A novel pathway to imidazo[1,2-a]pyridines. Access through imino pyridinium salts

Article abstract of DOI:10.1515/znb-2012-0403

A new synthetic strategy for the preparation of imidazo[1,2-a]pyridines 10 is reported, which is based on the electrocyclization reaction of imino pyridinium salts 7 upon treatment with a strong base. The starting materials are easily prepared from 2-amin

Full text of DOI:10.1515/znb-2012-0403

A Novel Pathway to Imidazo[1,2-a]pyridines.
Access through Imino Pyridinium Salts
Benedikt Neue, Roland Fro¨hlich, and Ernst-Ulrich Wu¨rthwein
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t, Corrensstraße 40,
48149 Mu¨nster, Germany
Reprint requests to Prof. Dr. Ernst-Ulrich Wu¨rthwein. Fax: +49-251-8339772.
E-mail: wurthwe@uni-muenster.de
Z. Naturforsch. 2012, 67b, 295 – 304; received January 31, 2012
A new synthetic strategy for the preparation of imidazo[1,2-a]pyridines 10 is reported, which is
based on the electrocyclization reaction of imino pyridinium salts 7 upon treatment with a strong
base. The starting materials are easily prepared from 2-aminopyridine (3) by imine condensation
and subsequent alkylation at the pyridine nitrogen atom. The ring closure reaction of the zwitteri-
onic intermediate 8 to give a five-membered ring proceeds in low yield forming first the dihydro
compound 9, which under the reaction conditions is transformed into the corresponding aromatic
compounds 10 and 11 by air oxidation. The mechanism of the electrocyclization reaction is inter-
preted in detail by quantum-chemical calculations.
Key words: Imines, Pyridinium Salts, Electrocyclization, Imidazo[1,2-a]pyridines,
Quantum-chemical Calculations
Introduction
nitrogen atom(s) – underwent electrocyclic ring clo-
sure reactions. Thus, polyenyl metal compounds
with nitrogen atoms in even positions were found
to be destabilized. They show a high tendency to
transform into the more stable N-heterocyclic iso-
mers [9]. Based on this concept we have described in-
ter alia the efficient synthesis of 3-aminoindoles (2)
starting from 2,6-diazaheptatrienyl metal compounds
([1]−M+) (Scheme 1) [10].
Herein we investigate the utility of related zwitter-
ionic compounds with nitrogen atoms in position 2
and 4 for heterocyclic synthesis (Scheme 2). Here,
imino pyridinium salts 7 were chosen as starting mate-
rials, which were expected to generate the zwitterionic
intermediate 8 upon treatment with base. The positive
charge of 7 was assumed to facilitate the deprotona-
tion, leading to an overall neutral equivalent of the pre-
viously investigated highly reactive 2-azapolyenyl an-
ions. Similar to those, compounds 8 were expected to
be destabilized intermediates, thus enabling a cycliza-
Imidazo[1,2-a]pyridines are examples of bridge-
head nitrogen compounds, being of interest not only
due to their manifold pharmaceutical activities [1] but
also in view of their electronic properties, e. g. the use
as chromophores [2,3]. Several elegant methods for the
synthesis of such compounds are reported in the litera-
ture [4, 5]. For pharmaceutical purposes it is of impor-
tance to have access to diverse substitution patterns.
Often, this is a difficult task which requires several re-
action steps [6].
In the context of our previous work on the synthe-
sis of five- and seven-membered nitrogen heterocycles
by ionic electrocyclization reactions of azapolyenyl
anions or cations, we became interested in the syn-
thesis of imidazo[1,2-a]pyridines by such an electro-
cyclization route. For example Hunter et al. [7] and
our group[8] reported on aza- and diazapolyenyl metal
compounds which – depending on the position of the
Scheme 1. 2,6-Diazaheptatrienyl metal
compounds ([1]−M+) in the synthesis of
3-aminoindole derivatives 2.
c
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
Scheme 2. Proposed reaction of
2,4-diazaheptatrienyl zwitterions
7 upon deprotonation to give
imidazo[1,2-a]pyridines 10.
Table 1. Yields for compounds 5.
Compound
tion reaction for stabilization to give the cyclic pro-
ducts 9. In this article we report on imidazo[1,2-a]pyr-
idines of type 10, which were found to be the products
of this ring closure reaction upon air oxidation of the
initially formed dihydro compounds 9.
R1
Yield (%)
5a
5b
5c
5d
Ph
98
87
89
86
2-Naphth
4-Cl-Ph
4-Me-Ph
Results and Discussion
Synthesis of precursors
Table 2. Yields for compounds 7.
Compounds
R1
Ph
R2
X−
Br−
Br−
Br−
I−
Yield (%)
7a
7b
7c
7d
7e
7f
Ph
Ph
CH=CH2
CH=CH2
CH=CH2
CH=CH2
93
50
60
99
38
33
The 2-alkylideneamino-pyridinium salts 7, which
were used as starting materials for the cyclization reac-
tion, were synthesized by a two step procedure starting
from the commercially available 2-aminopyridine 3
(Scheme 3). Condensation reaction [11] of 3 with var-
ious arylaldehydes 4 (2.0 eq.) led to imino pyridines 5.
The excess of aldehyde was removed by Kugelrohr
distillation. In some cases recrystallization was neces-
sary for purification. Some compounds of type 5 have
already been described in the literature [12, 13]. We
were able to increase the yield of the imine products in
several cases by the indicated reaction conditions (Ta-
ble 1).
2-Naphth
Ph
Ph
4-Cl-Ph
4-Me-Ph
Br−
Br−
In the second step pyridinium salt (7) formation was
achieved by pyridine-N-alkylation using various ben-
zyl or allyl halides 6 in 10-fold excess. The yields
ranged from moderate to excellent (Table 2). The ben-
zyl derivatives (7a, b) were investigated with respect
to a possible five-membered ring formation, the allyl
derivatives (7c–f) might also be suitable for the corre-
sponding seven-membered products.
