N-azinylpyridinium N-aminides: An approach to pyrazolopyridines via an intramolecular radical pathway

Article abstract of DOI:10.1055/s-2002-32596

Intramolecular radical arylation, under thermal conditions, to a π-deficient pyridinium, linked to a π-excessive 2-azinyliminopyridine moiety is described. The method allows a new entry to pyrazolo[1,5-a]pyridine nucleus.

Full text of DOI:10.1055/s-2002-32596

LETTER
1093
N-Azinylpyridinium N-Aminides: An Approach to Pyrazolopyridines via an
Intramolecular Radical Pathway
An
A
pproachtoPy
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razolop
a
yridines via
c
anIntramo
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lecular Rad
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ical Pa
i
thway Nuñez, Aránzazu García de Viedma, Valentín Martínez-Barrasa, Carolina Burgos, Julio Alvarez-Builla*
Departamento de Química Orgánica, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain
Fax +34(91)88546 86; E-mail: julio.alvarez@uah.es
Received 3 May 2002
heteroaromatic compounds, via an ipso substitution radi-
Abstract: Intramolecular radical arylation, under thermal condi-
tions, to a -deficient pyridinium, linked to a -excessive 2-azi-
nyliminopyridine moiety is described. The method allows a new
entry to pyrazolo[1,5-a]pyridine nucleus.
cal mechanism are known,12 to our knowledge, only one
method of arylation of quaternized heteroaryl substrates
has been published. In this case, a pyridinium radical was
added onto another aromatic nucleus, with subsequent
rearomatisation of the aryl ring.7
Key words: aminides, pyrazolopyridines, intramolecular radical
reactions, ylides
The generation and subsequent reactions of aryl radicals,
derived from aryl halides using tri-n-butyltin hydride
(Bu3SnH) and azobisisobutyronitrile (AIBN) is now well
documented, and several syntheses, based on aryl radical
cyclisations have been reported.1 Few examples of het-
eroaryl radicals are known, and presumably they would
behave similarly to aryl radicals, since the lone electron
would be in an orbital orthogonal to the aromatic -system
and hence, its nature ( -excessive or -deficient) should
have little or no effect on the reactivity of such radicals.2
Particular attention has been devoted to pyridyl radicals;
both Snieckus3 and Nadin4 have reported pyridyl radical
cyclisations. Harrowven5 has published some papers,
which include pyridyl radical cyclisations and aryl radical
cyclisations onto pyridines. Jones6 has disclosed the use
of radicals derived from 3-bromopyridine and the exten-
sion of this chemistry to pyridinium radicals.7 However,
to the best of our knowledge, pyrazinyl radical cyclisa-
tions have not been reported before.
Scheme 1
On the other hand, alkylation of heteroaromatic bases via
a radical pathway is an useful synthetic method with a
broad potential. Radical alkylations onto heteroaromatic
systems, under oxidative conditions, were initially studied
by Minisci’s group,8 but more recently, Minisci and co-
workers9 and Togo and co-workers10 have reported inter-
molecular radical alkylations onto heteroaromatic sub-
strates by alkyl halides, using tris(trimethylsilyl)silane
(TTMSS) as mediator of the radical process. These au-
thors have shown that the heterocyclic ring needs to bear
a positive charge for successful attack by the nucleophilic
carbon radicals.
In the course of our studies on the reactivity of heteroaryl-
stabilized cycloimonium ylides [i.e. pyridinium N-(2 -azi-
nyl)aminides 1, (Scheme 1)],13 we attempted the intramo-
lecular arylation of ylide 1, through the radical 2. We
expected to obtain the bipyridine 3, by a reaction pathway
involving a 5-exo-trig cyclisation, and then, rupture of N-
N bond, as previously described.13c To our surprise, prod-
uct 3 was not detected, and only reduction compounds 4
and cyclisation products 5 were observed, the last ones
corresponding either to dipyrido[1,2-b; 3 , 2 -d]pyrazole
nucleus (compounds 5a–c, Y = CH) or pyrido[1 ,2 :
2,3]pyrazole[5,4-b]pyrazine derivatives (compounds 5d–
f, Y = N), obtained from ylides 1c,d or 1e,f, respectively
(Scheme 1). The reaction could follow a similar course to
those postulated by Murphy11 to generate the final prod-
uct. For the dipyridopyrazole nucleus, only few examples,
obtained by alternative ways, are known.14 The prepara-
tion of the unsubstituted nucleus, however, (compound
5b, Z = H) has not been reported to date. No references
have been found for the pyrazino derivatives (compounds
The first example of intramolecular radical addition to
quaternized pyridinium salts was described by Murphy
and co-workers11 who exploited the non oxidative chem-
istry of Bu3SnH. Although arylations of aromatic and
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1093,1096,ftx,en;G121ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1094
