Highly efficient and direct heterocyclization of dipyridyl ketone to N,N-bidentate ligands

Article abstract of DOI:10.1021/jo047853k

(Chemical Equation Presented) Reaction of various aromatic aldehydes with 2,2′-dipyridyl ketone and ammonium acetate in hot acetic acid provides ready access to a series of substituted 1-pyridylimidazo[1,5-a]pyridines, a class of ligands possessing an N,N-bidentate feature, in good yields.

Full text of DOI:10.1021/jo047853k

SCHEME 1
Highly Efficient and Direct
Heterocyclization of Dipyridyl Ketone to
N,N-Bidentate Ligands
Jie Wang, Leon Dyers, Jr., Richard Mason, Jr.,
Prince Amoyaw, and Xiu R. Bu*
Department of Chemistry, Laboratory for Electro-Optical
Materials & NASA Center for High Performance Polymers
and Composites, Clark Atlanta University,
Atlanta, Georgia 30314
an efficient synthetic method for their preparation. The
only two methods for such ligands reported so far involve
the use of amines to react with dipyridyl ketone in the
presence of a sensitive Lewis acid, BF3,9 or the oxidization
of Schiff bases in the presence of molecular sieves9 or
metal ions requiring two to three steps from dipyridyl
ketone.10 These approaches are encountered with overall
yields usually below 30%. Recently, we have disclosed a
direct method for the heterocyclization of 2,2′-pyridyl to
form imidazo[1,5-a]pyridines.11,12 Here we report a direct
cyclization of 2,2′-dipyridyl ketone with aldehydes in the
presence of ammonium acetate for the synthesis of
desirable N,N-bidentate ligands. The significance of this
approach is that the reaction is straightforward with only
one step without the use of any metal catalysts or highly
sensitive Lewis acids. Another advantage is that the
reaction scope is significantly wide because the reaction
is tolerant with various aldehyde substrates.
xbu@cau.edu
Received December 5, 2004
Reaction of various aromatic aldehydes with 2,2′-dipyridyl
ketone and ammonium acetate in hot acetic acid provides
ready access to a series of substituted 1-pyridylimidazo[1,5-
a]pyridines, a class of ligands possessing an N,N-bidentate
feature, in good yields.
The first reaction that was examined involved the use
of benzaldehyde whose reaction with 2,2′-dipyridyl ketone
and ammonium acetate was carried out in acetic acid.
The desired product 2a was obtained in 69% yield
(Scheme 1, entry 1 in Table 1), demonstrating that such
a direct approach was indeed working and the yield was
good as well. A series of benzaldehyde derivatives with
different substituents was then examined to study the
reaction scope. The results (entries 2-10, Table 1) clearly
demonstrated that all the reactions led to the target
products without exception. In addition to the wide scope
of the application, the yields are moderate to excellent.
For example, 2d and 2g are obtained in 95% and 64%
yield, respectively, while 2h and 2j are obtained in 81%
and 87% yield, respectively.
N,N-Bidentate ligands such as 2,2′-bipyridine and
1,10-phenanthroline play a pivotal role in key areas such
as photovoltaics,1 OLEDs,2 molecular sensors,3 DNA
intercalation,4 molecular wires,5 and supramolecular
structures (network, helical, box, etc.).6 The diverse
applications stem from the facts that the ligands are
capable of chelating various metal ions and the resultant
complexes possess a wide range of magnetic, photophysi-
cal, and electrochemical properties. Thus, the develop-
ment of synthetic methodologies for N,N-bidentate ligands
is of paramount importance in chemistry.
N,N-Bidentate ligands with mixed five- and six-mem-
bered heterocycles are a desirable class of compounds in
the pursuit of structural diversity for property perfor-
mance. In particular, 1-pyridylimidazo[1,5-a]pyridines
possess a bidentate structural feature with a pyridyl unit
directly next to a fused imidazole and have emerged as
a new class of ligands.7,8 In contrast, there is a lack of
(9) (a) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27, 3713.
(b) Grigg, R.; Kennewell, P.; Savic, V.; Sridharan, V. Tetrahedron 1992,
48, 10423.
(10) Bluhm, M. E.; Ciesielski, M.; Go¨rls, Walter, O.; Do¨ring, M.
Angew. Chem., Int. Ed. 2002, 41, 2962.
(11) Wang, J.; Mason, R.; VanDerveer, D.; Feng, K.; Bu, X. R. J.