All 2-alkylideneamino-pyridiniumsalts 7 turned out
to be very hygroscopic, which in some cases is fatal
since their imine functionality is highly sensitive to-
wards moisture and thus prone to hydrolysis. In any
case, these compounds are very sensitive and have
Fig. 1. Molecular structure of 7a in the crystalline state
(SCHAKAL [14]).
to be stored under argon. For the imino pyridinium
salt 7a, we were able to grow crystals suitable for
X-ray diffraction (Fig. 1). The benzylideneamino sub-
stituent is in plane with the pyridine framework. A
˚
value of 1.259(4) A was found for the E-configured
imine bond. The phenyl ring of the benzyl group is
placed out of plane with a dihedral angle of 84.4(3)◦
[C(6)–N(1)–C(15)–C(16)].
Synthesis of imidazo[1,2-a]pyridines
To generate the reactive 2,4-diazaheptatrienyl zwit-
terionic compounds 8 the imino pyridinium salts 7a, b
were deprotonated using KOtBu in THF (Scheme 4).
After stirring at 50 ◦C for 4 h while monitoring by TLC
and NMR, the imidazo[1,2-a]pyridines10a, b were ob-
Scheme 3. Synthesis of 2-alkylideneamino-pyridinium
salts 7.
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
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Scheme 4. Synthesis of imidazo[1,2-a]pyrid-
ines 10a, b.
Scheme 5. Synthesis
of imidazo[1,2-a]-
pyridines 10c, e and
oxidation to 11c, e.
Table 3. Synthesis of imidazo[1,2-a]pyridines 10c – f.
Starting Material
Product
R1
Ph
Ph
4-Cl-Ph
4-Me-Ph
Yield (%)
7c
10c
10c
10d
10e
18a
7d
11a
b
7e
–
7f
13a
a
Mixture of 10 (major product) and 11 (traces); b no isola-
tion possible, fast decomposition of starting material.
tained in low yield after purification by column chro-
matography. Interestingly, compounds 10a, b are pro-
ducts of an oxidation process, most likely due to the
workup under air.
Fig. 2. Molecular structure of compound 10b in the crys-
talline state (SCHAKAL [14]).
Similarly, the allyl derivatives 7c – f were depro-
tonated using KOtBu under the same reaction con-
data was given [3]. The framework of the imidazo-
[1,2-a]pyridine is planar (Fig. 2). The naphthalen-2-
ditions as described above. Here, the major products yl substituent is twisted relative to the core structure
by a torsion angle of 23.8(3)◦ (N7–C8–C10–C11).
The torsion angle between the phenyl substituent and
the imidazopyridine substructure amounts to 55.3(3)◦
were imidazo[1,2-a]pyridines10c and 10e, which were
found in 11 – 18 % yield. Products of the formation
of species with seven-membered rings (12) were not
observed. The formation of compounds 10c and 10e (C8–C9–C20–C21). For the imidazole substructure,
˚
may be traced back to an internal redox process (hy-
drogen transfer from the newly formed heterocycle to
the allyl system) (Scheme 5). Additionally, traces of and 1.376(2) A (N7–C8), respectively.
the lengths of the C–N bonds amount to 1.392(2) A
˚
˚
(N1–C6), 1.391(2) A (N1–C9), 1.328(2) A (C6–N7),
˚
oxidized compounds 11c and 11e were detected by
1H NMR spectroscopy in admixtures with 10c and 10e
(Table 3), again possibly formed due to workup under
air. In case of 7e we were not able to isolate any prod-
ucts (e. g. 10d), because of the fast decomposition of
the starting material.
Several attempts were undertaken to optimize the
conditions of the cyclization reaction. Changing the
solvent from THF to DMF causes a better solubility of
the pyridinium salt but the yield was not significantly
increased. By use of different bases (LDA, LiTMP,
LHMDS), lower temperatures and the explicit appli-
In case of 10b it was possible to grow single crys- cation of oxidants like DDQ the yields of 10 (and 11)
tals for X-ray diffraction. Compound 10b has already could not be increased further. Purification was further
been mentioned in the literature, but no analytical attempted by recrystallization and column chromato-
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298
B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
Scheme 6. Proposed reaction steps for the electrocyclization of compound 8c to give the corresponding cis (cis-9c, upper
line) and trans (trans-9c, lower line) dihydro-imidazo[1,2-a]pyridines (energies in kcal mol−1, B3LYP/6-31+G(d)//B3LYP/6-
31+G(d)+ZPE, SCS-MP2/6-311+G(d,p)//B3LYP/6-31+G(d)+ZPE) and B97-D/def2-TZVP//B97-D/def2-TZVP+ZPE).
graphy on either silica gel or aluminum oxide. The
analysis of the crude reaction mixture suggested that a
high amount of the starting material decomposed prior
to the 1,5-electrocyclic ring closure reaction. Typi-
cal decomposition products which could be identified
were products of imine hydrolysis.
Mechanistic considerations and quantum-chemical
calculations
In order to interpret the experimental results, e. g.
the preferred formation of the five-membered ring over
the seven-membered ring from compound 7c, high-
level quantum-chemical calculations were performed.
Two levels of methods were employed: The geometries
of the species corresponding to minima and transition
states were optimized using the B3LYP/6-31+G(d)
method [15] as implemented in the program GAUS-
SIAN 09 [16]. Frequency and IRC calculations were
used to characterize the stationary points on the en-
ergy hypersurface. Single point energies were obtained
using the SCS-MP2 method of S. Grimme [17]. Fur-
thermore B97-D/def2-TZVP geometry optimizations
were performed to account for dispersion effects [18].
The methods give similar results, except for the sig-
nificantly lower relative energy of the final products as
calculated by the SCS-MP2 method. All energies re-
ported here contain zero point correction (ZPE).
Scheme 7. Proposed reaction steps for the electrocycliza-
tion of compound 8c to give the experimentally not ob-
served seven-membered ring species 12c (energies in kcal
mol−1, B3LYP/6-31+G(d)//B3LYP/6-31+G(d)+ZPE, SCS-
MP2/6-311+G(d,p)//B3LYP/6-31+G(d)+ZPE) and B97-D/
def2-TZVP//B97-D/def2-TZVP+ZPE).
