A new class of pyrazolopyridine nucleus with fluorescent properties, obtained through either a radical or a Pd arylation pathway from N-azinylpyridinium N-aminides

Article abstract of DOI:10.1021/jo801549u

(Chemical Equation Presented) The synthesis of dipyridopyrazole and pyridopyrazolopyrazine derivatives - both of which incorporate a 3-aryl moiety - can be achieved in moderate yields by intramolecular radical arylation of pyridinium N-aminides using tris(trimethylsilyl)silane and azobisisobutyronitrile. Improved results were obtained on using Pd direct arylation in conjunction with microwave irradiation. A preliminary study into the fluorescent properties of the target compounds is also reported.

Full text of DOI:10.1021/jo801549u

A New Class of Pyrazolopyridine Nucleus with Fluorescent
Properties, Obtained through Either a Radical or a Pd Arylation
Pathway from N-Azinylpyridinium N-Aminides
Valentina Abet,† Araceli Nun˜ez,† Francisco Mendicuti,‡ Carolina Burgos,*,† and
Julio Alvarez-Builla*,†
Departamentos de Qu´ımica Orga´nica and Qu´ımica F´ısica, UniVersidad de Alcala´, 28871 Alcala´ de
Henares, Madrid, Spain
carolina.burgos@uah.es; julio.alVarez@uah.es
ReceiVed July 17, 2008
The synthesis of dipyridopyrazole and pyridopyrazolopyrazine derivativessboth of which incorporate a
3-aryl moietyscan be achieved in moderate yields by intramolecular radical arylation of pyridinium
N-aminides using tris(trimethylsilyl)silane and azobisisobutyronitrile. Improved results were obtained on
using Pd direct arylation in conjunction with microwave irradiation. A preliminary study into the fluorescent
properties of the target compounds is also reported.
Introduction
Azaindolizines (e.g., II-IV, Figure 1) with additional nitro-
gens in either the azine ring (II) or the azole ring (III) or both
(IV) are rare systems in nature, and their similarity to both
indoles and purines has triggered recent interest in their study.
Some remarkable members of these families are the biologically
relevant variolins1 and luciferins,2 which are related to classes
II and IV, respectively (Figure 1). Examples of type III systems
include the antiallergic and cerebroactive agent ibudilast and
† Departamento de Qu´ımica Orga´nica.
‡ Departamento de Qu´ımica F´ısica.
(1) (a) Anderson, R. J.; Hill, J. B.; Morris, J. C. J. Org. Chem. 2005, 70,
6204–6212. (b) Karpov, A. S.; Merkul, E.; Rominger, F.; Muller, T. J. J. Angew.
Chem., Int. Ed. 2005, 44, 6951–6956. (c) Perry, N. B.; Ettouati, L.; Litaudon,
M.; Blunt, J. W.; Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50,
3987–3992. (d) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.;
Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994,
50, 3993–4000.
(2) (a) Zhou, W.; Shultz, J. W.; Murphy, N.; Hawkins, E. M.; Bernad, L.;
Good, T.; Moothart, L.; Frackman, S.; Klaubert, D. H.; Bulleit, R. F.; Wood,
K. V. Chem. Commun. 2006, 4620–4622. (b) Travert, N.; Al-Mourabit, A. J. Am.
Chem. Soc. 2004, 126, 10252–10253. (c) Topalov, G.; Kishi, Y. Angew. Chem.,
Int. Ed. 2001, 40, 3892–3894.
FIGURE 1. General structure of indolizine and azaindolizines and some
related natural products.
the highly selective D4 receptor partial agonist FAUC 113
(Figure 2), which have been prepared for assessment of their
pharmacological activity.3
8800 J. Org. Chem. 2008, 73, 8800–8807
10.1021/jo801549u CCC: $40.75 2008 American Chemical Society
Published on Web 10/21/2008

Pyrazolopyridine Nucleus with Fluorescent Properties
SCHEME 1. Preparation of Compounds 3 and the Planned
Extension of the Process to 6 and 7
FIGURE 2. Structure of pyrazolo[1,5-a]pyridine and some examples
of products with interesting pharmacological activity.
In recent years our research group has been developing a
project centered on the study of the type II azaindolizines4
(Figure 1). Our initial interest in these systems resulted from
the scarce precedents on their basic chemistry and the absence
of viable synthetic methods for some of these compounds.
Bearing in mind the interest in azaindolizines, in which the
additional nitrogen is located on the azole ring (i.e., type III),
the work described here focused on the synthesis of a new class
of pyrazolo[1,5-a]pyridine, a type III azaindolizine.
SCHEME 2. Previously Described Route
During the course of our studies into the reactivity of
pyridinium N-aminides5 (i.e., 1, Scheme 1), it was shown that
it is possible to generate the pyrazolopyridine nucleus 3 from
1, through the radical intermediate 2, using tris(trimethylsilyl-
)silane and azobisisobutyronitrile (TTMSS/AIBN).6 This study
represented the first example of the intramolecular addition of
an aryl radical to a π-deficient pyridinium fragment linked to a
π-excessive 2-azinyliminopyridine moiety. This process gave
dipyridopyrazoles 3a-c and pyridopyrazolopyrazines 3d-f, all
of which contain the pyrazolopyridine nucleus. Although a few
examples of the synthesis of dipyridopyrazole derivatives by
alternative routes were already known,7 our approach allowed
the preparation of the fully aromatic and unsubstituted nucleus,
as well as the previously unreported pyrazine structures.
Moreover, these chromophores exhibit a high degree of
conjugation and display bright color and strong fluorescence
properties.