Org. Chem. 2003, 68, 5415.
(1) Nazeeruddin, Md. K.; Kay, A.; Rodicio, I.; Humphry-Baker, R.;
Mu¨ller, E.; Liska, P.; Vlachopoulos, N.; Gra¨tzel, M. J. Am. Chem. Soc.
1993, 115, 6382.
(2) Rudmann, H.; Shimada, S.; Rubner, M. J. Am. Chem. Soc. 2002,
124, 4918. Gao, F. G.; Bard, A. J. J. Am. Chem. Soc. 2000, 122, 7426.
(3) Mizuno, T.; Wei, W.-H.; Eller, L. R.; Sessler, J. L. J. Am. Chem.
Soc. 2002, 124, 1134. Grigg, R.; Norbert, W. D. J. A. J. Chem. Soc.,
Chem. Commun. 1992, 1300.
(4) O¨ nfelt, B.; Lincoln, P.; Norden, B. J. Am. Chem. Soc. 2001, 123,
3630.
(5) Hortholary, C.; Coudret, C. J. Org. Chem. 2003, 68, 2167.
(6) Baxter, P.; Lehn, J.-M.; Decian, A.; Fischer, J. Angew. Chem.,
Int. Ed. 1993, 32, 69. Kra¨mer, R.; Lehn, J.-M.; De Cian, A.; Fischer, J.
Angew. Chem., Int. Ed. 1993, 32, 703.
(7) Ligtenbarg, A. G.; Spek, A. L.; Hage, R.; Feringa, B. L. J. Chem.
Soc., Dalton Trans. 1999, 659.
(8) Bluhm, M. E.; Ciesielski, M.; Go¨rls, Walter, O.; Do¨ring, M. Inorg.
Chem. 2003, 42, 8878.
(12) Other methods for imidazo[1,5-a]pyridines: (a) Bourdais, J.;
Omar, A.-M. E. J. Heterocycl. Chem. 1980, 17, 555. (b) Abushanab,
E.; Bindra, A. P. J. Org. Chem. 1973, 38, 2049. (c) Bower, J. D.;
Ramage, G. R. J. Chem. Soc. 1955, 2834. (d) Fuentes, O.; Paudler, W.
W. J. Org. Chem. 1975, 40, 1210. (e) Montgomery, J. A.; Secrist, J. A.,
III. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 5, p 614.(f) Katritzky,
A. R.; Qiu, G. J. Org. Chem. 2001, 66, 2862. (g) Palacios, F.; Alonso,
C.; Rubials, G. Tetrahedron 1995, 51, 3683. Benincori, T.; Brenna, E.;
Sannicolo, F. J. Chem. Soc., Perkin Trans. 1 1993, 675. (h) Kaminki,
J. J.; Bristol, J. A.; Lovey, R. G.; Elliot, A. J.; Duzik, H.; Solomon, D.
M.; Conn, D. J.; Domalski, M. S.; Wong, S.-C.; Gold, E. H.; Long, J. F.;
Chiu, P. J. S.; Steinberg, M.; McPhail, A. T. J. Med. Chem. 1985, 28,
876. (i) Tachikawa, R.; Tanaka, S.; Terada, A. Heterocycles 1981, 15,
369. (j) Kovtun, Y. P.; Prostota, Y. A. Chem. Heterocyl. Comput. (New
York) 2000, 36, 557. (k) D’Anello, M.; Erba, E.; Gelmi, M. L.; Pocar, D.
Chem. Ber. 1988, 121, 67. (l) Albrecht, W. L.; Corona, J. A.; Edwards,
M. L. J. Heterocycl. Chem. 1979, 16, 1349.
10.1021/jo047853k CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/09/2005
J. Org. Chem. 2005, 70, 2353-2356
2353

TABLE 1. Yields from 1:1.5:4 Ketone/Aldehyde/NH4OAca
TABLE 4. Yields Using Heterocyclic Aldehydesa
entry
1: Ar in 1
2: yield (%)
1
2
1a: Ph
2a: 69
2b: 78
2c: 87
2d: 95
2e: 68
2f: 90
2g: 64
2h: 81
2i: 88
2j: 87
1b: 2-MeC6H4
1c: 3-MeC6H4
1d: 4-i-PrC6H4
1e: 3-OMeC6H4
1f: 4-OEtC6H4
1g: 4-NMe2C6H4
1h: 2-FC6H4
3
4
5
6
7
8
9
1i: 3-ClC6H4
1j: 3-NO2C6H4
10
a Molar ratio.
