Regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4] triazolo-[4,3-a]pyrazines. Reactivity of aliphatic and aromatic hydrazides

Article abstract of DOI:10.1021/jo0478398

(Chemical Equation Presented) The one-pot synthesis of new 9-alkyl-6-chloropyrido[3,2-e]-[1,2,4]triazolo[4,3-a]pyrazines has been achieved. Hydrazides regioselectively reacted as nucleophiles with the 3-chloro substituent of 2,3-dichloropyrido[2,3-6]pyrazine. An intramolecular cyclization afforded the tricycle nonxanthine adenosine receptor antagonists.

Full text of DOI:10.1021/jo0478398

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Regioselective One-Pot Synthesis of
9-Alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo-
[4,3-a]pyrazines. Reactivity of Aliphatic
and Aromatic Hydrazides
Asier Unciti-Broceta,† Maria J. Pineda-de-las-Infantas,†
Juan J. D´ıaz-Mocho´n,†,§ Romeo Romagnoli,‡
Pier G. Baraldi,‡ Miguel A. Gallo,† and
Antonio Espinosa*,†
FIGURE 1. The structure of 4-(diethylamino)[1,2,4]triazolo-
[4,3-a]quinoxaline (CP-41,475), a tricycle nonxanthine adeno-
sine antagonist.
dichloroquinoxaline.7,8 Following the reaction with hy-
drazine, triethyl orthoalkanoates are used to accomplish
the ring closure (Scheme 1). This methodology suffers
from drawbacks such as moderate yields, side product
formation, and the two-step synthesis of the fused triazolo
ring. Other strategies have also been reported but
without major improvements.9,10
Departamento de Quı´mica Farmace´utica y Orga´nica,
Facultad de Farmacia, Campus Cartuja s/n,
18071 Granada, Spain, and Dipartimento di Scienze
Farmaceutiche, Via Fossato di Mortara 17/19,
I/44100, Ferrara, Italy
aespinos@ugr.es
Herein, we report the synthesis of 9-alkyl-6-chloro-
pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines which were
obtained from 2,3-dichloropyrido[2,3-b]pyrazine 3 in a
single step. A first approach to obtain these fused
heterocycles starting from 3 as depicted in Scheme 1 also
resulted in low yield reactions and side product forma-
tion. We devised a new synthetic pathway to overcome
some of the previous drawbacks and which provided a
more straightforward and flexible synthesis of new
tricycle nonxanthine adenosine antagonists. The cyclo-
condensation involved nucleophilic displacement followed
by cyclization using several aliphatic and aromatic hy-
drazides. The key step was the regioselective nucleophilic
aromatic substitution that gave rise to unique isomers
before ring closure.
The dichloro derivative 3 was prepared from com-
mercially available 2,3-diaminopyridine 1 in very high
yields, following the procedure outlined in Scheme 2.
Synthesis of the 5-azaquinoxaline ring were achieved by
using oxalic acid in 4 N HCl aqueous solution.11 Halo-
genation of 2 by treatment with thionyl chloride and
DMF in catalytic amounts provided 3.12
Following reaction between 3 and aliphatic hydrazides
unique tricyclic isomers were isolated in good yields.13
The reaction that leads to tricycles 4a-e proceeded
through the nucleophilic attack of the corresponding
aliphatic hydrazide to the more electrophilic position of
the 2,3-dichloropyrido[2,3-b]pyrazine system (Scheme 3).
Therefore, the position of the nitrogen contained in the
pyrido ring dictates the regiochemistry of the reaction.
The corresponding hydrazones14 then afford compounds
Received December 7, 2004
The one-pot synthesis of new 9-alkyl-6-chloropyrido[3,2-e]-
[1,2,4]triazolo[4,3-a]pyrazines has been achieved. Hydrazides
regioselectively reacted as nucleophiles with the 3-chloro
substituent of 2,3-dichloropyrido[2,3-b]pyrazine. An intra-
molecular cyclization afforded the tricycle nonxanthine
adenosine receptor antagonists.
The tricyclic nonxanthine adenosine antagonists are
nitrogen-containing heterocycles based on the adenosine
moiety.1-3 During an empirical screening effort, it was
discovered that 4-(diethylamino)[1,2,4]triazolo[4,3-a]qui-
noxaline4 (CP-41,475, Figure 1) was effective in reducing
immobility in rats following a single dose.5 These results
suggested that compounds with structures related to this
family might therefore be rapid-onset antidepressants.
Furthermore, biochemical studies early on indicated that
these compounds displayed adenosine receptor affini-
ties.1,5 Currently, this class of compounds is being inves-
tigated and the results have been reported.6
The traditional synthetic strategy for these fused
heterocycles involves a two-step approach from 2,3-
(7) Shiho, D.; Tagami, S. J. Am. Chem. Soc. 1960, 82, 4044-4054.
(8) Sarges, R. U.S. Patent 4495187, 1985.
* To whom the correspondence should be addressed. Fax: +34-958-
243845. Phone: +34-958-243850.
(9) Bradan, M. M.; Abouzid, K. A. M.; Hussein, M. H. M. Arch.
Pharm. Res. 2003, 26, 107-113.
† Universidad de Granada.
(10) Rashed, N.; El Massry, A. M.; El Ashry, E. S. H.; Amer, A.;
Zimmer, H. J. Heterocycl. Chem. 1990, 27, 691-694.
§ Current address: School of Chemistry, Highfield Campus,
Southampton, SO17 1BJ, UK.
(11) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S.
J. Med. Chem. 1997, 40, 2053-2063.
‡ Universita` di Ferrara.
(1) Trivedi, B. K.; Bruns, R. F. J. Med. Chem. 1988, 31, 1011-1014.
(2) Mu¨ller, C. E.; Stein B. Curr. Pharm. Des. 1996, 2, 501-530.
(3) Jacobson, K. A.; Suzuki, F. Drug Dev. Res. 1990, 39, 289-300.
(4) This compound was initially prepared by Dr. S. B. Kadin at Pfizer
Central Research for antiallergy testing.
(12) Ohmori, J.; Kubota, H.; Shimizu-Sasamata M.; Okada M.;
Sakamoto, S. J. Med. Chem. 1996, 39, 1331-1338.
(13) To a solution of 2,3-dichloropirido[2,3-b]pirazine 3 (0.2 g, 1
mmol) and suitable hydrazide (1 mmol) in THF or acetonitrile (10 mL)
was added dropwise a solution of concentrated H2SO4 (54 µL, 1 mmol)
in THF or acetonitrile (5 mL) and the mixture was refluxed for 20 h.
(14) These compounds were observed by TLC. The bigger the
substituent R, the higher the stability of the corresponding hydrazones.
(5) Sarges, R.; Howard, H. R.; Browne, R. G.; Lebel L. A.; Seymour,
P. A.; Koe, B. K. J. Med. Chem. 1990, 33, 2240-2254.
(6) Matuszczak, B.; Mueller, C. E. PCT Int. Appl. WO 03/053973.
10.1021/jo0478398 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/05/2005
2878
J. Org. Chem. 2005, 70, 2878-2880