The intramolecular arylation method has now been extended
to the preparation of aryl derivatives 6 and 7, both of which
have a more extended π-system and, consequently, a higher
degree of conjugation. The synthesis of 6 and 7 was achieved
through the bromo ylides 4 and 5 using either radical- or
palladium-catalyzed methodologies. A preliminary study of the
fluorescence properties of these compounds is also described.
(3) (a) Gibson, L.; Hasting, S.; McPhee, I.; Clayton, R.; Darroch, C. E.;
MacKenzie, A.; MacKenzie, F. L.; Nagasawa, M.; Stevens, P. A.; MacKenzie,
S. J. Eur. J. Pharmacol. 2006, 538, 39–42. (b) Lo¨ber, S.; Ortner, B.; Bettinetti,
L.; Hu¨bner, H.; Gmeiner, P. Tetrahedron: Asymmetry 2002, 13, 2303–2310. (c)
Lo¨ber, S.; Aboul-Fadl, T.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
2002, 12, 633–636. (d) Aboul-Fadl, T.; Lo¨ber, S.; Gmeiner, P. Synthesis 2000,
1727–1732.
(4) (a) Castellote, I.; Moron, M.; Burgos, C.; Alvarez-Builla, J.; Martin, A.;
Gomez-Sal, P.; Vaquero, J. J. Chem. Commun. 2007, 1281–1283. (b) Mendiola,
J.; Castellote, I.; Alvarez-Builla, J.; Fernandez-Gadea, J.; Gomez, A.; Vaquero,
J. J. J. Org. Chem. 2006, 71, 1254–1257. (c) Minguez, J. M.; Vaquero, J. J.;
Garcia-Navio, J. L.; Alvarez-Builla, J.; Castan˜o, O.; res, J. L. J. Org. Chem.
1999, 64, 7788–7801. (d) Minguez, J. M.; Castellote, M. I.; Vaquero, J. J.; Garcia-
Navio, J. L.; Alvarez-Builla, J.; Castan˜o, O.; res, J. L. Tetrahedron 1997, 53,
9341–9356. (e) Minguez, J. M.; Castellote, M. I.; Vaquero, J. J.; Garcia-Navio,
J. L.; Alvarez-Builla, J.; Castan˜o, O.; res, J. L. J. Org. Chem. 1996, 61, 4655–
4665. (f) Minguez, J. M.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.
Tetrahedron Lett. 1996, 37, 4263–4266. (g) De Pablo, M. S.; Gandasegui, T.;
Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J. Tetrahedron 1992, 48,
8793–8800. (h) Matia, M. P.; Ezquerra, J.; Sanchez-Ferrado, F.; Garcia-Navio,
J. L.; Vaquero, J. J.; Alvarez.Builla, J. Tetrahedron 1991, 47, 7329–7342.
(5) (a) Nun˜ez, A.; Sanchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron
2007, 63, 6774–6783. (b) Sanchez, A.; Nun˜ez, A.; Burgos, C.; Alvarez-Builla,
J. Tetrahedron Lett. 2006, 47, 8343–8346. (c) Martinez-Barrasa, V.; Garcia de
Viedma, A.; Burgos, C.; Alvarez-Builla, J. Org. Lett. 2000, 2, 3933–3935. (d)
Martinez-Barrasa, V.; Delgado, F.; Burgos, C.; Garcia-Navio, J. L.; Izquierdo,
M. L.; Alvarez-Builla, J. Tetrahedron 2000, 56, 2481–2490. (e) Garcia de
Viedma, A.; Martinez-Barrasa, V.; Burgos, C.; Izquierdo, M. L.; Alvarez-Builla,
J. J. Org. Chem. 1999, 64, 1007–1010. (f) Burgos, C.; Delgado, F.; Garcia-
Navio, J. L.; Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron 1995, 51, 8649–
8654.
Results and Discussion
As shown in Scheme 2 and Table 1, and bearing in mind
previous literature data,8 the intramolecular arylation was
attempted on ylides 1 via radical 2. It was expected that
bipyridine 8 would be obtained through a reaction pathway
involving a 5-exo/endo-trig cyclization followed by cleavage
of the N-N bond, as described previously.5e To our surprise,
compound 8 was not detected and only reduction compounds 9
(7) (a) Bast, K.; Behrens, M.; Durst, T.; Grashey, R.; Huisgen, R.; Schiffer,
R.; Temme, R. Eur. J. Org. Chem. 1998, 379–385. (b) Phadke, R. C.; Rangnekar,
D. W. Synthesis 1987, 484–485. (c) Kakehi, A.; Kitajima, K.; Ito, S.; Takusagawa,
N. Acta Crystallogr., Sect. C 1995, 942–944. (d) Kakehi, A.; Ito, S.; Ono, T.;
Miyazima, T. J. Chem. Res., Synop. 1980, 18–19. (e) Kakehi, A.; Ito, S.;
Watanabe, K.; Ono, T.; Miyazima, T. Chem. Lett. 1979, 205–206.
(8) (a) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31, 1625–
1628. (b) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31, 3495–
3496.
(6) Nun˜ez, A.; Garcia de Viedma, A.; Martinez-Barrasa, V.; Burgos, C.;
Alvarez-Builla, J. Synlett 2002, 1093–1096.