TABLE 2. Yields of 2a Obtained under Various Ratios
run
molar ratioa
yield of 2a (%)
1
2
3
4
5
6
7
1:1.5:4
1:2:4
1:3:4
1:2:3
1:2:5
1:2:6
1:2:7
69
75
66
66
81
57
55
a Ketone/aldehyde/NH4OAc 1:2:5 (molar ratio).
a Ketone/benzaldehyde/ammonium acetate.
ligand with intrinsic terpyridine13 character. Most im-
portantly, a significantly wide application scope was
further demonstrated with the use of these heterocyclic
aldehydes.
Triphenylamine is known to be a charge-transporting
species and a thermally stable electron-donating group,14
used in nonlinear optical,15 two-photon absorption,16 and
OLED materials.17 The treatment of aldehyde 1o18 with
dipyridyl ketone and ammonium acetate gave 2o in 84%
yield (Scheme 2).
The plausible reaction mechanism involves the initial
addition of ammonia to aldehyde to form an imine,
followed by the nucleophilic attack of the in situ gener-
ated imine to carbonyl of the ketone (Scheme 3). These
two steps bring the three individual components together.
The subsequent intramolecular interaction leads to the
cyclization and eventually to the formation of the desir-
able imidazopyridine.
In conclusion, a new method for the development of
bidentate and multiple dentate ligands has been estab-
lished to be both straightforward and highly efficient. The
strategy involves the use of three easily accessible
substrate-aldehydes, dipyridyl ketone, and ammonium
acetate without the use of any highly sensitive Lewis
acids or metal-based catalysts. This approach is tolerant
with various aromatic aldehydes with different types of
substituted groups. The wide scope of this application
also includes heterocyclic aromatic aldehydes. Since the
new ligands also possess an inherent imidazopyridine, a
class of compounds of medicinal importance,19,20 this
approach will offer a new and direct route not only for
TABLE 3. Yields Using Optimal Conditionsa
entry
product
yield (%)
1
2
3
4
5
6
2a
2b
2e
2g
2h
2j
81
79
75
70
88
90
a Ketone/aldehyde/NH4OAc 1:2:5 (molar ratio).
Other reaction conditions have been also investigated
using benzaldehyde as a model substrate (Table 2). The
optimal conditions are established to have a 1:2:5 molar
ratio of ketone/aldehyde/NH4OAc. Several aldehydes
were then examined under these optimal conditions
(Table 3), and yields are generally improved compared
to those from the 1:1.5:4 ratio conditions. Other aldehydes
which have already given high yields in the 1:1.5:4
conditions have not been examined further. For example,
2d was already obtained in 95% yield while 2f was
obtained in 90% yield.
This strategy was further applied for the preparation
of potential multi-dentate ligands using aromatic het-
erocyclic aldehydes. Results from a series of aldehydes
containing thiophene, furan, and pyridine showed that
all the reactions led to the desired products with no
exception (Table 4). These reactions only need a short
period of reaction time (1.5 h) and a moderately elevated
temperature (80 °C). The extended reaction time and
reflux temperature are not only unnecessary but should
be also avoided since the yields of the formed products
will decrease. For example, the reaction using 2-carbox-
aldehyde furan (1k) afforded 2k only in 5% yield at 110
°C for 5 h but in 52% yield at 80 °C for 1.5 h. Compounds
2k and 2m are potential tridentate ligands because the
heteroatom (O or S) from the heterocyclic ring is in close
proximity with the N,N-bidentate unit. For the same
reason, compound 2n is another potential tridentate
(13) Thompson, A. M. W. C. Coord. Chem. Rev. 1997, 160, 1.
(14) Tanaka, H.; Tokito, S.; Taga, Y.; Okada, A. Chem. Commun.
1996, 2175.
(15) Moylan, C. R.; Twieg, R. J.; Lee, V. Y.; Swanson, S. A.;
Betterton, K. M.; Miller, R. D. J. Am. Chem. Soc. 1993, 115, 12599.
(16) Rumi, M.; Ehrlich, J. E.; Heikal, A. A.; Perry, J. W.; Barlow,
S.; Hu, Z.; McCord-Maughon, D.; Parker, T. C.; Ro¨ckel, H.;
Thayumanavan, S.; Marder, S. R.; Beljonne, D.; Bre´das, J.-L. J. Am.
