger in the presence of iodide than in the
presence of bromide. This probably explained that more satisfac-
tory N-1/N-3 ratios were obtained with benzyl iodide (Table 2, en-
try 2). However, in the case of N-alkylation of derivative 4, both
steric effects induced either by the presence of a CH3 group on
C-2 position or by the use of a bulky iodide atom have a competi-
tive influence on the structures TS-6a and TS-6b. So, the rationali-
zation of the energetic gap between the latter structures is clearly
more complex than the qualitative understanding previously
given.
imidazo[4,5-b]pyridine
2 (1.587 g, 12 mmol) in chloroform (78 mL). The
mixture was stirred for 4 h at room temperature. Evaporation of the solvent
afforded a yellow powder which was loaded onto silica and was purified by
column chromatography (CH2Cl2/acetone/MeOH = 7:1.5:1.5, Rf = 0.19) to give 4
(1.400 g, 79%) as a pale yellow solid. Mp 266–268 °C. 1H NMR (300 MHz,
DMSO-d6): d = 8.09 (d, 3J(H,H) = 6.4 Hz, 1H, H-5), 7.50 (d, 3J(H,H) = 8.1 Hz, 1H,
H-7), 7.14 (dd, 3J(H,H) = 6.4 and 8.1 Hz, 1H, H-6), 2.53 ppm (s, 3H, CH3). HRMS
(CI): m/z: calcd for C7H8N3O: 150.0666, [M++H]; found: 150.0667.
10. (a) Geen, G. R.; Kincey, P. M.; Spoors, P. G. Tetrahedron Lett. 2001, 42, 1781–
1784; (b) Novak, J.; Linhart, I.; Dvarakova, H.; Kubelka, V. Org. Lett. 2003, 5,
637–639.
11. (a) Wenzel, T.; Seela, F. Helv. Chim. Acta 1996, 79, 169–178; (b) Geen, G. R.;
Grinter, T. J.; Kincey, P. M.; Jarvest, R. L. Tetrahedron 1990, 46, 6903–6914.
12. Typical experimental procedure for N-alkylation of imidazopyridine-4-oxide 3 and
4: K2CO3 (0.442 g, 3.2 mmol) was added under argon to a suspension of the
imidazopyridine-4-oxide (2 mmol) in DMF (5 mL). After stirring at room
temperature for 1 h, benzyl halide (2.4 mmol) was added. After overnight
stirring, water was added and aqueous phase was extracted by AcOEt. The
combined organic extracts were washed with water, dried (Na2SO4) and
evaporated to give a red oil which was purified by column chromatography. In
4.4. Concluding remarks
N-Benzylation of imidazo[4,5-b]pyridine-4-oxide derivatives
substituted or not on C-2 position has been realized to afford, in
each case, a mixture of N-1 and N-3 regioisomers. Both synthetic
and theoretical studies have shown the following. (1) Calculations
have determined that this nucleophilic substitution reaction oc-
curred through a SN2 pathway in solvent phase. (2) Experimental
N-1/N-3 regioselectivities have been confirmed by DFT study. For
each imidazo[4,5-b]pyridine-4-oxide derivatives, electronic factors
(atomic charge and dipolar polarization) allowed concluding that
nucleophilic attack was a slightly more favorable on N-1 site. But
observed N-1/N-3 ratios essentially depended on the relative sta-
bilities of TS involved in the SN2 process in solvent. Our calcula-
tions have confirmed that regioselectivity in N-alkylation of
azaheterocycles has appeared essentially governed by the ‘steric
approach control’. Indeed, the presence of a methyl group on C-2
position has induced additional steric interaction between the ben-
zyl group and the CH3 moiety. Therefore, in the case of 4-oxide 4,
N-3 regioisomer is the major one. Finally, syntheses of 1-substi-
tuted or 3-substituted imidazo[4,5-b]pyridin-7-one derivatives
are in progress in our laboratory.
both cases, this general procedure afforded to
a mixture of N-1/N-3
regioisomers. Regioisomer 5a (CH2Cl2/MeOH = 95:5, Rf = 0.08, white powder,
71%). Mp 174–176 °C. 1H NMR (300 MHz, DMSO-d6, ppm): d = 8.64 (s, 1H, H-2),
8.20 (d, 3J(H,H) = 6.3 Hz, 1H, H-5), 7.60 (d, 3J(H,H) = 8.3 Hz, 1H, H-7), 7.40–7.25
(m, 5H, Harom), 7.21 (dd, 3J(H,H) = 6.3 and 8.3 Hz, 1H, H-6), 5.54 (s, 2H, CH2).