J. Org. Chem. Vol. 73, No. 22, 2008 8801

Abet et al.
method
TABLE 1. Preliminary Results for the Radical Cyclization
entry
starting material
3
yield (%)
9
yield (%)
1
2
3
4
5
6
7
Y ) CH, Z ) Cl, 1c
Y ) CH, Z ) Cl, 1c
Y ) CH, Z ) Br, 1d
Y ) CH, Z ) Cl, 3a
Y ) CH, Z ) Cl, 3a
Y ) CH, Z ) H, 3b
Y ) CH, Z ) Ph, 3c
Y ) N, Z ) Cl, 3d
Y ) N, Z ) H, 3e
Y ) N, Z ) Ph, 3f
2
56
21
23
52
24
20
Y ) CH, Z ) Cl, 9a
Y ) CH, Z ) Cl, 9a
Y ) CH, Z ) H, 9b
60
5
21
Aa
Bb
B
Y ) N, Z ) Cl, 1e
Y ) N, Z ) Br, 1f
Y ) N, Z ) Cl, 9c
Y ) N, Z ) H, 9d
10
20
B
B
a Method A: TTMSS (2 equiv) and AIBN (2 equiv) in 40 mL of dry acetonitrile/benzene (7:3) were added during 32 h to a solution of aminide 1c (1
equiv) in 50 mL of acetonitrile, 80 °C, 24 h. b Method B: TTMSS (2 equiv) and AIBN (2 equiv) in 40 mL of dry acetonitrile/benzene (7:3) were added
during 32 h to a dispersion of potassium carbonate (2 equiv) and the corresponding aminide 1c-f (1 equiv) in 50 mL of dry acetonitrile, 80 °C, 24 h.
SCHEME 3. Reactivity of Azinylpyridinium N-Aminides
and tricyclic products 3 were observed, the latter corresponding
to the dipyrido[1,2-b:3′,2′-d]pyrazole nucleus obtained from
ylides 1c,d. When the reaction was carried out on ylides 1e,f,
pyrido[1′,2′:2,3]pyrazolo[5,4-b]pyrazine derivatives (compounds
3d-f, Y ) N) were obtained.
The results obtained are summarized in Table 1. In initial
experiments only poor yields of 3a were obtained in the absence
of potassium carbonate (entry 1, method A), a finding consistent
with the reaction pathway previously reported.6 Indeed, only
when the reaction was carried out in benzene/acetonitrile in the
presence of 2 equiv each of TTMSS, AIBN, and potassium
carbonate did the reaction go to completion in satisfactory yield
(entry 2, method B). When the reaction was performed on the
amidine 1d, which has an additional bromo substituent, two
tricyclic derivatives were observed (3b and 3c) as a result of
bromoreduction or concomitant phenylation, respectively, as
reported previously (entries 3 and 4).6 Similar results were
obtained under comparable experimental conditions on using
the pyrazino aminides 1e,f as starting materials. All of the
compounds obtained showed moderate fluorescence under
visible light, probably due to the presence of three conjugated
aromatic rings and the bathochromic effect exerted by the
endocyclic imino moiety.9
To explore the general utility of the method, and taking into
consideration the remarkable fluorescence properties, a broader
study of the process was planned to include more complex
systems. In this context, compounds 4 and 5 (Scheme 3) would
meet the requirements as starting materials for the radical
cyclization process to generate the tricyclic systems 6 and 7.
For many years, part of our research has been dedicated to
heteroaryl-stabilized cycloiminium ylides (e.g., 1a,b, Scheme
3) as building blocks for the synthesis of heterocyclic derivatives
and, more recently, in relation to their synthetic utility in
palladium-catalyzed cross-coupling processessparticularly in
the Suzuki-Miyaura reaction.10 Due to their peculiar structures,
these compounds show a clearly defined reactivity. Thus, for
example, the dibromo derivatives 1d and 1f (Scheme 3) show
regioselectivity in the coupling reaction at the 3′-position to give
compound 10. In addition, this type of structure (i.e., 1a,b,
Scheme 3) only undergoes bromination at the 3′-position if the
5′-position has previously been substituted (i.e., to yield 1c,e,
Scheme 3)′.5f Bearing these findings in mind, a strategy to build
the tricyclic systems 6 and 7 was envisaged. This approach
involved the use of 5′-bromo derivatives 12 and 5′-aryl
TABLE 2. Synthesis of 4 and 5
entry
starting material
Y
Ar
4, 5
yielda (%)
1
2
3
4
5
6
7
8
9
13a
13b
13c
13d
13e
14a
14b
14c
14d
CH
CH
CH
CH
CH
N
N
N
N
C6H5
4a
4b
4c
4d
4e
5a
5b
5c
5d
76
89
87
86
4-MeC6H4
4-MeOC6H4
4-MeCOC6H4
4-Me2NC6H4
C6H5
4-MeC6H4
4-MeOC6H4
4-MeCOC6H4
91
93
84
86
a Isolated pure product.
derivatives 13 and 14 to provide 4 and 5, which would then be
cyclized through the radical process described above.
The preparation of intermediates 13 and 1410 has previously
been reported from 12a,b.5f Subsequent halogenation under mild
conditions with N-bromosuccinimide (NBS) provided 4 and 5
in excellent yields. The results are summarized in Table 2.
However, N-aminide 13e, which is an electron-rich substrate
(9) Gryko, D. T.; Piechowska, J.; Tasior, M.; Waluk, J.; Orzanowska, G.
Org. Lett. 2006, 8, 4747–4750.
(10) (a) Castillo, R.; Reyes, M. J.; Izquierdo, M. L.; Alvarez-Builla, J.
