An unexpected aromatization during the N-alkylation reaction of 3,4-dihydro-1H-pyrazole derivatives: insight into the reaction mechanism

Article abstract of DOI:10.1016/j.tetlet.2006.06.141

In this letter we describe the unexpected aromatization that takes place during the N-alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid methyl esters, giving rise to a mixture of 1-alkyl-3-(2-nitrobenzoy

Full text of DOI:10.1016/j.tetlet.2006.06.141

Tetrahedron Letters 47 (2006) 6239–6242
An unexpected aromatization during the N-alkylation reaction
of 3,4-dihydro-1H-pyrazole derivatives: insight into the
reaction mechanism
´
´
´
´
Luisa C. Lopez-Cara, M. Encarnacion Camacho, Marıa D. Carrion, Miguel A. Gallo,
Antonio Espinosa and Antonio Entrena*
Departamento de Quı´mica Farmace´utica y Orga´nica, Facultad de Farmacia, Campus de Cartuja s/n, 18071 Granada, Spain
Received 15 May 2006; revised 24 June 2006; accepted 27 June 2006
Available online 17 July 2006
Abstract—In this letter we describe the unexpected aromatization that takes place during the N-alkylation reaction performed on
several 3-(2-nitrobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid methyl esters, giving rise to a mixture of 1-alkyl-3-(2-nitro-
benzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid methyl esters and 1-alkyl-3-(2-nitrobenzoyl)-1H-pyrazole-5-carboxylic acid
methyl esters.
Ó 2006 Elsevier Ltd. All rights reserved.
Several neurological diseases1–3 and other types of phys-
iological disorders4–6 involve the overproduction of
nitric oxide (NO) by the different nitric oxide synthase
(NOS) isoforms. For this reason, the design of new
NOS inhibitors is a matter of high potential therapeutic
interest.
We have recently synthesized and evaluated a series of
NOS inhibitors with general structure 1-4.7–10 Among
them, the 1-benzoyl-D2-pyrazoline derivatives 4 have
shown a moderate selectivity in the inhibition of the
iNOS isoform.10
A key step in the synthesis of compounds 4 is the N-
acylation of the appropriated 3-(5-substituted-2-nitro-
O
CO2H
O
R2
N
MeO
benzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic
acid
R1
N
H
R
N
O
ethyl ester 5 (Scheme 1) to yield the nitro derivative 6
that was further reduced to the corresponding derivative
4.
NH2
NH2
1a, R= Me
1b, R = Pr
(ref. 7)
2: R1= H, Cl, MeO
R2= Me, Et, Pr, etc.
(ref. 8)
This synthetic scheme was followed to obtain 1-alkyl-D2-
pyrazoline analogues of 4 by N-alkylation of compound
5 (Scheme 1). In this reaction, besides the desired
compound 7, an important amount of the pyrazole
derivative 8 is also obtained, as a consequence of an
unexpected aromatization process.
O
O
O
R1
R1
N
H
R2
CO2Et
N
N
NH2
NH2
R2
O
The aromatization can be due to the action of the atmo-
spheric oxygen, but the reaction was repeated under
argon atmosphere with similar results, and a deeper
investigation of the reaction mechanism was tackled.
3: R1= H, MeO
R2= Me, Et, Pr, etc.
(ref. 9)
4, R1 = H, Cl, OMe
R2 = Me, Et, Pr, etc.
(ref. 10)
Several methods have been described in the literature
to oxidize the pyrazoline ring into the corresponding
pyrazole. Among them, some inorganic compounds
like bromine have been used in the synthesis of
Keywords: D2Pyrazoline; 1H-Pyrazole; Redox.
Corresponding author. Tel.: +34 958 243849; fax: +34 958 243845;
e-mail: aentrena@ugr.es
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.141