Chem. Soc. 2000, 122, 9500.
(17) Bellmann, E.; Shaheen, S. E.; Grubbs, R. H.; Marder, S. R.;
Kippelen, B.; Peyghambarian, N. Chem. Mater. 1999, 11, 399-407.
(18) Lai, G.; Bu, X. R.; Santos, J.; Mintz, E. A. Synlett 1997, 1275.
2354 J. Org. Chem., Vol. 70, No. 6, 2005

SCHEME 2
was added to 200 mL of ice-water and then extracted with
methylene chloride. The organic phase was washed with water
(100 mL and then 2 × 75 mL) and then dried over sodium
sulfate. Upon the removal of solvent under reduced pressure,
the residue was purified by chromatography on a silica column,
followed by further recrystallization from solvents.
SCHEME 3
1-(2-Pyridyl)-3-phenylimidazo[1,5-a]pyridine (2a): 81%
(method A, ketone/aldehyde/NH4OAc ) 1:2:5, molar ratio);
yellow solid; mp 92-93 °C (EtOAc/hexanes); 1H NMR (CDCl3) δ
8.66 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5 Hz), 8.21 (2H, d,
J ) 7.5 Hz), 7.80 (2H, d, J ) 7.5 Hz), 7.67 (1H, t, J ) 7.5 Hz),
7.50 (2H, t, J ) 7.5 Hz), 7.42 (1H, t, J ) 7.5 Hz), 7.05 (1H, t, J
) 6.5 Hz), 6.88 (1H, dd, J ) 9.0 Hz), 6.60 (1H, t, J ) 6.5 Hz);
13C NMR (CDCl3) δ 155.2, 149.2, 138.3, 136.5, 130.8, 130.5,
130.4, 129.3, 129.2, 128.6, 122.1, 121.8, 121.3, 120.7, 120.2, 114.1;
GC-MS m/z 271 (M+). Anal. Calcd for C18H13N3: C, 79.68; H,
4.83; N, 15.49. Found: C, 79.55; H, 4.82; N, 15.41.
1-(2-Pyridyl)-3-(2-methylphenyl)imidazo[1,5-a]pyri-
dine (2b): 79% (method A, ketone/aldehyde/NH4OAc ) 1:2:5,
molar ratio); yellow solid; mp 112-113 °C (EtOAc/hexanes); 1H
NMR (CDCl3) δ 8.66 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5
Hz), 8.19 (1H, d, J ) 8.0 Hz), 7.65 (1H, t, J ) 8.0 Hz), 7.57 (1H,
d, J ) 7.5 Hz), 7.45 (1H, d, J ) 7.5 Hz), 7.38-7.21 (3H, m), 7.03
(1H, t, J ) 6.5 Hz), 6.86 (1H, dd, J ) 9.0 Hz), 6.54 (1H, t, J )
6.5 Hz), 2.21 (3H, s); 13C NMR (CDCl3) δ 155.2, 149.0, 139.14,
138.6, 137.8, 136.3, 130.9, 130.6, 129.9, 129.7, 129.3, 126.2, 121.7,
121.6, 121.0, 120.4, 119.9, 113.6, 19.8; GC-MS m/z 285 (M+).
Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found:
C, 80.04; H, 5.29; N, 14.75.
the ligand synthesis but also for the potential pharma-
ceutical synthesis.
Experimental Section
General Methods. All the reactions were manipulated in
nitrogen atmosphere. All the chemicals were used as received.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded with TMS as an internal standard for reference. The
C, H, and N contents were obtained through combustion
analysis. Melting points are uncorrected.
1-(2-Pyridyl)-3-(3-methylphenyl)imidazo[1,5-a]pyri-
dine (2c): 87.0% (method A, ketone/aldehyde/NH4OAc ) 1:1.5:
4, molar ratio); yellow solid; mp 105-107 °C (EtOAc/hexanes);
1H NMR (CDCl3) δ 8.65 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5
Hz), 8.20 (2H, t, J ) 8.0 Hz), 7.68-7.63 (2H, m), 7.57 (1H, d, J
) 8.0 Hz), 7.38 (1H, t, J ) 8.0 Hz), 7.22 (1H, d, J ) 8.0 Hz),
7.04 (1H, t, J ) 7.0 Hz), 6.85 (1H, dd, J ) 9.0 Hz), 6.57 (1H, d,
J ) 7.0 Hz), 2.57 (3H, s); 13C NMR (CDCl3) δ 155.1, 149.0, 139.0,
138.2, 136.2, 130.5, 130.1, 130.0, 129.7, 129.3, 128.9, 125.2, 121.8,
121.7, 121.0, 120.4, 120.0, 113.8, 21.6; GC-MS m/z 285 (M+).
Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found:
C, 80.01; H, 5.29; N, 14.79.
1-(2-Pyridyl)-3-(4-isopropylphenyl)imidazo[1,5-a]pyri-
dine (2d): 95% (method A, ketone/aldehyde/NH4OAc ) 1:1.5:4,
molar ratio); yellow solid; mp 100-101°C (hexanes); 1H NMR
(CDCl3) δ 8.65 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5 Hz), 8.20
(1H, d, J ) 8.0 Hz), 7.71 (2H, d, J ) 8.0 Hz), 7.66 (1H, t, J ) 8.0
Hz), 7.35 (2H, d, J ) 8.0 Hz), 7.03 (1H, t, J ) 6.5 Hz), 6.85 (1H,
dd, J ) 9.0 Hz), 6.56 (1H, t, J ) 6.5 Hz), 2.95 (1H, hept, J ) 7.0
Hz), 1.26 (6H, d, J ) 7.0 Hz); 13C NMR (CDCl3) δ 155.4, 145.1,
148.9, 138.5, 136.2, 130.6, 130.3, 128.4, 127.6, 127.1, 121.8, 121.7,
120.9, 120.4, 119.9, 113.7, 34.1, 23.9; GC-MS m/z 313 (M+).
Anal. Calcd for C21H19N3: C, 80.48; H, 6.11; N, 13.41. Found:
C, 80.47; H, 6.13; N, 13.39.
Method A: General Procedure for the Preparation of
Compound 2a-j. A mixture consisting of either 2,2′-dipyridyl
ketone (0.92 g, 5.0 mmol), substituted benzaldehyde (10.0 mmol),
NH4OAc (1.93 g, 25.0 mmol), or 2,2′-dipyridyl ketone (0.92 g,
5.0 mmol), substituted benzaldehyde (7.5 mmol), and NH4OAc
(1.54 g, 20.0 mmol) in 50 mL of glacial acetic acid was stirred at
110 °C under N2. After 5 h, the reaction mixture was cooled to
room temperature and poured into 250 mL of ice water. The
formed solid was then filtered, dried, and recrystallized with
appropriate mixed solvent. If there no solid formed, the mixture
was extracted with CH2Cl2 and washed with brine and then
water. The organic layer was separated and dried over Na2SO4.
Upon the removal of solvent, the residue was recrystallized to
afford analytically pure compound.
Method B: General Procedure for the Preparation of
Compounds 2k-o. To a 100 mL three-necked round-bottom
flask was added 30 mL of glacial acetic acid and 2,2′-dipyridyl
ketone (0.92 g, 5.0 mmol). The mixture was allowed to stir at
room temperature under nitrogen until all the solid was dis-
solved. Aldehyde (10.0 mmol) was then added, followed by the
addition of ammonium acetate (25.0 mmol). The reaction was
monitored by the TLC. The reaction mixture was stirred at 80
°C for 1.5 h and then cooled to room temperature. The mixture
1-(2-Pyridyl)-3-(3-methoxyphenyl)imidazo[1,5-a]pyri-
dine (2e): 75% (method A, ketone/aldehyde/NH4OAc ) 1:2:5,
molar ratio); yellow solid; mp 96-98 °C (EtOAc/hexanes); IR/
(19) Ford, N. F.; Browne, L. J.; Campell, T.; Gemenden, C.; Gold-
stein, R.; Gude, C.; Waley, J. W. F. J. Med. Chem. 1985, 28, 164.
(20) Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei,
G.; Chavignon, O.; Teulade, J.-C.; Kerbal, A.; Essassi, E. M.; Debouzy,
J.-C.; Witvrouw, M.; Blache, Y.; Balzarini, J.; Clercq, E. D.; Chapet,
J.-P. J. Med. Chem. 1996, 39, 2856.