Tetrahedron 2008, 64, 1351–1370. (b) Reyes, M. J.; Castillo, R.; Izquierdo, M. L.;
Alvarez-Builla, J. Tetrahedron Lett. 2006, 47, 6457–6460. (c) Reyes, M. J.;
Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron Lett. 2004, 45, 8713–8715.
8802 J. Org. Chem. Vol. 73, No. 22, 2008

Pyrazolopyridine Nucleus with Fluorescent Properties
TABLE 3. Results for the Radical Arylation from N-Aminides 4
and 5
TABLE 4. Results for the Palladium Arylation from N-Aminides
1, 4, and 5
starting
material
yielda
(%)
yielda
(%)
entry
Ar
3, 6, 7
15, 16
entry starting material
Y
Z
3, 6, 7 yield (%) method
1
2
3
4
5
6
7
8
4a,Y)CH C6H5
3c
6b
6c
6d
3f
7b
7c
7d
29
32
30
9
34
35
45
32
15a
15b
15c
15d
16a
16b
16c
16d
44
63
50
79
31
58
17
56
Ca
Db
D
D
D
D
D
Ec
D
E
4b,Y)CH 4-MeC6H4
4c,Y)CH 4-MeOC6H4
4d,Y)CH 4-MeCOC6H4
5a,Y) N C6H5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1c
1c
4a
4b
4c
4d
1e
1e
5a
5a
5b
5b
5c
5c
5d
5d
CH Cl
CH Cl
CH C6H5
CH 4-MeC6H4
CH 4-MeOC6H4
CH 4-MeCOC6H4
N
N
N
N
N
N
N
N
N
N
3a
3a
3c
6b
6c
6d
3d
3d
3f
47
72
73
40
37
53
5b,Y) N 4-MeC6H4
5c,Y) N 4-MeOC6H4
5d,Y) N 4-MeCOC6H4
Cl
Cl
C6H5
C6H5
a Isolated pure product.
50
78
31
41
27
39
24
31
3f
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeCOC6H4
4-MeCOC6H4
7b
7b
7c
7c
7d
7d
D
E
D
E
D
E
(entry 5, Table 2, Y ) CH, Ar ) 4-Me2NC6H4), did not generate
the expected product 4e, probably due to competition between
the bromo substitution and oxidation processes. Indeed, only
small amounts of highly colored products were isolated.
Having obtained substrates 4 and 5, initial radical cyclization
experiments were undertaken on the basis of our previous
experience in this area.6 The slow dropwise addition (32 h,
syringe pump) of a solution of TTMSS (2 equiv) and AIBN (2
equiv) to a solution of the corresponding substrate 4 or 5 in
benzene/acetonitrile gave only poor yields of 6 or 7. The best
results are summarized in Table 3. Other catalysts (such as
a Method C: 1c (1 equiv), Pd(OAc)2 (20% mol), K2CO3 (5 equiv),
LiCl (1.5 equiv), and n-Bu4Br (1 equiv) in DMF in a sealed tube (110
°C, 48 h). b Method D: N-amidine (1 equiv), Pd(OAc)2 (20 mol %),
K2CO3 (5 equiv), LiCl (1.5 equiv), and n-Bu4NBr (1 equiv) in DMF in
a sealed tube, MW (170 °C, 10 min). c Method E: N-amidine (1 equiv),
Pd(OAc)2 (20 mol %), K2CO3 (5 equiv), LiCl (1.5 equiv), and
n-Bu4NBr (1 equiv) in DMF in a sealed tube, MW (150 °C, 80 min).
SmI2 or InCl312) or experimental conditions proved unsuc-
11
cessful. Although this radical methodology seems to be efficient
in the preparation of the chloro-substituted nuclei 3a and 3d
(Scheme 2, Table 1, entries 2 and 5), 3-aryldipyridopyrazole
derivatives 3c and 6b-d (Y ) CH) were only obtained in low
yields (Table 3, entries 1-4). In particular, 6d was obtained in
only 9% yield as practically all of the starting material had been
reduced and dehalogenated to 15d.
The best results were achieved with electron-rich substrates,
an observation consistent with previous reports,13 although the
increases in the reaction yields were only moderate. The results
obtained were slightly better for the 3-arylpyridopyrazolopy-
razine derivatives 3f and 7b-d (Y ) N) (Table 3, entries 5-8).
It is possible, however, that this effect could only be due to the
easier isolation of the products. Once again, the electron-rich
substituents seem to favor the cyclization process.
nonfunctionalized arene. However, there has been considerable
debate concerning the possible mechanism for the formation
of biaryl bonds on electron-deficient aromatics and heteroaro-
matics, and in this context, works by Echavarren15 and
Fagnou14,16 suggest a reaction course that is incompatible with
a classical electrophilic aromatic substitution. Bearing in mind
the papers cited above, as well as the study reported by
Dominguez et al.17 concerning Heck-like processes, our initial
studies in this area concerned the feasibility of this reaction on
1c, as a readily available model, using experimental conditions
similar to those reported previously.17 Thus, the reaction of 1c
(0.5 mmol) in the presence of Pd(OAc)2 (0.1 mmol, 22 mg),
K2CO3 (2.5 mmol, 0.345 g), LiCl (0.75 mmol, 31 mg), and
n-Bu4NBr (0.33 mmol, 106 mg) in DMF in a sealed tube (110
°C, 48 h) furnished moderate yields of cyclized product 3a
together with some unreacted starting material (Table 4, entry
1, method C). Changes in the catalyst [Pd2(dba)3, PdCl2], base
(K2CO3, 2.5-5.0 mmol; Cs2CO3, 2.5-5.0 mmol), ammonium
salt, and amount of LiCl (0.5-1.5 mmol) or solvent (acetonitrile,
THF) did not improve the reaction yield. In an effort to find
The poor results obtained in the radical cyclization led us to
turn our attention to palladium-promoted C-C bond formation.