13C NMR (75 MHz, DMSO-d6, ppm): d = 147.5, 146.0, 136.8, 134.1, 131.2, 129.7,
129.2, 128.4, 120.0, 110.7, 49.4. HRMS (CI): m/z: calcd for C13H12N3O:
226.0980, [M++H]; found: 226.0977. Regioisomer 5b: (CH2Cl2/MeOH = 95:5,
Rf = 0.22, yellow powder, 17%). Mp 101–103 °C. 1H NMR (300 MHz, DMSO-d6,
ppm): d = 8.39 (d, 3J(H,H) = 6.8 Hz, 1H, H-5), 8.37 (s, 1H, H-2), 8.32 (d,
3J(H,H) = 7.7 Hz, 1H, H-7), 7.51–7.39 (m, 5H, H-arom), 7.17 (dd, 3J(H,H) = 6.8
and 7.7 Hz, 1H, H-6), 5.72 (s, 2H, CH2). 13C NMR (75 MHz, DMSO-d6, ppm):
d = 160.2, 146.3, 146.1, 133.0, 129.9, 129.5, 129.4, 128.9, 128.6, 112.0, 80.1.
HRMS (EI): m/z: calcd for C13H11N3O: 225.0902, [M+]; found: 225.0903.
Regioisomer 6a: (CH2Cl2/MeOH = 90:10, Rf = 0.25, white powder, 30%). Mp
194–196 °C. 1H NMR (300 MHz, DMSO-d6, ppm): d = 8.12 (d, 3J(H,H) = 6.4 Hz,
1H, H-5), 7.55 (d, 3J(H,H) = 8.3 Hz, 1H, H-7), 7.38–7.27 (m, 3H, H-arom), 7.20–
6.97 (m, 3H, H-6, 2 ꢂ H-arom), 5.53 (s, 2H, CH2), 2.55 (s, 3H, CH3). 13C NMR
(75 MHz, DMSO-d6, ppm): d = 171.5, 149.9, 148.3, 134.0, 130.7, 130.3, 129.5,
127.6, 126.6, 112.2, 80.7, 19.6. HRMS (EI): m/z: calcd for C14H13N3O: 239.1059,
[M+]; found: 239.1058. Regioisomer 6b: (CH2Cl2/MeOH = 90:10, Rf = 0.62,
white powder, 70%). Mp 100–102 °C; 1H NMR (300 MHz, DMSO-d6, ppm):
d = 8.18 (d, 3J(H,H) = 6.8 Hz, 1H, H-5), 8.05 (d, 3J(H,H) = 7.7 Hz, 1H, H-7), 7.50–
7.41 (m, 5H, H-arom), 7.03 (dd, 3J(H,H) = 6.8 and 7.7 Hz, 1H, H-6), 5.67 (s, 2H,
CH2), 2.58 ppm (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6, ppm): d = 162.9,
154.7, 146.5, 133.7, 132.8, 129.8, 128.7, 127.7, 119.2, 109.7, 47.9, 14.7. HRMS
(EI): m/z: calcd for C14H13N3O: 239.1059, [M+]; found: 239.1055.
13. (a) Chang, L. C. W.; von Frijtag Drabbe Künzel, J. K.; Mulder-Krieger, T.;
Westerhout, J.; Spangenberg, T.; Brussee, J.; IJzerman, A. P. J. Med. Chem. 2007,
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C. J. Org. Chem. 1995, 60, 960–965; (c) Franchetti, P.; Cappellacci, L.; Grifantini,
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M. G.; La Colla, P. J. Med. Chem. 1994, 37, 3534–3541; (d) Cristalli, G.;
Franchetti, P.; Grifantini, M.; Vittori, S.; Bordoni, T.; Geroni, C. J. Med. Chem.
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