1
cm-1; H NMR (CDCl3) δ 8.66 (1H, d, J ) 9.0 Hz), 8.57 (1H, d,
J ) 4.5 Hz), 8.21 (2H, d, J ) 8.0 Hz), 7.66 (1H, t, J ) 8.0 Hz),
7.41-7.34 (3H, m), 7.04 (1H, t, J ) 6.5 Hz), 6.95 (1H, d, J ) 8.0
J. Org. Chem, Vol. 70, No. 6, 2005 2355

Hz), 6.86 (1H, dd, J ) 9.0 Hz), 6.58 (1H, t, J ) 6.5 Hz), 3.84
(3H, s); 13C NMR (CDCl3) δ 160.2, 155.1, 149.0, 137.9, 136.3,
131.4, 130.5, 130.3, 130.1, 121.9, 121.7, 121.1, 120.5, 120.0, 115.0,
113.9, 113.8, 55.3; GC-MS m/z 301 (M+). Anal. Calcd for
1-(2-Pyridyl)-3-(2-furyl)imidazo[1,5-a]pyridine (2k): 52%
(method B, ketone/aldehyde/NH4OAc ) 1:2:4, molar ratio);
yellow solid; flash silica column: EtOAc/hexanes ) 1/3 (v/v); mp
123-124 °C (EtOAc/hexanes); 1H NMR (CDCl3) δ 8.66 (1H, d, J
) 9.0 Hz), 8.60 (1H, d, J ) 7.0 Hz), 8.57 (1H, d, J ) 4.5 Hz),
8.19 (1H, d, J ) 8.0 Hz), 7.67 (1H, t, J ) 8.0 Hz), 7.55 (1H, s),
7.07-7.02 (2H, m), 6.90 (1H, t, J ) 8.0 Hz), 6.69 (1H, t, J ) 7.0
Hz), 6.56 (1H, s); 13C NMR (CDCl3) δ 154.7, 149.0, 146.1, 142.3,
136.3, 130.09, 130.1, 129.9, 123.0, 121.7, 121.3, 120.7, 120.1,
114.5, 111.7, 108.8; GC-MS m/z 261 (M+). Anal. Calcd for
C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.63; H,
4.28; N, 15.91.
1-(2-Pyridyl)-3-(3-furyl)imidazo[1,5-a]pyridine (2l): 55%
(method B, ketone/aldehyde/NH4OAc ) 1:2:4, molar ratio);
yellow solid; flash silica column: EtOAc/hexanes ) 1/3 (v/v); mp
103-104 °C (EtOAc/hexanes); 1H NMR (CDCl3) δ 8.64 (1H, d, J
) 9.0 Hz), 8.57 (1H, d, J ) 4.5 Hz), 8.17 (1H, d, J ) 8.0 Hz),
8.01 (1H, d, J ) 7.0 Hz), 7.96 (1H, s), 7.67 (1H, t, J ) 8.0 Hz),
7.56 (1H, s), 7.04 (1H, t, J ) 6.5 Hz), 6.95 (1H, s), 6.87 (1H, t, J
) 8.0 Hz), 6.66 (1H, t, J ) 6.5 Hz); 13C NMR (CDCl3) δ 155.1,
149.2, 143.8, 140.7, 136.5, 131.6, 130.6, 130.2, 122.1, 121.9, 120.9,
120.7, 120.1, 116.5, 114.3, 110.3; GC-MS m/z 261 (M+). Anal.
Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C,
73.64; H, 4.26; N, 16.05.
1-(2-Pyridyl)-3-(2-thienyl)imidazo[1,5-a]pyridine (2m):
53% (method B, ketone/aldehyde/NH4OAc ) 1:2:5, molar ratio);
yellow solid; mp 131-132 °C (EtOAc/hexanes); 1H NMR (CDCl3)
δ 8.67 (1H, d, J ) 9.0 Hz), 8.57 (1H, d, J ) 4.5 Hz), 8.28 (1H, d,
J ) 7.0 Hz), 8.20 (1H, d, J ) 8.0 Hz), 7.67 (1H, t, J ) 8.0 Hz),
7.51 (1H, s), 7.40 (1H, d, J ) 4.5 Hz), 7.16 (1H, m), 7.05 (1H, t,
J ) 6.5 Hz), 6.88 (1H, t, J ) 8.0 Hz), 6.68 (1H, t, J ) 6.5 Hz);
13C NMR (CDCl3) δ 155.0, 149.2, 136.5, 132.8, 132.3, 130.9,
130.6, 127.9, 126.6, 125.7, 122.2, 122.1, 121.3, 120.9, 120.3, 114.7;
GC-MS m/z 277 (M+). Anal. Calcd for C16H11N3S: C, 69.29; H,
4.00; N, 15.15. Found: C, 69.38; H, 3.95; N, 15.21.