In Scheme 6, the formation of the cis- and trans-
configured five-membered ring systems cis- and trans-
9c is shown. In accordance with the concept of electro-
cyclization reactions of azapolyenyl anions from previ-
ous studies, a quite exothermic reaction enthalpy was
calculated for both products with a small preference
– as expected – for the trans product. Interestingly,
several internal rotational changes are necessary to
achieve the necessary conformation for the cyclization
step. The rotation of the allyl moiety attached to the
Schemes 6 and 7 illustrate the proposed mech-
anism for the cyclization of N-allyl compound 7c.
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
299
significant charge control. These data allow the inter-
esting comparison to our earlier reported anionic cy-
clization reactions [8, 10], where certainly counterion
effects played an important role, which is of no or little
influence for the neutral zwitterionic species investi-
gated here.
Conclusion
Scheme 8. Comparison of the relative energies of prod-
ucts 9c, 10c, and 11c (energies in kcal mol−1, B3LYP/6-31
+G(d)//B3LYP/6-31+G(d)+ZPE, SCS-MP2/6-311+G(d,p)//
B3LYP/6-31+G(d)+ZPE) and B97-D/def2-TZVP//B97-D/
def2-TZVP+ZPE).
2-Alkylideneamino-pyridinium salts 7 were inves-
tigated with respect to their ability as precursors for
the synthesis of bridgehead nitrogen heterocyclic com-
pounds like imidazo[1,2-a]pyridines. In the literature
the synthesis of these compounds usually requires sev-
eral reaction steps and various expensive starting ma-
terials. Using the synthetic pathway described here the
starting materials for the cyclization reaction could
be obtained in moderate to excellent yields by use
of cheap reagents and easy purification. The last re-
action step, the 1,5-electrocyclic reaction, turned out
to be more difficult, and the products were obtained
only in low yield. However, the confirmation of the
successful synthesis of the imidazo[1,2-a]pyridines
by NMR spectroscopy and X-ray diffraction analysis
makes this pathway interesting for further investiga-
tions. Quantum-chemical calculations of the ring clos-
ing process allow valuable comparisons of these zwit-
terionic systems with the earlier studied azapolyenyl
anion cyclization reactions.
pyridinium nitrogen atom affords the highest activa-
tion barrier. Thus, the formation of the trans products is
predicted to be kinetically disfavored. Experimentally,
cis and trans products can not be distinguished due
to the immediately following oxidation step. Similarly,
the formation of the seven-membered ring system 12c
(Scheme 7) suffers from the barriers of such rotational
isomerizations, in spite of the small barrier of the fi-
nal cyclization step and its exothermicity. In summary,
these calculational results are in agreement with the ex-
perimental findings and reaction conditions.
In Scheme 8, two products derived of compound 9c
are compared with respect to their relative energies.
The formation of the aromatic species 10c by an in-
tramolecular redox process is highly favored, the de-
hydrogenated species 11c, which is observed as mi-
nor species, might be formed more likely from 9c than
from 10c, if dihydrogen is efficiently removed by oxi-
dation.
Experimental Section
General information
1H and 13C NMR spectra were recorded at 298 K
on ARX 300, AV300, WM300 and AMX400 spectrom-
eters from Bruker, on a Jeol AL-400 spectrometer and
on Inova 500 and Unity 600 spectrometers from Varian.
The transition states, leading to the cis- and trans-
configured five-membered ring systems 9c, are char-
acterized by the features of a 6π-disrotatory ring clo-
sure reaction. They are almost planar with unexpect-
edly long C···C distances of the developing bonds Chemical shifts are given in parts per million (ppm) and
˚
were referenced to the residual proton signal of the sol-
vent. Electron spray ionization (ESI) mass spectra were
measured on a quadrupole mass spectrometer Quattro LC-
Z from Micromass. Exact masses were measured with a
MAT 8200 spectrometer from the same manufacturer. Melt-
ing points were determined with a Bu¨chi melting point
B-540 apparatus and are uncorrected. Column chromatog-
raphy was carried out using Merck silica gel 60. Solvents
were purified and dried using standard procedures. THF
was kept refluxing over potassium and was freshly dis-
tilled prior use. Dichloromethane was distilled over phos-
phorous pentoxide and filtered through alumina before use.
(about 2.6 A). The terminal carbon atoms show only
small charge separation of 0.2 and 0.24 electrons
(NBO calculations) [19], the NICS(0) values [20] are
quite negative (−11.0 to −11.4 ppm), which is well in
accordance with Hu¨ckel aromaticity.
The helical transition state, however, leading to the
seven-membered ring (12c), involves 8π electrons and
indicates a conrotatory movement of the two termini.
Here, we find significant charge separation between
˚
the two reacting carbon atoms (2.49 A bond length,
0.48 electrons, exclusively located on the allyl termi-
nus) and a NICS(0) value of −8.9 ppm. Thus, we con-
Toluene was distilled over sodium and kept over molecular
clude that here the transition state is Mo¨bius-like with sieves (4 A).
˚
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
General procedure for the synthesis of methylidene-pyridine- methylbenzaldehyde was added. 5.90 g (30.06 mmol, 86 %)
2-amines 5
of 5d was obtained as a colorless solid. The analytical data
correspond to the literature [12].
˚
In a Schlenk flask containing molecular sieves 4 A, 2-
aminopyridine (3) (1.0 eq.) was dissolved in dry CH2Cl2.
Then, 2.0 equivalents of aldehyde 4 were added in pure form
or dissolved in dry CH2Cl2. The reaction mixture was stirred
for a defined period of time and was subsequently filtered
through a pad of celite which was washed with CH2Cl2
(3×50 mL). The excess of aldehyde was removed by Kugel-
rohr distillation. For some compounds additional recrystal-
lization was necessary to obtain the pure product.