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SCHEME 1. Traditional Synthesis of 4-Chlorotriazolo[4,3-a]quinoxalines
SCHEME 2. Synthesis of
2,3-Dichloropyrido[2,3-b]pyrazine 3
SCHEME 4. Synthesis of Tetracycle 5
SCHEME 3. Regioselective Synthesis of 4a-e
SCHEME 5. Regioselective Synthesis of 6a,b and
7a,b13,17
the same compound 5, better kinetics were observed
when DBU was used.16
This suggests that once the tricycle is formed the
halogenated carbon is able to react with a second
molecule of hydrazide obtaining a tetracyclic system.
Also, if hydrazides were not completely consumed before
cyclization takes place, tetracyclic systems would be
identified as the main side product. Therefore, the
reactivity of the 6-carbon position in the monochloro
compound 4 is greater than the 3-carbon position in the
dichloro derivative 3.
As mentioned before, the ring closure reaction con-
ducted under basic conditions was faster. However, the
higher reactivity of the tricycles 4 to nucleophiles caused
a higher ratio of the tetracycle as side product. Further-
more, tricycles with a hydroxy group in the 6-carbon
position have been isolated under these conditions and
therefore acidic conditions are the best in order to
improve the yields. However, hydrazides with electron
withdrawing substituents under acid conditions also lead
to the substitution of the chloro at the 6-carbon position
by a hydroxy group (see the synthesis of 6a,b in Scheme
4a-e at high temperature. The cyclization proceeds
either in acidic, neutral, or basic conditions.
The structures of tricycles 4a-e were undoubtedly
established by nuclear magnetic resonance (NMR) spec-
troscopy and mass spectroscopy analysis. Additionally,
the structure of compound 4d was assigned by X-ray
crystallography, verifying the nucleophilic attack of the
hydrazide to the 3-carbon of 3.
Hydrazides with bulky substituents were less prone
to cyclize due to steric reasons. Therefore compound 4d
was achieved at higher refluxing temperatures in aceto-
nitrile.15 Although cyclization kinetics are affected by the
substituent size, in this case nucleophilic substitution
was improved because of the increased nucleophilicity of
the hydrazides.
To study the reactivity of the tricycles 2 equiv of
hydrazide of the cyclopropanecarboxylic acid were used
to react with the dichloro derivative 3. Following these
conditions a unique compound was isolated whose struc-
ture was assigned to be the tetracyclic system 5 (Scheme
4). This reaction was carried out with either acidic
conditions, using H2SO4, or basic conditions, using DBU.
Compound 5 was assigned by nuclear magnetic resonance
spectroscopy, mass spectroscopy analysis, and X-ray
crystallography. Although both conditions gave rise to
(16) To a solution of 2,3-dichloropirido[2,3-b]pirazine 3 (0.2 g, 1
mmol) and the suitable hydrazide (2 mmol) in acetonitrile (10 mL) was
added dropwise a solution of DBU (0.285 mL, 2 mmol) in acetonitrile
(5 mL). The mixture was refluxed for 3 h.
(17) To a solution of 2,3-dichloropirido[2,3-b]pirazine 3 (0.2 g, 1
mmol) and the benzoic or parachlorobenzoic hydrazide (1 mmol) in
acetonitrile (10 mL) was added dropwise a solution of DBU (0.285 mL,
2 mmol) in acetonitrile (5 mL). The mixture was refluxed with stirring
for 3 h.
(15) Reactions were monitorized by TLC.
J. Org. Chem, Vol. 70, No. 7, 2005 2879