However, in the case of 2-pyridyl derivatives, the precursors
required (i.e., 2-pyridylboronic acids or 2-pyridylstannanes) limit
the utility of the process due to their low stability, high price,
and difficult synthesis.
On the other hand, in recent years direct arylation reactions
have emerged as an attractive alternative to typical cross-
coupling reactions.14 In direct arylation, one of the preactivated
partners (typically the organometallic species) is replaced by a
(14) For a recent report see: (a) Campeau, L. C.; Fagnou, K. Chem. Soc.
ReV. 2007, 36, 1058–1068. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174–238. (c) Campeau, L. C.; Fagnou, K. Chem. Commun. 2006,
1253–1264.
(15) Garcia-Cuadrado, D.; Braga, A. A. C; Maseras, F.; Echavarren, A. J. Am.
Chem. Soc. 2006, 128, 1066–1067.
(11) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun. 2004,
2228–2229.
(16) (a) Leclerc, J. P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781–
7786. (b) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020–18021.
(17) Herna´ndez, S.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett. 2003,
5, 1095–1098.
(12) Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981–4983.
´
(13) Nun˜ez, A.; Sa´nchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004,
60, 6217–6224.
J. Org. Chem. Vol. 73, No. 22, 2008 8803

Abet et al.
TABLE 5. Results for the Palladium Arylation from Pyridinium
milder conditions that would be more appropriate for this
nucleus, direct arylation using microwave (MW) heating was
investigated. Microwave experiments were performed in sealed
reaction vessels using a CEM-Discover microwave unit (IR
monitoring of temperature), working at 200-250 W power (170
°C) and using experimental conditions similar to those reported
previously [1c (0.5 mmol) in the presence of Pd(OAc)2 (0.1
mmol, 22 mg), K2CO3 (2.5 mmol, 0.345 g), LiCl (0.75 mmol,
31 mg), and n-Bu4NBr (0.33 mmol, 106 mg) in DMF in a sealed
tube, 170 °C, 10 min]. Under these conditions compound 3a
(Table 4, entry 2, method D) was obtained in satisfactory yield
(72%). When the same cyclization was applied to substrate 4a
(Y ) CH, Z ) C6H5, Table 4, entry 3), 3c was obtained in
73% yield without traces of debrominated 13. However, with
the substrates 4b and 4c (entries 4 and 5), both of which have
electron-donating ring substituents, only poor yields of the
corresponding tricyclic derivatives 6b and 6c were obtained,
probably due to the destabilizing effect exerted by the negatively
charged exocyclic nitrogen. In contrast, when the arylation
process was tried on 4d (R ) 4-MeCOC6H4) (entry 6),
compound 6d was obtained in 53% yieldsa finding consistent
with the π-stabilizing effect exerted by the aryl substituent. In
addition, for compounds 4b-d, small amounts of debrominated
derivatives 13b-d, respectively, were characterized. In the case
of the pyrazine series (compounds 1e and 5a-d, entries 7-16),
however, controversial results were obtained. Attempts to
prepare the tricyclic compound 3d from 1e using different
experimental conditions [methods D (170 °C, 10 min) and E
(150 °C, 80 min), entries 7 and 8, Table 4] did not generate
any cyclized product at all. Once again, the best result was
obtained with the phenyl derivative 5a (entries 9 and 10,
methods D and E, respectively), while the electronic effect of
the 4-aryl substituent seems to have only a small effect on the
cyclization process (entries 11-16). A number of questions arise
from the results of these experiments.
In the first place, some authors have found that an azine
nitrogen on pyridine or pyrazine rings could function as an
effective poison for the palladium catalyst.16 This effect could
be increased by the negatively charged aminide nitrogen and
its mesomeric resonance forms on the azine nitrogen for both
pyridine and pyrazine derivatives. In addition, pyrazine deriva-
tives possess a second free nitrogen atom that could bind and
poison the catalyst, thus reducing the efficiency of the process.
To overcome catalyst inhibition, an excess of palladium catalyst
(20 mol %) was required in these experiments and in all cases
the use of LiCl as an additive was found to be necessary. When
the reaction was carried out in the absence of LiCl, poor yields
of pyrazolo[1,5-a]pyridine were obtained and the direct reduc-
tion of the starting aminide was observed as the main process.18
Second, Fagnou described competitive experiments on N-
oxides in which direct arylation arises from the reaction of the
more electron-deficient pyridine N-oxide.16b It is noteworthy
that in these species (4 and 5, Table 4) resonance contributions
fromthe4-arylsubstituentinduceadifferentstabilizing-destabilizing
effect on the negatively charged N-exocyclic nitrogen. This
nitrogen in turn induces a partial negative charge on the
pyridinium ring, thus reducing its electron-poor character.