General procedure for the synthesis of 2-alkylideneamino-
pyridinium salts 7
In a Schlenk flask the amino-2-pyridines 5 (1.0 eq.) were
reacted with an excess of different halogenides (10.0 eq.).
After 48 h of stirring the precipitate was filtered and washed
with diethyl ether (3 × 100 mL). Afterwards the salt was
dried in vacuo. These very hygroscopic compounds were
used for follow-up reaction without further purification.
(Phenyl-meth-(E)-ylidene)pyridin-2-yl-amine (5a)
1-Benzyl-2-[(1-phenyl-meth-(E)-ylidene)amino]pyridinium
bromide (7a)
13.85 g (0.15 mol) of 2-aminopyridine was dissolved
in 100 mL of dry CH2Cl2. Subsequently, 29.76 mL
(0.30 mmol) of benzaldehyde was added. Recrystallization
from pentane gave 25.51 g (0.14 mol, 96 %) of 5a as colorless
crystals. The analytical data correspond to the literature [12].
2.90 g (16.00 mmol) of 5a was reacted with 13.85 mL
(160 mmol) of benzyl bromide. Yield: 93 % (5.25 g,
◦
14.86 mmol), colorless, hygroscopic solid, m. p. 190 C. –
IR (neat): ν = 3042 (w), 3013 (w), 2994 (m), 1659 (w),
1614 (vs), 1597 (m), 1585 (w), 1578 (w), 1560 (vs),
1530 (w), 1512 (vs), 1501 (vs), 1450 (vs), 1395 (s), 1364 (w),
1331 (w), 1315 (m), 1298 (m), 1285 (s), 1209 (vs), 1171 (vs),
1146 (vs), 1109 (w), 1080 (w), 1074 (w), 1038 (w), 1022 (w),
1013 (w) cm−1. – 1H NMR (CDCl3, 599.55 MHz): δ =
6.10 (s, 2H, CH2), 7.26 – 7.31 (m, 3H, CHarom.), 7.45 –
7.47 (m, CHarom.), 7.55 (t, 3J = 7.8 Hz, 2H, CHarom.), 7.66 (t,
(Naphthalen-2-yl-meth-(E)-ylidene)pyridin-2-yl-amine (5b)
0.99 g (10.53 mmol) of 2-aminopyridine was dissolved in
50 mL of dry CH2Cl2. Subsequently, 3.29 g (21.07 mmol)
of naphthalene-2-carbaldehyde dissolved in 50 mL of dry
CH2Cl2 was added. 2.14 g (9.20 mmol, 87 %) of 5b was
obtained as a colorless solid, m. p. 95 – 96 ◦C. – IR (neat):
ν = 1612 (s), 1601 (m), 1477 (m), 1435 (m), 1398 (m), 1366
(m), 1348 (m), 1335 (m), 1308 (m), 1275 (w), 1269 (w),
1234 (w), 1196 (m), 1007 (m) cm−1. – 1H NMR (C6D6,
300.13 MHz): δ = 6.62 – 6.67 (m, 1H, CHarom.), 7.13 –
7.22 (m, 3H, CHarom.), 7.40 – 7.43 (m, 1H, CHarom.), 7.50 –
7.58 (m, 3H, CHarom.), 7.95 (s, 1H, CHarom.,Naph.), 8.42 –
8.49 (m, 2H, CHarom.), 9.66 (s, 1H, CH=N). – 13C NMR
(C6D6, 75.47 MHz): δ = 121.2, 122.0, 124.5, 126.6,
128.2, 128.4, 128.9, 129.2, 133.3 (CHarom.), 133.6, 134.6,
135.7 (Cipso), 137.9, 149.3 (CHarom.), 161.5 (Cipso) 162.9
(CH=N). – HRMS (ESI): m/z = 233.1070 (calcd. 233.1073
for C16H12N2H).
3
3J = 7.5 Hz, CHarom.), 7.77 (t, J = 7.5 Hz, 1H, CHarom.),
3
4
8.05 (dd, J = 7.2 Hz, J = 1.2 Hz, 1H, CHarom.), 8.11 (dd,
3J = 8.4 Hz, 4J = 1.2 Hz, 2H, CHarom.), 8.46 (td, 3J =
8.4 Hz, 4J = 1.8 Hz, 1H, CHarom.), 9.24 (s, 1H, CH=N),
9.51 (dd, 3J = 6.3 Hz, 4J = 1.2 Hz). – 13C NMR (CDCl3,
150.77 MHz): δ = 78.9 (CH2), 111.7, 115.3, 117.4, 120.1,
128.4, 128.5, 128.7, 129.0, 132.2, 133.2, 133.4 (CHarom.),
140.2, 140.7 (Cipso), 148.1 (Cipso,Py.), 166.1 (CH=N). –
HRMS (ESI): m/z
= 273.1383 (calcd. 273.1386 for
C19H17N). For crystal structure data, see Table 4.
1-Benzyl-2-[(1-naphthalen-2-yl-meth-(E)-ylidene)amino]-
pyridinium bromide (7b)
[(4-Chlorophenyl)-meth-(E)-ylidene)]pyridin-2-yl-
amine (5c)
2.90 g (12.48 mmol) of 5b was reacted with 10.80 mL
(124.80 mmol) of benzyl bromide. An orange solid was
obtained. Yield: 50 % (2.52 g, 6.25 mmol), orange, hy-
groscopic solid, m. p. 198 ◦C. – IR (neat): ν = 3235 (w),
3100 (w), 3038 (m), 3003 (m), 2980 (m), 2920 (w),
1693 (vw), 1659 (m), 1632 (w), 1609 (s), 1595 (s), 1580 (m),
1557 (vs), 1528 (m), 1514 (s), 1497 (m), 1468 (w), 1450 (s),
1437 (m), 1395 (w), 1387 (w), 1369 (w), 1358 (m), 1331 (w),
1315 (w), 1294 (m), 1273 (m), 1244 (w), 1207 (m), 1169 (s),
1138 (m), 1126 (m), 1115 (m), 1078 (w), 1065 (w),
1.94 g (20.64 mmol) of 2-aminopyridine was dissolved in
50 mL of dry CH2Cl2. Subsequently, 4.90 g (40.75 mmol)
of 4-chlorobenzaldehyde dissolved in 50 mL of dry CH2Cl2
was added. 3.95 g (18.33 mmol, 89 %) of compound 5c was
obtained as pale-yellow crystals. The analytical data corre-
spond to the literature [12].