A. Nuñez et al.
LETTER
5d–f). In this paper we wish to report our preliminary re- As indicated in Scheme 1 and the Table, the dipyridopy-
sults on the intramolecular radical arylation of stable het- razole 5a was satisfactorily obtained by slow dropwise ad-
erocyclic betaine systems, using TTMSS/AIBN under dition, by a syringe pump, of a solution of TTMSS and
thermal conditions to supply this kind of pyridopyrazole AIBN in a mixture of dry benzene/acetonitrile, to a disper-
derivatives. This study represents the first example of an sion, at 80 ºC, of potassium carbonate and the halogenated
aryl radical addition to a -deficient pyridinium fragment aminide 1c in dry acetonitrile (entry 1, Method A).15 The
linked to a -excessive 2-azinyliminopyridine moiety.
reaction did not go to completion when only 1 equivalent
of each TTMSS and AIBN were employed (entry 2, Meth-
od B), as previously reported.11a When the reaction was
carried out in the absence of potassium carbonate, poor
yields of pyrazolo[1,5-a]pyridine 5a were observed, and
the direct reduction of aminide 1c (to give 4a) appeared as
the main process (entry 3, Method C).16 Although several
reaction mechanisms could explain this transformation,
we suggest what appears as the simplest pathway, involv-
ing a 5-exo/endo-trig cyclisation, as described in
Scheme 2, which agrees with the role of potassium car-
bonate and with the production of arylated compound 5
during the reaction process.17
Table Radical Cyclisation for Compound 1c–f
En- Starting
try amidine
Cyclizated Yielda Reduced
Yielda Method
(%)
product
(%)
product
1
2
3
4
5
6
Z = Cl, 1c
Z = Cl, 1c
Z = Cl, 1c
Z = Cl, 5a 56
Z = Cl, 5a 18
Z = Cl, 4a
5
2
A
B
C
A
A
D
When the reaction was carried out in benzene and the
starting aminide has an additional bromine (e.g. N-
aminides 1d and 1f, entries 4, 5 and 8, 9 respectively) a
concomitant phenylation was observed.18 However, when
the reaction was performed in THF/acetonitrile (entry 6,
Method D), only poor yields of the cyclised compounds
were obtained, probably due to H abstraction from the sol-
vent. In similar manner, aminides 1e,f reacted using
Method A, to afford pyridopyrazolepyrazine derivatives
5d–f (entries 7–9, Table).
Z = Cl, 5a
2
60
Z = Br, 1d Z = H, 5b
21
Z = H, 4b 21
Z = Br, 1d Z = Ph, 5c 23
Z = Br, 1d Z = H, 5c 20
19
Preparation of starting aminides 1a,b (Scheme 3) has
been previously described from 2,4-dinitrophenyl pyri-
dinium chloride and the corresponding 2-heteroaryl hy-
drazine, producing the corresponding hydrazones. Then,
cyclisation in acetic acid and treatment with potassium
carbonate provides the stable aminides 1a,b in good
yields.13a Halogenation of 1a under very mild conditions,
with N-chlorosuccinimide (NCS), provides the chloro de-
rivative 8a,13b which was halogenated again by treatment
with N-bromosuccinimide (NBS), yielding the dihalo de-
rivative 1c (Z = Cl, Method E, Scheme 3). When this pro-
cess was carried out using a two molar excess of NBS, the
dibromoaminide 1d was obtained in one step (Z = Br,
Method F, Scheme 3). In a similar way, halogenation of
aminide 1b yielded the halo derivatives 1e,f.19
7
8
9
Z = Cl, 1e
Z = Br, 1f
Z = Br, 1f
Z = Cl, 5d 52
Z = Cl, 4c 10
Z = H, 4d 20
A
A
A
Z = H, 5e
Z = Ph, 5f
24
20
a Yields refer to isolated pure product. All the products were identified
by spectroscopic and literature data. Method A: TTMSS (2 equiv),
AIBN (2 equiv) in 40 mL of dry (acetonitrile:benzene, 7:3) were add-
ed during 16 h to a dispersion of potassium carbonate (2 equiv) and the
corresponding aminide 1c–f (1 equiv) in 50 mL of dry acetonitrile,
80 ºC, 24 h. Method B: TTMSS (1 equiv), AIBN (1 equiv) in 20 mL
of dry (acetonitrile:benzene, 7:3) were added during 8 h to a dispersion
of potassium carbonate (2 equiv) and the aminide 1c (1 equiv) in 50
mL of dry acetonitrile, 80 ºC, 24 h. Method C: TTMSS (2 equiv),
AIBN (2 equiv) in 40 mL of dry (acetonitrile:benzene, 7:3) were add-
ed during 16 h to a solution of aminide 1c (1 equiv) in 50 mL of ace-
tonitrile, 80 ºC, 24 h. Method D: TTMSS (2 equiv), AIBN (2 equiv)
in 40 mL of dry (acetonitrile:THF, 7:3) were added during 16 h to a
dispersion of potassium carbonate (2 equiv) and the aminide 1d
(1 equiv) in 50 mL of dry acetonitrile, 80 ºC, 24 h.