Taking into account these premises and the previously reported
work on the synthesis and reactivity of N-acylaminides,5a,19
N-Acyl Derivatives 17-20
entry starting material
Y
Z
3, 6, 7 yielda (%)
1
2
3
4
5
6
7
8
9
17
CH Cl
CH C6H5
CH 4-MeC6H4
CH 4-MeOC6H4
CH 4-MeCOC6H4
3a
3c
6b
6c
6d
3d
3f
7b
7c
7d
81
59
63
70
51
22
59
74
74
66
18a
18b
18c
18d
19
20a
20b
20c
20d
N
N
N
N
N
Cl
C6H5
4-MeC6H4
4-MeOC6H4
4-MeCOC6H4
10
a Method F: N-amidine (1 equiv), Pd(OAc)2 (20 mol %), K2CO3 (5
equiv), LiCl (1.5 equiv), and n-Bu4NBr (1 equiv) in DMF in a sealed
tube, MW (170 °C, 10 min).
additional experiments were carried out on the N-acyl salts
17-20. Acylation on the N-exocyclic nitrogen could partially
neutralize its electron-donating effect on both the pyridinium
and 2-aminopyridine rings. This class of pyridinium salt was
obtained in excellent yield by benzoylation of the corresponding
N-aminides 1c, 1e, 4, and 5, but these compounds were only
moderately stable due to the leaving group behavior of N-
aminides. In particular, compound 19, prepared from N-[(3′-
bromo-5′-chloropyrazin-2-yl]pyridinium aminide 1e, is a stable
yellow solid, but in solution it evolves to the starting aminide
1e through N-acyl bond fission.
Pd arylation experiments on N-acylaminides were performed
using method F (MW, 170 °C, 10 min). In these cases a variety
of substituents are tolerated on the aryl residue, including
electron-donating and electron-withdrawing groups. The results
are shown in Table 5. Although several reaction mechanisms
could be used to explain this transformation, we suggest a
cyclization involving intermediates 21 and in situ N-acyl bond
fission. This mechanism is consistent with the poor yield
obtained for compound 3d from the highly unstable N-
acylaminide 19 because, bearing in mind previous experimental
results (see Table 4, entries 7 and 8), only a fraction of
N-acylaminide 19 present could furnish the tricyclic derivative
3d. However, other tricyclic derivatives were obtained in
satisfactory yields in most of the cases studied.
As far as spectroscopic studies are concerned, the absorption
spectra of dipyridopyrazole derivatives 3a, 6b, and 6d are shown
in Figure 3a. The spectrum of 3a exhibits peaks centered at
324, 364, 382, and 402 nm in THF at 25 °C. The peak located
at 364 nm becomes a shoulder in 6b,d. This red shift increases
in the order 3a, 3c, 6b, 6c, and 6d. This shift is particularly
significant for the most energetic band. The presence of an aryl-
containing π-electron moiety on the dipyridopyrazole nucleus
contributes to extension of the π-delocalization by stabilizing
the system, thus inducing a shift in the π*-π transitions
responsible for such bands to higher wavelength.
(18) Al-Masum, M.; Livinghouse, T. Tetrahedron Lett. 1999, 40, 7731–7734.
(19) Sa´nchez, A.; Nun˜ez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004,
60, 11843–11850.
8804 J. Org. Chem. Vol. 73, No. 22, 2008

Pyrazolopyridine Nucleus with Fluorescent Properties
FIGURE 4. Emission spectra of tricyclic derivatives in THF at 25 °C:
(a) dipyridopyrazole and (b) pyridopyrazolopyrazine derivatives.
Excitation wavelengths are collected in Table 6.
FIGURE 3. Absorption spectra of tricyclic derivatives in THF at 25
°C in the 280-500 nm range: (a) dipyridopyrazole and (b) pyridopy-
razolopyrazine derivatives.
The fluorescence quantum yields (Φf) and lifetimes (τ) for
all of the systems were determined in THF at 25 °C upon
excitation at the selected wavelengths, and the results are given
in Table 6. The Φf values for all the systems cover a wide
rangesfrom 3a, which only fluoresces slightly (0.05), to 3f,
where almost all deactivation takes place in a radiative way
(0.96). Other samples exhibit quite reasonable fluorescence
levels. In general, pyridopyrazolopyrazine derivatives seem to
have higher fluorescence quantum yields than dipyridopyrazole
systems. The fluorescence intensity decays for all samples were
reasonably fitted to a monoexponential, indicating emission from
the singlet excited state in each case. Several photophysical
parameters such as rate constants for radiative (k°r) and
nonradiative (knr) deactivation processes and radiative lifetime
(τ°) are also gathered in Table 6. Fluorescence lifetimes for
pyridopyrazolopyrazines are longer than those of the dipyri-
dopyrazole derivatives. As a consequence, and broadly speaking,
the nonradiative rates of the singlet state are higher for
dipyridopyrazole derivatives than for the pyridopyrazolopyra-
zines ones. This fact is clearly related to the influence of the
additional amino moiety on the spectroscopic properties of
conjugated aromatic systems.9
On the other hand, the absorption spectra displayed by some
of the pyridopyrazolopyrazine derivatives (e.g., 3d, 7b, and 7d,
Figure 3b) are quite similar to the dipyridopyrazole spectra,
although the bands are significantly displaced to higher wave-
lengths. The bathochromic effect exerted by the pyrazinylamino
moiety that forms part of the conjugated aromatic system is
known.9 Thus, the spectrum of 3d shows bands centered at 405
and 424 nm and shoulders at 321 and 385 nm, which were also
displaced to the red with increasing degree of conjugation from
3d to 7d.
The fluorescence emission spectra of both types of pyrazol-
opyridine (see Figure 4) exhibit features similar to those of the
absorption spectra. This is a consequence of the change in the
conjugation upon attaching a π-electron-containing substituent
to the dipyridopyrazole or pyridopyrazolopyrazine rings and/
or on passing from the dipyridopyrazole to pyridopyrazolopy-
razine series.
The emission spectrum of 3a shows two peaks at 410 and
432 nm and a shoulder at approximately 460 nm. Compound
3d, however, exhibits two bands centered at 448 and 468 nm.