(p-Tolyl-meth-(E)-ylidene)pyridin-2-yl-amine (5d)
3.30 g (35.00 mmol) of 2-aminopyridine was dissolved in 1028 (m) cm−1. – 1H NMR (CD2Cl2, 300.13 MHz): δ =
100 mL of dry CH2Cl2. Then, 8.30 mL (70.00 mmol) of 4- 6.15 (s, 2H, CH2), 7.29 – 7.31 (m, 3H, CHarom.), 7.49 –
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
301
7.52 (m, 2H, CHarom.), 7.57 – 7.63 (m, 1H, CHarom.), 7.66 – CH=N). – 13C NMR (CDCl3, 75.48 MHz): δ = 58.1 (CH2),
7.71 (m, 1H, CHarom.), 7.74 – 7.79 (m, 1H, CHarom.), 7.93 – 119.4 (CH=CH2), 122.9 (CH=CH2), 123.0 (Cipso), 124.4,
8.04 (m, 3H, CHarom.), 8.09 – 8.12 (m, 1H, CHarom.), 8.18 – 129.5, 129.7, 131.5 (CHarom.), 133.9 (Cipso), 135.3, 144.0,
8.21 (m, 1H, CHarom.), 8.42 – 8.48 (m, 1H, CHarom.), 8.60 (s, 147.7 (CHarom.), 171.5 (CH=N). – HRMS (ESI): m/z =
1H, CHarom.,Naph.), 9.29 (s, 1H, CH=N), 9.58 – 9.61 (m, 1H, 223.1234 (calcd. 223.1230 for C15H15N2).
CHPy.). – 13C NMR (CD2Cl2, 75.48 MHz): δ = 59.0 (CH2),
119.4, 124.1, 124.5, 127.9, 128.6, 128.8, 129.5, 129.7, 1-Allyl-2-[(1-(4-chlorophenyl)-meth-(E)-ylidene)amino]pyr-
129.7, 129.9, 130.3, 130.3 (CHarom.), 132.2, 133.2, 134.1, idinium bromide (7e)
137.0 (Cipso), 137.5, 145.1, 147.6 (CHarom.), 158.2 (Cipso),
2.20 g (10.00 mmol) of compound 5c was dissolved in
171.5 (CH=N). – HRMS (ESI): m/z = 323.1542 (calcd.
8.70 mL (100.00 mmol) of allyl bromide. A light-yellow
323.1543 for C23H19N2).
solid was obtained, which was contaminated with products
of hydrolysis. Yield: 38 % (1.◦29 g, 3.81 mmol), light-yellow,
3065 (m), 3055 (w), 3042 (m), 3034 (m), 3015 (m), 2980 (s),
1-Allyl-2-[(1-phenyl-meth-(E)-ylidene)amino]pyridinium
hygroscopic solid, m. p. 212 C. – IR (neat): ν = 3078 (m),
bromide (7c)
2947 (w), 2907 (w), 2880 (w), 1626 (vs), 1618 (vs),
1589 (vs), 1560 (vs), 1526 (m), 1503 (vs), 1485 (vs),
1447 (vs), 1433 (vs), 1414 (m), 1391 (s), 1381 (s), 1354 (m),
1337 (w), 1327 (w), 1302 (vs), 1211 (vs), 1161 (vs),
1148 (vs), 1103 (m), 1088 (vs), 1061 (m), 1011 (vs) cm−1. –
1H NMR (CDCl3, 300.13 MHz): δ = 5.41 – 5.44 (m, 2H,
CH2), 5.48 – 5.50 (m, 2H, CH=CH2), 6.01 – 6.14 (m, 1H,
CH=CH2), 7.52 (d, 3J = 9.0 Hz, 2H, CHarom.), 7.84 (t, 3J =
9.0 Hz, 1H, CHarom.), 8.10 (d, 3J = 9.0 Hz, 2H, CHarom.),
8.16 (d, 3J =9.0 Hz, 1H, CHarom.), 8.51 (t, 3J = 9.0 Hz,
1H, CHarom.), 9.25 (d, 3J = 6.0 Hz, 1H, CHarom.,Py.), 9.47 (s,
3.64 g (20.00 mmol) of pyridine imine 5a was reacted
with 17.30 mL (200.00 mmol) of allyl bromide. Yield: 60 %
(3.62 g, 11.94 mmol), light-yellow, hygroscopic solid, m. p.
207 ◦C. – IR (neat): ν = 3071 (w), 3057 (w), 3034 (w),
2988 (w), 1693 (vw), 1661 (w), 1614 (s), 1599 (m), 1576 (w),
1560 (s), 1524 (m), 1508 (s), 1449 (s), 1410 (w), 1393 (m),
1356 (m), 1317 (m), 1300 (m), 1211 (s), 1177 (m), 1163 (s),
1152 (m) cm−1. – 1H NMR (CDCl3, 300.13 MHz): δ =
3
3
5.17 (d, J = 5.5 Hz, 1H, CH=CH2), 5.38 (d, J = 5.5 Hz,
1H, CH=CH2), 5.51 (d, 3J = 6.0 Hz, 2H, CH2), 5.94 –
6.12 (m, 1H, CH=CH2), 7.52 (t, 3J = 7.2, 2H, CHarom.),
7.58 – 7.70 (m, 1H, CHarom.), 7.83 – 7.90 (m, 1H, CHarom.), 1H, CH=N). – 13C NMR: not possible due to rapid decom-
8.09 – 8.13 (m, 3H, CHarom.), 8.55 (t, 3J = 8.0 Hz, 1H, position. – HRMS (ESI): m/z = 275.0835 (calcd. 275.0840
CHarom.), 9.33 (s, 1H, CH=N), 9.40 (dd, J = 6.3 Hz, J = for C15H14ClN2). – C15H14BrClN2 (337.64): calcd. C 53.36,
1.2 Hz, 1H, CHPy). – 13C NMR (CDCl3, 75.47 MHz): H 4.18, N 8.30; found C 52.86, H 3.99, N 8.46.
δ = 58.0 (CH2), 119.1 (CH=CH2), 122.6 (CH=CH2), 124.4,
3
4
129.4, 130.0, 131.4, 134.0, 135.2, 144.5, 147.7 (CHarom.),
154.5, 157.6 (Cipso), 171.6 (CH=N). – HRMS (ESI): m/z =
223.1232 (calcd. 223.1230 for C15H15N2).
