Regiospecific synthesis of 3-substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine

Article abstract of DOI:10.1021/jo026797p

3-Substituted imidazo[1,2-a]pyridines, imidazo- [1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine were obtained regiospecifically in yields of 35-92% in one pot by reaction of 2-aminopyridines or 2-(or 4-)aminopyrimidines, respectively, with 1,2-bis(benzotriazolyl)-1,2-(dialkylamino)-ethanes.

Full text of DOI:10.1021/jo026797p

SCHEME 1
Regiosp ecific Syn th esis of 3-Su bstitu ted
Im id a zo[1,2-a ]p yr id in es,
Im id a zo[1,2-a ]p yr im id in es, a n d
Im id a zo[1,2-c]p yr im id in e
Alan R. Katritzky,* Yong-J iang Xu, and Hongbin Tu
Center for Heterocyclic Chemistry, Department of Chemistry,
University of Florida, Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received December 3, 2002
Abstr a ct: 3-Substituted imidazo[1,2-a]pyridines, imidazo-
[1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine were ob-
tained regiospecifically in yields of 35-92% in one pot by
reaction of 2-aminopyridines or 2-(or 4-)aminopyrimidines,
respectively, with 1,2-bis(benzotriazolyl)-1,2-(dialkylamino)-
ethanes.
agents,1a antibacterials,9 antifungal agents,10 and calcium
channel blockers.11
Syntheses of the imidazo[1,2-a]pyridine ring system
include: (i) coupling reactions of 2-aminopyridines with
R-halocarbonyl compounds;1a,b,12a-e (ii) reactions of 2-
chloropyridine with 1,2,3-triazoles and subsequent elimi-
nation of nitrogens;13 (iii) cyclizations of 1-(2-alkynyl)-2-
aminomethylimidazoles, which are obtained from sub-
stituted imidazoles via six steps;14 (iv) reactions of
(arylacetyl)imidazoles with acetylenedicarboxylic esters;15
(v) condensation of 2-aminopyridine with glyoxal trimer
dihydrate in aqueous NaHSO3;16 and (vi) one-pot con-
densations of aldehydes, isonitriles, and 2-amino-
pyridines (Scheme 1).17 Moreover, methods i and vi are
also used for the preparation of imidazo[1,2-a]pyrim-
idines.17-19
Imidazo[1,2-a]pyridines show anticytomegalo-zoster
and antivaricella-zoster virus,1a-e antibacterial,2 anti-
inflammatory, analgesic, antipyretic,3a-c hypnoselective
and anxioselective activities.4 They are â-amyloid forma-
tion inhibitors5 and constitute a novel class of orally
active nonpeptide bradykinin B2 receptor antagonists.6
Several imidazo[1,2-a]pyridines already on the market
include zolimidine (an antiulcer drug),3c zolpidem (a
hypnotic drug), and alpidem (a nonsedative anxiolytic).7
Imidazo[1,2-a]pyrimidine structural moieties are also
important as benzodiazepine receptor agonists,8 antiviral
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[1,2-a]pyridines and imidazo[1,2-a]pyrimidines, since a
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10.1021/jo026797p CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003
J . Org. Chem. 2003, 68, 4935-4937
4935