1,3-Di(2-pyridyl)imidazo[1,5-a]pyridine (2n): 12% (method
B, ketone/aldehyde/NH4OAc ) 1:2:5, molar ratio); yellow solid;
flash column: EtOAc/hexanes ) 1/5; mp 151-152 °C (EtOAc/
hexanes); 1H NMR (CDCl3) δ 9.98 (1H, d, J ) 7.0 Hz), 8.73 (1H,
d, J ) 9.0 Hz), 8.60 (2H, s), 8.43 (1H, d, J ) 8.0 Hz), 8.25 (1H,
d, J ) 8.0 Hz), 7.77-7.68 (2H, m), 7.21-7.15 (1H, m), 7.09-
6.99 (2H, m), 6.78 (1H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 155.1,
151.2, 149.1, 148.3, 136.7, 136.5, 135.1, 131.9, 126.5, 122.6, 122.4,
122.0, 121.2, 120.8, 120.3, 114.5; GC-MS m/z 272 (M+). Anal.
Calcd for C17H12N4: C,74.98; H, 4.44; N, 20.58. Found: C, 74.86;
H, 4.50; N, 20.58.
C
19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C, 75.72; H,
4.99; N, 13.94.
1-(2-Pyridyl)-3-(4-ethoxyphenyl)imidazo[1,5-a]pyri-
dine (2f): 90% (method A, ketone/aldehyde/NH4OAc ) 1:1.5:4,
molar ratio); yellow solid; mp 130-131 °C (EtOAc/hexanes); 1H
NMR (CDCl3) δ 8.63 (1H, d, J ) 9.0 Hz), 8.57 (1H, d, J ) 4.5
Hz), 8.19 (1H, d, J ) 8.0 Hz), 8.12 (1H, d, J ) 7.0 Hz), 7.70-
7.63 (3H, m), 7.04-6.99 (3H, m), 6.83 (1H, dd, J ) 9.0 Hz), 6.56
(1H, t, J ) 7.0 Hz), 4.06 (2H, tetra, J ) 7.0 Hz), 1.41 (4H, t, J
) 7.0 Hz); 13C NMR (CDCl3) δ 159.5, 155.1, 149.0, 136.2, 130.2,
129.8, 123.0, 121.8, 121.6, 120.8, 120.3, 119.9, 115.0, 113.7, 63.6,
14.8; GC-MS m/z 315 (M+). Anal. Calcd for C20H17N3O: C,
76.17; H, 5.43; N, 13.32. Found: C, 76.06; H, 5.40; N, 13.29.
1-(2-Pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]-
pyridine (2g): 70% (method A, ketone/aldehyde/NH4OAc ) 1:2:
5, molar ratio); yellow solid; mp 180-182 °C (EtOAc/hexanes);
1H NMR (CDCl3) δ 8.61 (1H, d, J ) 9.0 Hz), 8.57 (1H, d, J ) 4.5
Hz), 8.21 (1H, t, J ) 6.5 Hz), 8.14 (1H, d, J ) 7.0 Hz), 7.67-
7.63 (3H, m), 7.01 (1H, t, J ) 6.0 Hz), 6.82-6.78 (3H, m), 6.52
(1H, t, J ) 7.0 Hz), 2.97 (6H, s); 13C NMR (CDCl3) δ 155.3, 150.7,
148.9, 139.0, 130.2, 129.9, 129.8, 129.4, 121.9, 121.7, 120.6, 120.2,
119.9, 117.6, 113.3, 112.3, 40.4; GC-MS m/z 314 (M+). Anal.
Calcd for C20H18N4: C, 76.41; H, 5.77; N, 17.82. Found: C, 76.22;
H, 5.71; N, 17.70.
1-(2-Pyridyl)-3-(2-fluorophenyl)imidazo[1,5-a]pyridine
(2h): 88% (method A, ketone/aldehyde/NH4OAc ) 1:2:5, molar
1
ratio); yellow solid; mp 127-128 °C (EtOAc/hexanes); H NMR
(CDCl3) δ 8.68 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5 Hz), 8.18
(1H, d, J ) 8.0 Hz), 7.75 (2H, t, J ) 6.0 Hz), 7.67 (1H, t, J ) 8.0
Hz), 7.47-7.42 (1H, m), 7.30 (1H, t, J ) 8.0 Hz), 7.21 (1H, t, J
) 9.0 Hz), 7.05 (1H, t, J ) 7.0 Hz), 6.92 (1H, dd, J ) 9.0 Hz),
6.64 (1H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 161.2, 159.6, 155.2,
149.2, 136.5, 133.6, 132.8, 132.7, 131.4, 131.3, 131.2, 130.6, 125.2,
125.1, 122.7, 122.6, 121.7, 121.5, 120.7, 120.1, 116.5, 116.3, 113.9;
GC-MS m/z 289 (M+). Anal. Calcd for C18H12FN3: C, 74.73; H,
4.18; N, 14.52. Found: C, 74.65; H, 4.18; N, 14.42.