1-Allyl-2-[(1-p-tolylmeth-(E)-ylidene)amino]pyridinium
bromide (7f)
1.29 g (6.57 mmol) of compound 5d was reacted with
5.69 mL (65.70 mmol) of allyl bromide. Yield: 33 % (0.69 g,
2.16 mmol), light-yellow, hygroscopic solid, m. p. 217 ◦C. –
IR (neat): ν = 3082 (m), 3067 (m), 3057 (m), 3042 (m),
1-Allyl-2-[(1-phenyl-meth-(E)-ylidene)amino]pyridinium
iodide (7d)
2.02 g (11.09 mmol) of compound 5a was reacted with 3030 (m), 3013 (m), 2982 (s), 2945 (m), 2909 (w), 1663 (m),
9.60 mL (110.90 mmol) of allyl iodide. Yield: 99 % (3.86 g, 1641 (w), 1622 (vs), 1605 (vs), 1582 (m), 1560 (vs),
◦
11.02 mmol), yellow, hygroscopic solid, m. p. 141 C. – IR 1526 (s), 1516 (vs), 1501 (vs), 1449 (vs), 1433 (vs), 1393 (s),
(neat): ν = 3296 (m), 3256 (w), 3117 (s), 3078 (m), 3057 (m), 1354 (m), 1339 (w), 1302 (vs), 1217 (vs), 1209 (vs),
3032 (m), 3011 (m), 2988 (s), 2955 (w), 2905 (w), 1699 (m), 1173 (vs), 1161 (vs), 1150 (vs), 1111 (m), 1105 (m),
1
1655 (s), 1612 (vs), 1597 (vs), 1584 (vs), 1558 (vs), 1063 (m), 1036 (m), 1016 (m), 1009 (s cm−1). – H NMR
1526 (vs), 1518 vs), 1504 (vs), 1447 (vs), 1433 (vs), (CDCl3, 300.13 MHz): δ = 2.45 (s, 3H, CH3), 5.19 – 5.46 (m,
1408 (s), 1391 (vs), 1344 (m), 1337 (m), 1323 (w), 1312 (vs), 2H, CH2), 5.53 (d, 3J = 6.0 Hz, 1H, CH=CH2), 5.98 –
1296 (vs), 1265 (m), 1206 (vs), 1180 (s), 1165 (vs), 6.09 (m, 1H, CH=CH2), 7.34 (d, 3J = 9.0 Hz,2H, CHarom.),
1150 (vs), 1130 (s), 1096 (m), 1072 (m), 1061 (m), 1024 (m), 7.78 – 7.83 (m, 1H, CHarom.), 8.00 (d, 3J = 9.0 Hz,2H,
3
1013 (m) cm−1. – 1H NMR (CDCl3, 300.13 MHz): δ = CHarom.), 8.07 (dd, J = 9.0 Hz, 4J = 1.0 Hz, 1H, CHarom.),
5.43 – 5.45 (m, 2H, CH2), 5.47 – 5.48 (m, 1H, CH=CH2), 8.49 – 8.55 (m, 1H, CHarom.), 9.23 (s, 1H, CH=N), 9.45 (dd,
6.01 – 6.14 (m, 1H, CH=CH2), 7.52 – 7.57 (m, 2H, CHarom.), 3J = 6.0 Hz, 4J = 1.3 Hz, 1H, CHarom.). – 13C NMR (CDCl3,
7.63 – 7.67 (m, 1H, CHarom.), 7.83 – 7.88 (m, 1H, CHarom.), 75.48 MHz): δ = 22.3 (CH3), 57.9 (CH2), 118.9 (CH=CH2),
8.07 – 8.14 (m, 3H, CHarom.), 8.52 – 8.58 (m, 1H, CHarom.), 122.6 (CH=CH2), 124.0 (Cipso), 130.1, 130.3, 131.6,
9.18 (dd, 3J = 6.3 Hz, 4J = 1.2 Hz, 1H, CHarom.), 9.33 (s, 1H, 131.6 (CHarom.), 144.6 (Cipso), 147.0, 147.4 (CHarom.),
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302
B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
157.8 (Cipso), 171.1 (CH=N). – HRMS (ESI): m/z = 1148 (s), 1136 (s), 1124 (m), 1099 (s), 1070 (s), 1028 (s),
237.1386 (calcd. 237.1386 for C16H17N2).
1018 (s), 1013 (s) cm−1. – 1H NMR (CD2Cl2, 300.13 MHz):
δ = 6.77 (td, 3J = 6.9 Hz, 1H, CH), 7.21 – 7.27 (m, 1H,
CH), 7.40 – 7.46 (m, 2H, CH/CHarom.), 7.49 – 7.60 (m, 5H,
CH/CHarom.), 7.66 (dt, 3J = 9.0 Hz, 4J = 1.2 Hz, 1H,
CHarom.), 7.73 – 7.82 (m, 4H, CHarom.), 7.92 – 8.06 (m, 1H,
CHarom.), 8.22 (s, 1H, CHarom.,Naph.). – 13C NMR (CD2Cl2,
100.62 MHz): δ = 112.7, 117.9, 124.0, 125.3, 126.4, 126.5,
126.6, 127.4, 128.0, 128.1, 128.7, 129.5, 130.1, 130.6,
131.4, 133.3, 134.0. – HRMS (ESI): m/z = 321.1396 (calcd.