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TABLE 1. Summary of the Conditions Used To Obtain
Tricyclic Compounds
higher the temperature required to obtain the final
tricycles, and therefore the smaller the amount of tetra-
cycle obtained as a side product. If electron withdrawing
hydrazides are used or an excess of DBU is required, then
the chloro at the 6-carbon position is substituted by a
hydroxy group after the ring closure.
In conclusion, a regioselective single-step reaction to
synthesize triazolo fused rings using several hydrazides
has been achieved. This reaction is suitable for a straight-
forward synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]-
triazolo[4,3-a]pyrazines which can be easily derivatized
by nucleophilic displacement of the 6-chloro. Compounds
6 and 7 could be used in the same way after their
chlorination back to 6-like chloro derivatives. The strat-
egy described is suitable to generate larger libraries of
compounds as tricycle nonxanthine adenosine antago-
nists. These libraries are crucial for the understanding
of the different adenosinic receptor (A1, A2a, A2b, A3) as
well as their biological activities.
R1
reagent
solvent temp, °C time, h R2 yields, %
H
HCl 36%
THF
55
60
85
66
66
85
85
85
66
12
16
22
20
20
24
4
OH
Cl
57
59
65
65
71
81
91
89
67
Me
CF3
Et
H2SO4 concd THF
HCl 36%
CH3CN
OH
Cl
H2SO4 concd THF
H2SO4 concd THF
H2SO4 concd CH3CN
Pr
Cl
cPra
Ph
Cl
DBU
CH3CN
CH3CN
OH
OH
Cl
p-ClPh DBU
Bn
4
20
H2SO4 concd THF
a cPr) cyclopropyl.
5). On the other hand, an excess of DBU was necessary
to carry out cyclization with bulky aromatic hydrazides.
Under these basic conditions the chloro at the 6-carbon
position was also substituted by a hydroxy group (see the
synthesis of 7a,b in Scheme 5).
Acknowledgment. A.U.B. is grateful to Ramon
Areces Foundation for funding. We thank Prof. J. A.
Go´mez-Vidal for his helpful discussions.
Briefly, steric hindrance slows down the cyclization
process and therefore bulky hydrazides gave rise to
higher yields because of the reduced tetracycle formation
(see Table 1).
Finally, it was noticed from the experimental results
that the intramolecular cyclization is under thermo-
dynamic control, which is directly correlated to the size
of the substituent R. The bigger the substituent R, the
Supporting Information Available: Experimental pro-
cedures for the synthesis of compounds 3-7b as well as their
analytical data (NMR and MS). This material is available free
of charge via the Internet at http://pubs.acs.org. Supplemen-
tary crystallographic data for compounds 4d and 5 (CCDC
250469 and CCDC 251372, respectively) can be obtained from
the CCDC free of charge.
JO0478398
2880 J. Org. Chem., Vol. 70, No. 7, 2005