1-(2-Pyridyl)-3-(3-chlorophenyl)imidazo[1,5-a]pyri-
dine (2i): 88% (method A, ketone/aldehyde/NH4OAc ) 1:1.5:4,
molar ratio); yellow solid; mp 130-131 °C (EtOAc/hexanes); 1H
NMR (CDCl3) δ 8.67 (1H, d, J ) 9.0 Hz), 8.58 (1H, d, J ) 4.5
Hz), 8.18 (2H, d, J ) 7.0 Hz), 7.82 (1H, s), 7.68 (2H, t, J ) 7.5
Hz), 7.44-7.37 (2H, m), 7.06 (1H, t, J ) 6.5 Hz), 6.89 (1H, dd,
J ) 9.0 Hz), 6.64 (1H, t, J ) 6.5 Hz); 13C NMR (CDCl3) δ 155.1,
149.2, 136.7, 136.5, 135.3, 132.1, 131.2, 130.7, 130.5, 129.1, 128.6,
126.3, 122.2, 121.6, 121.5, 120.9, 120.2, 114.6; GC-MS m/z 306
(M+). Anal. Calcd for C18H12ClN3: C, 70.71; H, 3.96; N, 13.74.
Found: C, 70.92; H, 3.99; N, 13.71.
1-(2-Pyridyl)-3-(4-diphenylaminophenyl)imidazo[1,5-a]-
pyridine (2o): 84% (method B, ketone/aldehyde/NH4OAc ) 1:2:
5, molar ratio); yellow solid; mp 154-155 °C (HOAc/EtOAc); 1H
NMR (DMSO-d6) δ 8.54 (2H, m), 8.41 (1H, m), 8.05 (1H, m), 7.73
(3H, m), 7.30 (4H, m), 7.06 (10H, m), 6.76 (1H, m); 13C NMR
(CDCl3) δ 155.0, 151.2, 149.1, 148.3, 136.7, 136.6, 135.2, 131.9,
130.7, 126.5, 122.6, 122.4, 122.0, 121.2, 120.8, 120.3, 114.6; GC-
MS m/z 438 (M+). Anal. Calcd for C30H22N4: C, 82.17; H, 5.06;
N, 12.78. Found: C, 82.23; H, 5.04; N, 12.62.
1-(2-Pyridyl)-3-(3-nitrophenyl)imidazo[1,5-a]pyridine (2j):
90% (method A, ketone/aldehyde/NH4OAc ) 1:2:5, molar ratio);
red solid; mp 185-186 °C (HOAc/ethanol); 1H NMR (DMSO-d6)
δ 8.61-8.57 (4H, m), 8.31 (1H, d, J ) 8.0 Hz), 8.26 (1H, d, J )
8.0 Hz), 8.10 (1H, d, J ) 8.0 Hz), 7.83-7.79 (2H, m), 7.15 (1H,
t, J ) 7.0 Hz), 7.09 (1H, t, J ) 7.0 Hz), 6.88 (1H, t, J ) 7.0 Hz);
13C NMR (DMSO-d6) δ 154.9, 149.8, 149.0, 137.4, 135.9, 134.5,
131.8, 131.4, 131.0, 130.7, 123.8, 123.5, 123.3, 123.2, 121.6, 121.5,
Acknowledgment. Financial support in part by the
U.S. Army (DAAD19-01-0746), DOE (De-FC02-02E-
W15254), NASA (NCC3-552), and NIH (G12-RR03062)
is gratefully acknowledged. We also thank Dr. Hongjun
Pan for invaluable assistance.
120.0, 115.7; GC-MS m/z 316 (M+). Anal. Calcd for C18H12
-
N4O2: C, 68.35; H, 3.82; N, 17.71. Found: C, 68.32; H, 3.82; N,
17.66.
JO047853K
2356 J. Org. Chem., Vol. 70, No. 6, 2005