321.1386 for C23H17N2). For crystal data, see Table 4.
General procedure for the synthesis of imidazo[1,2-a]pyrid-
ines 10/11
In a Schlenk flask a solution of KOtBu (2.0 eq., 1 M so-
lution or solid) was dissolved in dry THF. The solution was
heated to 50 ◦C. Then, 1.0 eq. of pyridinium salt 7 dissolved
in dry THF was added slowly to the stirred mixture. A deep
brown color appeared. After a defined period of time at 50 ◦C,
10 mL of distilled H2O were added. Immediately the color of
the solution faded. The yellow mixture was extracted with di-
ethyl ether (3×50 mL), and the organic layer was dried over
MgSO4. After removal of the solvent, the crude product was
purified by column chromatography.
3-Ethyl-2-phenylimidazo[1,2-a]pyridine (10c) and 2-phenyl-
3-vinylimidazo[1,2-a]pyridine (11c)
A solution of 2.00 mL (2.00 mmol) of KOtBu (1.0 M
in THF) in 50 mL of dry THF was prepared. Then, 0.30 g
(1.00 mmol) of compound 7c dissolved in 70 mL of dry THF
was added slowly. The color of the reaction mixture immedi-
ately changed to brown. The solution was stirred for 15 min
at 50 ◦C. By use of column chromatography it was not pos-
sible to separate compound 10c from the minor product 11c
(Rf 10c: 0.40, Rf 11c: 0.48 SiO2, hexane-ethyl acetate 1 : 1).
Yield: 18 % (0.04 g, 0.18 mmol), mixture of compound 10c
and 11c, yellow-brown oil. – IR (neat): v = 3082 (vw),
3053 (vw), 3032 (vw), 2968 (w), 2932 (vw), 2874 (vw),
2857 (vw), 1634 (w), 1605 (w), 1578 (vw), 1555 (vw),
1528 (vw), 1501 (s), 1489 (m), 1460 (m), 1445 (m), 1393 (s),
1377 (w), 1358 (vs), 1306 (w), 1294 (w), 1267 (vs), 1227 (s),
1177 (w), 1150 (w), 1130 (w), 1109 (vw), 1092 (vw),
1072 (m), 1045 (w), 1024 (w), 1007 (vw) cm−1. – 1H NMR
(CDCl3, 399.95 MHz): δ = 1.37 (t, 3J = 7.2 Hz, 3H, CH3),
3.12 (q, 3J = 7.6 Hz, 2H, CH2), 6.86 (t, 3J = 6.8 Hz,
1H, CH), 7.18 – 7.22 (m, 1H, CH/CHarom.), 7.35 – 7.38 (m,
1H, CH/CHarom.), 7.46 – 7.49 (m, 2H, CH/CHarom.), 7.68 –
7.70 (m, 1H, CHarom.), 7.78 – 7.80 (m, 2H, CHarom.), 7.97 –
7.99 (d, 3J = 6.8 Hz, 1H, CHarom.). Additional peaks for 11c:
5.57 (d, 3J = 16.0 Hz, 1H, CH=CH2), 5.73 (d, 3J = 16.0 Hz,
1H, CH=CH2), 6.86 – 6.96 (m, 1H, CH=CH2). – 13C NMR
(CDCl3, 100.40 MHz): δ = 12.3 (CH3), 17.1 (CH2), 112.3,
117.9 (CH), 122.0 (Cquat.), 123.1, 123.9 (CH), 127.7, 128.4,
128.8 (CHarom.), 135.0, 142.0, 144.5 (Cipso). – HRMS (ESI):
m/z = 223.1226 (calcd. 223.1230 for C15H15N2 (10c)); m/z =
221.1079 (calcd. 221.1073 for C15H13N2 (11c)).
4,5-Diphenylimidazo[1,2-a]pyridine (10a)
0.57 g (5.10 mmol) of KOtBu was dissolved in 20 mL
of dry THF. Then, 0.90 g (2.55 mmol) of 7a in 20 mL of
dry THF was added slowly. The mixture was stirred for 4 h
at 50 ◦C. The crude product was purified by column
chromatography (Rf = 0.42, SiO2, cyclohexane-ethyl ac-
etate 1 : 1). Yield: 11 % (0.07 g, 0.27 mmol), brown solid,
m. p. 152 ◦C. – IR (neat): ν = 3063 (w), 2955 (w), 2924 (m),
2855 (w), 1601 (w), 1543 (w), 1504 (m), 1472 (w), 1445 (m),
1437 (m), 1385 (s), 1360 (m), 1341 (m), 1312 (w), 1271 (m),
1236 (s), 1213 (w), 1179 (w), 1148 (w), 1111 (w), 1072 (m),
1028 (w) cm−1. – 1H NMR (CDCl3, 300.13 MHz): δ =
6.73 (td, 3J = 6.9 Hz, 4J = 1.2 Hz, 1H, CH), 7.17 –
7.31 (m, 4H, CH/CHarom.), 7.44 – 7.56 (m, 5H, CHarom.),
7.65 – 7.70 (m, 3H, CHarom.), 7.96 (d, 3J = 6.9 Hz, 1H, CH-
N). – 13C NMR (CDCl3, 75.48 MHz): δ = 112.4, 117.6 (CH),
121.2 (Cquat.), 123.4, 124.8 (CH), 127.6, 128.2, 128.4, 129.0,
129.7 (CHarom.), 130.0 (Cipso), 130.8 (CHarom.), 134.3,
142.5, 144.9 (Cipso). – HRMS (ESI): m/z = 271.1228 (calcd.
271.1230 for C19H15N2).
2-Naphthalen-2-yl-3-phenylimidazo[1,2-a]pyridine (10b)
0.48 g (1.20 mmol) of pyridinium salt 7b dissolved in
70 mL dry THF was added to a stirred solution of 0.27 g
(2.39 mmol) KOtBu in 50 mL of dry THF. The mixture
◦
was heated for 4 h at 50 C. The product was purified by
column chromatography (Rf = 0.16 SiO2, pentane-diethyl
ether 2 : 1) and subsequent recrystallization from CH2Cl2.