In conclusion, it has been shown that it is possible to gen-
erate the pyrazolepyridine nucleus from N-azynilpyridin-
ium N-aminides through a radical pathway, using
TTMSS/AIBN under thermal conditions. Further experi-
ments are in progress to extend the process as a general
methodology to other azine derivatives.
Scheme 2
Synlett 2002, No. 7, 1093–1096 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Approach to Pyrazolopyridines via an Intramolecular Radical Pathway
1095
Vazquez, S. Synlett 2000, 475. (e) Studer, A.; Bossart, M.;
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Alvarez-Builla, J.; Fajardo, M.; Gomez-Sal, P.; Gago, F.
Tetrahedron 1994, 50, 4995. (b) Burgos, C.; Delgado, F.;
García-Navío, J. L.; Izquierdo, M. L.; Alvarez-Builla, J.
Tetrahedron 1995, 51, 8649. (c) García de Viedma, A.;
Martínez-Barrasa, V.; Burgos, C.; Izquierdo, M. L.;
Alvarez-Builla, J. J. Org. Chem. 1999, 64, 1007.
(d) Martínez-Barrasa, V.; Delgado, F.; Burgos, C.; García-
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Tetrahedron 2000, 56, 2481.
(14) (a) Kakehi, A.; Ito, S.; Ono, T.; Miyazima, T. Chem. Lett.
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Behrens, M.; Durst, T.; Grashey, R.; Huisgen, R.; Schiffer,
R.; Temme, R. Eur. J. Org. Chem. 1998, 379.
(15) Typical Procedure, Method A: 3-Chloro-dipyrido[1,2-b;
3 2 -d]pyrazole 5a: A solution of tris(trimethylsilyl)silane
(TTMSS) (0.149 g 0.6 mmol) and AIBN (0.099 g, 0.6 mmol)
in 6 mL of dry benzene was diluted with 14 mL of dry
acetonitrile. The resulting solution was added dropwise by a
syringe pump during 16 h, to a dispersion of potassium
carbonate (0.083 g, 0.6 mmol) and the aminide 1c (0.062 g,
0.3 mmol) in 50 mL of dry acetonitrile, stirred at 80ºC (bath
temperature), under an atmosphere of dry argon. After being
stirred at the same temperature until 24 h, full consumption
of 1c was observed (TLC analysis). The reaction mixture
was allowed to warm to r.t. and distilled water (5 mL) was
added. The organic extracts were dried (Na2SO4) and
concentrated in vacuo, providing a crude product that was
purified by flash chromatography [silicagel, ethyl
Scheme 3
Acknowledgement
We acknowledge support of this work by the Comisión Intermini-
sterial de Ciencia y Tecnología (CICYT, project 2FD97-1248),
Universidad de Alcalá, (project UAH2002/026) and the Comunidad
de Madrid for a grant to one of us (A.G.V).