Shifts to the red are observed in other members of both series.
J. Org. Chem. Vol. 73, No. 22, 2008 8805

Abet et al.
TABLE 6. Selected Photophysical Properties of the Tricyclic Derivatives
c
sample
Y
Z
εa (M-1 cm-1
)
λexc (nm)
λem (nm)
Φfb
τ (10-9s)
k°rc (108 s-1
)
knr (108 s-1
)
τ° c (10-9 s)
3a
3c
6b
6c
6d
3d
3f
7b
7c
7d
CH
CH
CH
CH
CH
N
N
N
N
N
Cl
C6H5
4-MeC6H4
4-MeOC6H4
4-MeCOC6H4
Cl
8.260
8.930
8.425
7.790
11.990
4.045
9.990
9.875
11.475
14.960
373
383
386
386
386
404
400
400
400
400
410
415
418
423
420
448
449
450
455
455
0.05
0.38
0.29
0.39
0.63
0.38
0.96
0.26
0.83
0.50
2.7
4.7
4.6
4.8
3.4
6.2
5.3
5.2
5.4
5.1
0.19
0.81
0.63
0.81
1.85
0.61
1.81
0.50
1.54
0.98
3.52
1.32
1.54
1.27
1.09
0.10
0.08
1.42
0.32
0.98
54.0
12.4
15.9
12.3
5.4
16.3
5.5
20.0
6.5
C6H5
4-MeC6H4
4-MeOC6H4
4-MeCOC6H4
10.2
a Measured at the λmax of the excitation band. b Fluorescence quantum yields (Φf) were determined in THF at 25 °C, using quinine sulfate/0.1 M
sulfuric acid as the standard, upon selection of λexc and λem (maximum of emission) as the excitation and emission wavelengths. c Some photophysical
parameters: rate constants for radiative (k°r) and nonradiative (knr) deactivation processes and radiative lifetime (τ°).
4H), 7.53 (m, 3H), 7.28 (d, 2H, J ) 7.9 Hz), 2.38 (s, 3H); 13C
NMR (75 MHz, CD3OD) δ 170.1, 150.2, 150.0, 148.8, 148.3, 146.2,
142.9, 141.9, 135.4, 130.8, 130.7, 130.6, 130.5, 130.4, 129.3, 128.5,
121.0, 21.6. HRMS: m/z calcd for C24H19BrN3OCl (M+) 444.0708,
found 444.0694.
General Procedure for the Preparation of Tricyclic
Derivatives 3, 6, and 7 through a Radical Pathway. Method
B. A solution of TTMSS (0.149 g 0.6 mmol) and AIBN (0.099 g,
0.6 mmol) in dry benzene (12 mL) was diluted with dry acetonitrile
(28 mL). The resulting solution was added dropwise by a syringe
pump during 32 h to a stirred dispersion of potassium carbonate
(0.083 g, 0.6 mmol) and the corresponding aminide (0.3 mmol) in
dry acetonitrile (50 mL) at 80 °C (bath temperature), under an
atmosphere of dry argon. The mixture was stirred for 48 h at 80
°C, and all of the aminide had been consumed (TLC analysis). The
reaction mixture was allowed to cool to room temperature and
concentrated. The crude product was purified by flash chromatog-
raphy and crystallization.
General Procedure for the Preparation of Tricyclic
Derivatives 3, 6, and 7 by Pd Arylation-Microwave Irradia-
tion. Methods D and E. A suspension of the corresponding
N-amidine (0.5 mmol), Pd(OAc)2 (0.1 mmol, 22 mg), K2CO3 (2.5
mmol, 0.345 g), LiCl (0.75 mmol, 31 mg), and n-Bu4NBr (0.33
mmol) in degassed dry DMF (4.20 mL), in a sealed tube under an
atmosphere of dry argon, was irradiated in a microwave oven
(CEM-Discover, IR temperature monitoring) working at 250-200
W power [170 °C, 10 min (method D), 150 °C, 80 min (method
E)]. The reaction mixture was allowed to cool to room temperature,
and distilled water (5 mL) was added. After extraction with EtOAc
the organic extracts were dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel followed by crystallization.
Conclusion
Some results on the synthesis of substituted dipyridopyrazoles
and pyridopyrazolopyrazines, obtained through an intramolecular
radical pathway from pyridinium N-aminides, are described. The
methodology seems to be efficient for the preparation of 3-chloro
derivatives. The method does, however, produce poor yields of
3-aryl derivatives. In these cases, Pd direct arylation of 3-aryl
N-aminides or their N-acyl derivatives using microwave irradia-
tion furnished better results. A preliminary study of the
fluorescence properties of the materials is also reported.
Experimental Section
General Procedure for the Preparation of N-[(5′-Aryl-3′-
bromo-)azin-2′-yl]pyridinium Aminide Derivatives 4 and 5. A
solution of NBS (0.213 g, 1.2 mmol) in CH2Cl2 (14 mL) was added
dropwise to a stirred solution of N-[(5′-aryl)azin-2′-yl]pyridinium
aminide 13 or 14 (1 mmol) in CH2Cl2 (14 mL) at room temperature.
The reaction mixture was stirred at room temperature until the
starting material had been consumed (TLC analysis). The solvent
was evaporated, and the residue was purified by flash chromatog-
raphy on silica gel followed by crystallization, yielding the
corresponding products 4 and 5.