Yield: 12 % (0.04 g, 0.14 mmol), light-yellow crystals, m. p.
134 ◦C. – IR(neat): ν = 3076 (w), 3051 (m), 3038 (m),
3-Ethyl-2-p-tolyl-imidazo[1,2-a]pyridine (10e) and 2-p-tol-
yl-3-vinylimidazo[1,2-a]pyridine (11e)
2.00 mL (2.00 mmol) of KOtBu (1.0 M solution in THF)
2988 (w), 2959 (w), 2947 (w), 2922 (m), 2868 (w), 2851 (w), in 50 mL of dry THF was prepared. While stirring, 0.32 g
1692 (m), 1634 (s), 1601 (s), 1576 (m), 1547 (m), 1526 (m), (1.00 mmol) of pyridinium salt 7f was added slowly. By use
1504 (vs), 1485 (s), 1466 (m), 1450 (s), 1435 (s), 1396 (m), of column chromatography it was not possible to separate
1379 (m), 1362 (vs), 1344 (vs), 1308 (m), 1273 (vs), compound 10e from the minor product 11e (Rf 10e: 0.40,
1248 (s), 1238 (vs), 1217 (s), 1196 (s), 1177 (m), 1161 (m), Rf 11e: 0.48 SiO2, hexane-ethyl acetate 1 : 1). Yield: 13 %
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B. Neue et al. · A Novel Pathway to Imidazo[1,2-a]pyridines
Table 4. Crystal structure data for 7a and 10b.
303
1H, CH), 6.60 – 6.65 (m, 1H, CH), 6.92 – 7.19 (m, 2H,
CH/CHarom.), 7.60 – 7.66 (m, 2H, CH/CHarom.), 8.05 (d, 2H,
CHarom.). Additional peaks for 11e: 5.03 (d, J = 18.0 Hz,
7a
10b
C23H16N2
320.38
3
Formula
Mr
C19H17BrN2
353.26
1H, CH=CH2), 5.15 (d, 3J = 12.0 Hz, 1H, CH=CH2), 6.36 –
6.40 (m, 1H, CH=CH2). – 13C NMR (C6D6, 75.48 MHz):
δ = 12.0 (CH3), 17.2 (CH2), 21.3 (Ph-4-CH3), 111.5,
118.0 (CH), 121.4 (Cquat.), 122.7, 123.0 (CH), 127.2, 128.7,
129.6 (CHarom.), 133.3, 137.1, 144.6 (Cipso). – HRMS (ESI):
m/z = 237.1381 (calcd. 237.1386 for C16H17N2 (10e)); m/z =
235.1223 (calcd. 235.1230 for C16H15N2 (11e)).
Crystal size, mm3
Crystal system
Space group
0.20×0.10×0.05 0.47×0.27×0.10
monoclinic
P21/c
monoclinic
P21/c
˚
a, A
7.6283(4)
19.9157(9)
10.7802(5)
91.272(2)
1637.36(14)
4
1.43
3.4 (CuKα )
720
6.3013(1)
17.9472(4)
14.4155(4)
95.141(1)
1623.70(6)
4
1.31
0.1 (MoKα )
672
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
Crystal structure analyses
Dcalcd, g cm−3
µ, mm−1
F(000), e
hkl range
Data sets were collected with Nonius KappaCCD diffrac-
tometers, in case of Mo radiation equipped with a ro-
tating anode generator. Programs used: data collection
COLLECT [21], data reduction DENZO-SMN [22], absorp-
tion correction DENZO [23], structure solution SHELXS-
97 [24]), structure refinement SHELXS-97 [25], graphics
SCHAKAL [14]. Table 4 summarizes the crystal data and
numbers pertinent to data collection and structure refeine-
ment.
CCDC 863101 (7a) and CCDC 863102 (10b) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data
request/cif.
−8→9, 23, 12 8, −23→21, 18
−1
˚
((sinθ)/λ)max, A
0.60
0.66
Refl. measured / unique
Rint
9830 / 2876
0.043
199
9142 / 3756
0.039
226
0.076 / 0.141
1.035
Param. refined
R(F) / wR(F2)a,b (all refl.) 0.039 / 0.095
GoF (F2)c
∆ρfin (max / min), e A
1.037
−3
˚
0.50 / −0.32
0.21 / −0.17
a
b
2
R = ΣꢀFo| − |Fcꢀ/Σ|Fo|; wR = [Σw(Fo − Fc2)2/Σw(Fo2)2]1/2
,
w = [σ2(Fo2)+(AP)2 +BP]−1, where P = (Max(Fo2,0)+2Fc2)/3;
GoF = [Σw(Fo −Fc2)2/(nobs −nparam)]1/2
.
c
2
(29 mg, 0.12 mmol), brown oil. – IR (neat): ν = 2965 (m),
2926 (w), 2876 (w), 2857 (w), 1724 (w), 1676 (w), 1634 (w),
1607 (w), 1576 (w), 1528 (w), 1503 (s), 1452 (m), 1433 (m),
1412 (w), 1391 (m), 1379 (m), 1360 (s), 1304 (m), 1260 (vs),
1227 (m), 1175 (m), 1148 (m), 1090 (vs), 1063 (vs),
1016 (vs) cm−1. – 1H NMR (C6D6, 399.65 MHz): δ =
0.88 (t, 3J = 7.1 Hz, 3H, CH2-CH3), 2.18 (s, 3H, CH3),
Acknowledgement
This work was supported by the IRTG 1143 Mu¨nster-
Nagoya [Deutsche Forschungsgemeinschaft (DFG, Bad
Godesberg)] and the Fonds der Chemischen Industrie
(Frankfurt).
3
3
2.62 (q, J = 7.1 Hz, 2H, CH2-CH3), 6.16 (t, J = 6.0 Hz,
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