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acetate:hexane (1:1) (Rf 0.30)]. Yellow solid (0.034 g,
56% yield, toluene, mp = 212–214 ºC). 1H NMR (300 MHz,
CDCl3): = 8.87 (ddd, 1 H, J = 6.9, 1.2 and 1.1 Hz), 8.80 (d,
1 H, J = 2.4 Hz), 8.39 (d, 1 H, J = 2.4 Hz), 8.11 (ddd, 1 H,
J = 8.5, 1.4 and 1.1 Hz), 7.51 (ddd, 1 H, J = 8.5, 7.3 and 1.2
Hz), 7.33 (ddd, 1 H, J = 7.3, 6.9 and 1.4 Hz). 13C NMR (75
MHz, CDCl3): = 157.7, 152.2, 146.5, 134.4, 129.0, 127.7,
124.0, 122.8, 118.5, 117.8. IR (KBr): 2922, 1706, 1641,
1437 cm–1. MS (CI): m/z = 204, 206 ([M+ + 1], 100, 32).
EIMS HR: calcd for C10H635ClN3: [M+] 203.0246. Found:
203.0240.
(4) Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40, 4073.
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Tetrahedron Lett. 2001, 42, 9061. (e) Harrowven, D. C.;
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8049. (b) Jones, K.; Fiumana, A.; Escudero-Hernandez, M.
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(17) Potassium carbonate could abstract a proton from the
substituted dihydropyridine radical 6 (Scheme 2), to form
the radical 7, that would be converted in the arylated
compound 5 (see ref.15b,c). In the absence of potassium
carbonate, dihydropyridine radical 6 did not evolve to 5, and
only decomposition products and N-N reduction compounds
were observed.
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(19) Typical Procedure, Method E: Pyridinium N-(3 -bromo-
5 -chloropyrazin-2 -yl)aminide 1e: To a solution of
pyridinium (N-(2 -pyrazinyl)aminide 1b (0.172 g, 1 mmol)
Synlett 2002, No. 7, 1093–1096 ISSN 0936-5214 © Thieme Stuttgart · New York

1096
A. Nuñez et al.
LETTER
in dry dichloromethane (5 mL) stirred at 0 ºC was added
dropwise a solution of N-chlorosuccinimide (NCS) (0.160 g,
1.2 mmol) in dry dichloromethane (10 mL). The reaction
mixture was stirred for 1 h at the same temperature, allowed
to warm up to r.t. and stirring for a further 24 h. The solvent
was evaporated and the residue was purified by flash
chromatography [silicagel, ethanol, (Rf 0.25)] to yield
0.149 g (72%) of pyridinium N-(5 -chloropyrazin-2 -
yl)aminide 8b: Yellow solid (ethyl acetate, mp = 158–161
ºC). 1H NMR (300 MHz, CD3OD): = 8.76 (dd, 2 H, J = 5.7
and 1.3 Hz), 8.13 (tt, 1 H, J = 8.2 and 1.3 Hz), 7.86 (dd, 2 H,
J = 8.2 and 5.7 Hz), 7.62 (d, 1 H, J = 1.4 Hz), 7.60 (d, 1 H,
J = 1.4 Hz). 13C NMR (75 MHz, CD3 OD): = 160.8, 145.0,
140.3, 139.5, 135.4, 132.1, 128.7. Anal. Calcd for
pyrazin-2 -yl)aminide 8b (0.206 g, 1 mmol) in dry dichloro-
methane (5 mL) stirred at r.t., was added dropwise a solution
of N-bromosuccinimide (NBS) (0.214 g, 1.2 mmol) in dry
dichlorometane (10 mL). The reaction mixture was stirred
until 24 h at the same temperature, the solvent was eva-
porated and the residue was purified by flash chromato-
graphy [silicagel, ethanol (Rf 0.75)] to yield 0.231 g (81%)
of pyridinium N-(3 -bromo-5 -chloropyrazin-2 -yl)aminide
1e: Yellow-orange solid (ethyl acetate, mp = 203–205 ºC).
1H NMR (300 MHz, CD3OD): = 8.70 (dd, 2 H, J = 6.9 and
1.4 Hz), 8.25 (tt, 1 H, J = 7.8 and 1.4 Hz), 7.93 (dd, 2 H,
J = 7.8 and 6.9 Hz), 7.60 (s, 1 H). 13C NMR (75 MHz,
CD3OD): = 158.4, 146.2, 141.4, 139.6, 130.8, 129.0,
126.0; Anal. Calcd for C9H6BrClN4: C, 37.86; H, 2.12; N,
19.62. Found: C, 38.01; H, 2.43; N, 19.31.
C9H7ClN4: C, 52.31; H, 3.41; N, 27.11. Found: C, 52.32; H,
3.69; N, 27.31. To a solution of pyridinium N-(5 -chloro-
Synlett 2002, No. 7, 1093–1096 ISSN 0936-5214 © Thieme Stuttgart · New York