Data for N-[(3′-bromo-5-phenyl)pyridin-2′-yl]pyridinium
Aminide (4a): reaction time 10 min; chromatography, EtOH; 76%;
orange solid (EtOAc); mp 154-156 °C; IR (KBr) νmax 1586, 1469,
1435, 1384, 1154, 1032, 789 cm-1; 1H NMR (300 MHz, CD3OD)
δ 8.73 (d, 2H, J ) 5.1 and 1.3 Hz), 8.18 (tt, 1H, J ) 7.9 and 1.3
Hz), 7.97 (d, 1H, J ) 2.2 Hz), 7.91 (m, 3H), 7.49 (dd, 2H, J ) 8.1
and 1.4 Hz), 7.40 (dd, 2H, J ) 8.1 and 7.3 Hz), 7.26 (tt, 1H, J )
7.3 and 1.4 Hz); 13C NMR (75 MHz CD3OD) δ 161.8, 145.9, 143.9,
139.6, 139.3, 138.6, 129.8, 128.5, 127.4, 126.3, 126.0, 106.6; MS
(EI) m/z (relative intensity) 327, 325 (M+, 52.3, 52.4), 326 (100),
246, 244 (4.5, 4.7), 167(22), 140 (97), 79 (23). Anal. Calcd for
C16H12BrN3 (326.20): C, 58.91; H, 3.71; N, 12.88. Found: C, 58.54;
H, 3.66; N, 12.97.
General Procedure for the Preparation of N-acyl-
pyridinium Salts 17-20. 4-Methylbenzoyl chloride (0.170 g, 1.1
mmol) was added dropwise to a stirred solution of N-[(5′-
substituted-3′-bromo)azin-2′-yl]pyridinium aminide derivatives 1c,e,
4, and 5 (1 mmol) in dry acetone (7 mL) at room temperature. The
reaction mixture was stirred at room temperature until all the starting
material had been consumed (TLC analysis). The suspension was
filtered, and the solid was washed with EtOAc and crystallized from
ethanol, yielding compounds 17-20.
Data for N-[(3′-bromo-5′-phenylpyridin-2′-yl)(4′′-methyl-
benzoyl)amino]pyridinium Chloride (18a): yellow solid; 98%;
mp 165-167 °C; IR (KBr) νmax, 3414, 3057, 1701, 1610, 1475,
1260, 1084, 831, 767 cm-1; 1H NMR (300 MHz, CD3OD) δ 9.56
(d, 2H, J ) 5.8 Hz), 8.93 (t, 1H, J ) 7.7 Hz), 8.82 (d, 1H, J ) 1.5
Hz), 8.55 (d, 1H, J ) 1.5 Hz), 8.41 (at, 2H, J ) 7.1 Hz), 7.70 (m,
General Procedure for the Preparation of Tricyclic
Derivatives 3, 6, and 7 by Pd Arylation-Microwave Irradia-
tion. Method F. A suspension of the corresponding pyridinium
salt 17-20 (0.5 mmol), Pd(OAc)2 (0.1 mmol, 22 mg), K2CO3 (2.5
mmol, 0.345 g), LiCl (0.75 mmol, 31 mg), and n-Bu4NBr (0.33
mmol) in degassed dry DMF (4.20 mL), in a sealed tube under an
atmosphere of dry argon, was irradiated in a microwave oven
(CEM-Discover, IR monitoring temperature), working at 250-200
W power (170 °C, 10 min). The reaction mixture was allowed to
warm to room temperature, and distilled water (5 mL) was added.
After extraction with EtOAc, the organic extracts were dried
(MgSO4) and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel followed by crystallization.
Data for 3-(4′′-methylphenyl)dipyrido[1,2-b:3′,2′-d]pyra-
zole (6b): chromatography, hexane/EtOAc (1:1), 32% (method B),
40% (method D), 63% (method F); yellow solid (EtOAc); mp
213-214 °C; IR (KBr) νmax 2918, 1642, 1504, 1437, 1288, 1258,
1
823, 741. cm-1; H NMR (300 MHz, CDCl3) δ 9.13 (d, 1H, J )
2.4 Hz), 8.86 (d, 1H, J ) 6.9 Hz), 8.50 (d, 1H, J ) 2.4 Hz), 8.13
(d, 1H, J ) 8.6 Hz), 7.56 (d, 2H, J ) 8.2 Hz), 7.46 (dd, 1H, J )
8806 J. Org. Chem. Vol. 73, No. 22, 2008

Pyrazolopyridine Nucleus with Fluorescent Properties
8.6 and 7.0 Hz), 7.28 (m, 3H), 2.41 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 158.9, 152.9, 137.1, 135.7, 135.0, 129.7, 128.9, 128.8,
127.0, 126.1, 123.4, 118.4, 117.2, 21.2; MS (EI) m/z (relative
intensity) 259 (M+, 100), 231 (11) 216 (5) 129 (3) 78 (6). Anal.
Calcd for C17H13N3 (259.31): C, 78.74; H, 5.05; N, 16.20. Found:
C, 78.61; H, 5.52; N, 15.99.
Alcala´ (UAH GC2005/006) for financial support and the
Ministerio de Educacio´n y Ciencia (MEC) for two studentships
(V.A. and A.N.).
Supporting Information Available: Experimental proce-
dures and copies of 1H and 13C spectra for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank D. Marco Antonio Ramirez for
his assistance in obtaining the UV spectra. We thank the
Comisio´n Interministerial de Ciencia y Tecnolog´ıa (CICYT-
BQU2001-1508 and CTQ2005-08902) and the Universidad de
JO801549U
J. Org. Chem. Vol. 73, No. 22, 2008 8807