SCHEME 2
tion conditions are avoided. However, the synthesis of
3-monosubstituted imidazo[1,2-a]pyridines and imidazo-
[1,2-a]pyrimidines would require a correspondingly sub-
stituted R-haloacetaldehyde. Significantly, no syntheses
of 3-amino monosubstituted imidazo[1,2-a]pyridines or
imidazo[1,2-a]pyrimidines using method i were found in
the literature. In fact, only two 3-amino monosubstituted
imidazo[1,2-a]pyridines have been made by ring synthe-
sis: 3-aminoimidazo[1,2-a]pyridine (from condensation
of potassium cyanide, formaldehyde, and 2-aminopyri-
dine20) and 3-(N-2-pyridinylamino)imidazo[1,2-a]pyridine
(from method v16). Some 3-amino-imidazo[1,2-a]pyri-
dines21,22 were prepared using 2-(2-pyridinylamino)aceto-
nitrile as a key starting material, which was synthesized
via reaction of sodium cyanide, formaldehyde, and 2-
aminopyridine. Many others have been obtained by
further reactions of 3-amino-imidazo[1,2-a]pyridines with
electrophiles.23-25 We now present a novel regiospecific
benzotriazole-mediated one-pot approach to 3-amino
monosubstituted imidazo[1,2-a]pyridines 3a -g, imidazo-
[1,2-a]pyrimidines 3h ,i, and imidazo[1,2-c]pyrimidine 3j
in moderate to excellent yields.
1,2-Bis(benzotriazolyl)-1,2-(dialkylamino)ethanes 2, pre-
viously synthesized in our group via double condensation
of glyoxal, benzotriazole, and amines,26 are readily avail-
able 1,2-bis-electrophiles. In the present paper, [3 + 2]
cyclizations of 2-aminopyridines or 2-(or 4-)aminopyri-
midines (as 1,3-bisnucleophiles) with compounds 2 formed
the imidazole ring to give the titled compounds in one-
pot reactions (Scheme 2).
Syn t h esis. The cyclizations proceeded in dichloro-
methane or in 1,2-dichloroethane. Reactions of 2-amino-
pyridines 1 with compounds 2 were carried out in
refluxing 1,2-dichloroethane to shorten the reaction time.
Reactions of 2-(or 4-)aminopyrimidines with 2 in reflux-
ing dichloromethane (or 1,2-dichloroethane) were done
in the presence of zinc bromide as Lewis acid to promote
the leaving ability of the benzotriazole group. Products
3 were obtained in moderate to excellent yields after
refluxing for 1.5-4.5 h (Scheme 2). The reaction works
smoothly when compounds 1 with various functional
groups (such as amino, benzyoxyl and methyl) are used
as starting materials. NOE experiments have shown that
all products are 3-substituted derivatives. No 2-substi-
tuted or 2,3-disubstituted products were observed. This
fact is well explained via the proposed mechanism (next
determined by APT spectra for 3, further supported the
successful outcome of the [3 + 2] cyclization.
Although reactions were successful using aliphatic
amines 2 as 1,2-biselectrophile synthons, the expected
imidazo[1,2-a]pyridines of type 3 were not obtained using
reagents 2 derived from aromatic amines in these reac-
tions: reactions attempted with phenyl and with benzyl
derivatives (2, Ph2N, PhCH2N) did not give the desired
products.
Regioselectivity an d th e P r oposed Reaction Mech -
a n ism . The position of substituents in imidazo[1,2-a]-
pyridines 3a -g, imidazo[1,2-a]pyrimidines 3h ,i, and
imidazo[1,2-c]pyrimidine 3j was determined by NOE
experiments. In all products, when the proton in the
imidazole ring (a singlet around 7.19-7.48 ppm) was
irradiated, no NOE effect for the proton(s) of R4 (H, NH2,
CH3) in the pyridine and pyrimidine rings was observed
and vice versa. Positive NOE effects were, however,
obtained between protons in R4 and certain protons in
morpholine and piperidine moieties. The detailed results
listed in Table 1 demonstrate that the substituents in
the imidazole ring are at the 3-position in each of these
imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and
imidazo[1,2-c]pyrimidine 3a -j. The NOE effects for
compounds 3d -j are given in Supporting Information as
Table 2.
1
paragraph). Structures 3 were characterized by H and
13C NMR and microanalysis. However, compound 3j was
1
unstable under normal conditions. In the H NMR, one
distinct singlet, usually near 7.19-7.48 ppm, was as-
cribed to the proton at the 2-position in the imidazole
ring. A new tertiary carbon in the aromatic region, as
(20) Astik, R. R.; Thaker, K. A. J . Ind. Chem. Soc. 1981, LVIII, 1013.
(21) Knott, E. B. J . Chem. Soc. 1956, 1644.
(22) Bristow, N. W.; Charlton, P. T.; Peak, D. A.; Short, W. F. J .
Chem. Soc. 1954, 616.
(23) Saint-Ruf, G.; Loukakou, B.; N’Zouzi, C. J . Heterocycl. Chem.
1981, 18, 1565.
(24) Bochis, R. J .; Olen, L. E.; Fisher, M. H.; Reamer, R. A.; Wilks,
G.; Taylor, J . E.; Olson, G. J . Med. Chem. 1981, 24, 1483.
(25) Chezal, J . M.; Moreau, E.; Delmas, G.; Gueiffier, A.; Blache,
Y.; Grassy, G.; Lartigue, C.; Chavignon, O.; Teulade, J . C. J . Org. Chem.
2001, 66, 6576.
A possible mechanism is that the lone electron pairs
on the nitrogen atoms in the pyridine ring and the amino
group could attack both BtCHN carbon atoms in 2 to form
intermediate A with the elimination of both benzotriazole
(26) Katritzky, A. R.; Fan, W.-Q.; Fu, C. J . Org. Chem. 1990, 55,
3209.
4936 J . Org. Chem., Vol. 68, No. 12, 2003

TABLE 1. NOE Effects in Com p ou n d s 3a -c
compd
irradiation peaks δ/ppm
observed NOE effects δ/ppm
3a
3.05 (N(CH2)2, morpholine ring)
3.90 (O(CH2)2, morpholine ring)
7.31 (H-2, imidazole ring)
8.00 (R4, pyridine ring)
8.00 (R4, pyridine ring)
3.05 (N(CH2)2, morpholine ring)
6.81 (R5, pyridine ring)
3b
3c
3.05 (N(CH2)2, morpholine ring)
3.89 (O(CH2)2, morpholine ring)
7.26 (H-2, imidazole ring)
7.63 (R4, pyridine ring)
7.63 (R4, pyridine ring)
6.64 (R5, pyridine ring)
3.05 (N(CH2)2, morpholine ring)
7.35 (H-2, imidazole ring)
3.74 (O(CH2)2, morpholine ring)
3.90 (O(CH2)2, morpholine ring)
6.30 (R5, pyridine ring)
2.99-3.11 (N(CH2)2, morpholine ring)
2.86 (R4, pyridine ring)
3.74 (O(CH2)2, morpholine ring)
3.90 (O(CH2)2, morpholine ring)
moieties, which are good leaving groups.27 Although in
theory both the amino moieties at 2- and 3-positions could
be eliminated, the elimination from the 2-position is more
favorable than that from the 3-position because of the
greater acidity of the proton adjacent to the positively
charged nitrogen. Intermediate B is formed by elimina-
tion of an amine moiety from the favorable 2-position to
give 3-substituted imidazo[1,2-a]pyridines, imidazo[1,2-
a]pyrimidines, and imidazo[1,2-c]pyrimidine 3 (Scheme
2).
In summary, we have developed an efficient and simple
approach to 3-substituted imidazo[1,2-a]pyridines, imid-
azo[1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine with
excellent regioselectivity. The reaction conditions are
mild, and reactions were completed in 1.5-4.5 h. A
mechanism was also proposed and discussed on the basis
of experimental results.
to room temperature. Potassium hydroxide powder (0.22 g, 3.3
mmol, 86%) was added to the solution and stirred for 0.5 h. Then,
the solid was filtered out and washed with chloroform. After
removal of the solvent, the residue was separated by column
chromatography on silica gel using a mixture of EtOAC/
methanol (from 100/0.5 to 100/10) as an eluent.
3-Mor p h olin oim id a zo[1,2-a ]p yr id in e (3a ): brown prisms
(acetone), mp 78-80 °C; 1H NMR δ 8.00 (d, J ) 6.9 Hz, 1H),
7.55 (d, J ) 9.1 Hz, 1H), 7.31 (s, 1H), 7.16-7.11 (m, 1H), 6.81
(t, J ) 6.3 Hz, 1H), 3.90 (t, J ) 4.7 Hz, 4H), 3.05 (t, J ) 4.7 Hz,
4H); 13C NMR δ 142.1, 134.9, 123.5, 122.1, 121.6, 118.0, 111.7,
67.1, 52.2. Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N,
20.67. Found: C, 64.98; H, 6.69; N, 20.78.
Gen er a l P r oced u r e for th e Syn th esis of 3-Su bstitu ted
Im id a zo[1,2-a ]p yr im id in es a n d Im id a zo[1,2-c]p yr im id in e
3h -j. The corresponding compounds 2 (1 mmol), substituted
2-(or 4-)aminopyrimidines 1(1 mmol), and zinc bromide (1 mmol)
were refluxed in dry dichloromethane for about 4.5 h until the
TLC showed the disappearance of compounds 2. The solid was
then filtered out and washed with chloroform. The filtrate was
washed with 2 N NaOH solution and dried with sodium sulfate.
After removal of the solvent, the residue was separated by
column chromatography on silica gel using a mixture of EtOAC/
methanol (from 100/0.5 to 100/15) as an eluent.
3-Mor ph olin oim idazo[1,2-a]pyr im idin e (3h ): yellow prisms
(acetone), mp 157-158 °C; 1H NMR δ 8.53 (br s,1H), 8.31 (dd, J
) 6.7, 1.9 Hz, 1H), 7.48 (s, 1H), 6.87 (dd, J ) 6.7, 4.1 Hz, 1H),
3.91 (t, J ) 4.5 Hz, 4H), 3.07 (t, J ) 4.7 Hz, 4H); 13C NMR δ
149.0, 145.0, 133.2, 129.8, 123.4, 108.1, 67.0, 52.1. Anal. Calcd
for C10H12N4O: C, 58.81; H, 5.92; N, 27.43. Found: C, 59.06; H,
6.32; N, 27.29.
Exp er im en ta l Section
1,2-Dichloroethane, 2-aminopyridines, and 2-(or 4-)amino-
pyrimidines were used as received without further purification.
Dichloromethane was distilled before use. Column chromatog-
raphy was performed on silica gel unless otherwise noted. All
of the reactions were carried out under N2.
Gen er a l P r oced u r e for th e Syn th esis of 3-Su bstitu ted
Im id a zo[1,2-a ]p yr id in es 3a -g. The corresponding compounds
2 (1 mmol) and substituted 2-aminopyridines 1 (1 mmol) were
refluxed in 1,2-dichloroethane (10 mL) for 1.5-2.5 h. All reac-
tions were monitored by TLC, which showed the disappearances
of the starting materials. The reaction mixture was then cooled
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 3b-g and 3i,j and NOE effects for
compounds 3d -j. This material is available free of charge via
the Internet at http://pubs.acs.org.
(27) (a) Katritzky, A. R.; Xu, Y.-J .; He, H.-Y.; Mehta, S. J . Org. Chem.
2001, 66, 5590. (b) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O.
V. Chem. Rev. 1998, 98, 409.
J O026797P
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