6240
L. C. Lo´pez-Cara et al. / Tetrahedron Letters 47 (2006) 6239–6242
O
O
CO2Et
H
N
R1
R1
i)
N
CO2Et
CO2Et
R2
N
N
N
N
NO2
NO2
6, R1 = H, Cl, OMe
H
O
5a, R1 = H
O
R2 = Me, Et, Pr,...
5b: R1 = Cl
5c; R1 = OMe
R
5a; R = NO2 (1.02 mmol)
9; R = NH2
ii)
K2CO3,THF,
O
70 °C, 6 h.
O
R1
R1
O
CO2Et
CO2Et
CO2Et
H
H
+
CO2Et
N
N
N
N
N
N
N
NO2
CO2Et
CO2Et
NO2
N
Et
Et
N
N
N
H
N
8a, R1 = H (26 %),
8b, R1 = Cl (27 %),
8c, R1 = OMe (17 %)
7a, R1 = H (46 %),
7b, R1 = Cl (37 %),
7c, R1 = OMe (38 %)
O
+
+
O
N
NO2
N
H
Scheme 1. Differences in the N-acylation and N-alkylation of 3-(5-
substituted-2-nitrobenzoyl)-4,5-dihydro-1H-pyrazoles 5. Reagents and
conditions: (i) R2CO–Cl, Et3N, CH2Cl2, room temperature, 3 h; (ii)
(EtO)2SO2, K2CO3, THF, 70 °C, 22 h.
NO2
10 (0.52 mmol)
11 (0.08 mmol)
12 (0.19 mmol)
Scheme 2. Reaction product obtained in the treatment of the D2-
pyrazoline 5a. Compound 9 does not react under the same conditions.
3,5-bis(ethoxycarbonyl)-1H-pyrazole from the corre-
sponding D2-pyrazoline.11
sis. Scheme 2 shows all the obtained compounds. Be-
sides the expected pyrazole 10 (0.052 mol), a mixture
of compounds 11 (0.08 mmol) and 12 (0.12 mmol) was
isolated.
Metallic nitrates constitute another class of oxidizing
reagents, and Fe(NO3)3 or Cu(NO3)2 deposited over
an inert mineral support was employed in the oxidation
of several 1-substituted D1- or -D2-pyrazolines.12 More
recently, Zr(NO3)4 has also been used in the synthesis
of several 1H-pyrrole derivatives.13
Formation of pyrazole 10 implies the loss of a hydrogen
molecule in D2-pyrazoline 5a, and this aromatization
could take place through the evolution of molecular
hydrogen, in a similar way to the Chichibabin reac-
tion.23 So, the reaction begins when the base takes the
C5–H atom yielding the stabilized carbanion i (Scheme
3), which can further transfer a hydride ion to the con-
jugated acid HB+ (route a), and a hydrogen molecule
is formed.
Organic compounds also constitute an important class
of oxidizing agents. Among them, DDQ (2,3-dichloro-
5,6-dicyano-1,4-benzoquinone) was used to oxidize con-
densed D2-pyrazoline derivatives,14 or in the synthesis of
5-acetyl-3-benzoyl-1H-pyrazole from the corresponding
D2-pyrazoline.15 Chloranil (2,3,5,6-tetrachloro-2,5-cyclo-
hexadiene-1,4-dione) has widely been used in the oxida-
tion of D2-pyrazoline rings, and a recent example is the
synthesis of several 3-benzoyl-4-styryl-1H-pyrazole
derivatives.16 Recent papers describe the use of
4-(p-chlorophenyl)-1,2,4-triazole-3,5-dione as a reusable
reagent in the oxidation of pyrazolines17 and 1,4-
dihydropyridines.18
The molecular hydrogen formed could also be responsi-
ble for the formation of the two reduction products 11
and 12 isolated in this reaction. Nevertheless, this route
does not seem to be correct since when 20-amino ana-
logue 9 is treated under the same conditions no transfor-
CO2Et
H
CO2Et
C
CO2Et
H
H
H
Finally, nitrobenzene has been used as a reagent for the
oxidation of several condensed pyrazoline to obtain the
corresponding pyrazole.19,20 This reagent constitutes a
mild oxidant that has been used to dehydrogenate
several organic systems under acidic and basic
conditions.21,22
N
N
N
B:
N
N
N
H2
H
H
H
B+
B:
+
+
+
a)
i
R
R
R
b)
O
N+
O
R
This background and the fact that compounds 5 bear a
nitro group on the benzene ring suggest that the D2-pyr-
azoline aromatization could be due to the action of the
20-NO2 group. One experiment, consisting in heating
compound 5a (1.02 mmol) under the same conditions
used in the N-alkylation reaction (THF, K2CO3,
70 °C, 6 h, argon atmosphere) without the alkylating
agent, was carried out in order to confirm this hypothe-
CO2Et
H
N
N
O
N R
+
H2O
+
R
Scheme 3. Possible routes for the hydride ion transfer in the D2-
pyrazoline aromatization.

L. C. Lo´pez-Cara et al. / Tetrahedron Letters 47 (2006) 6239–6242
6241
mation was observed, indicating the importance of the
20-NO2 group in the mechanism of the reaction.
On the other hand, an intermolecular redox can also be
considered. The pyrazoline moiety of one molecule of 5a
aromatizes to yield compound 10, and the hydride ion is
transferred to the nitro group of another molecule of 5a
yielding the nitroso intermediate 14. This nitroso-ketone
14 can easily cyclize to give benzoisoxazole 15 that is
further oxidized to 11.
Consequently, the nitro group is necessary for the reac-
tion and could act as an acceptor of the hydride ion
(Scheme 3, route b), allowing the pyrazoline aromatiza-
tion and giving rise to the corresponding 20-nitroso
derivative in several steps.
The 20-NO group of intermediate 14 can accept another
hydride ion and the reduction process continues yielding
hydroxylamine 16. Cyclization of 16 to produce inter-
mediate 15 can also take place easily. A further reduc-
tion of the hydroxylamine group of 16 can also take
place by accepting the transfer of another hydride ion
giving the intermediate amine 17. Condensation of 17
with the nitropyrazole compound 10 yields the interme-
diate 18 that is finally oxidized to the final compound 12.
The transfer of the hydride ion can take place in an
intramolecular manner, yielding the nitroso intermedi-
ate 13 that could cyclize24 to give the final product
3-(benzo[c]isoxazol-3-yl)-1H-pyrazol-5-carboxylic acid
ethyl ester 11 (Scheme 4). Nevertheless, this process does
not explain the formation of compound 10 where the D2-
pyrazoline moiety is oxidized to the corresponding pyr-
azole with the 20-NO2 group still remaining unaffected.
EtO2C
H
N
EtO2C
H
N
N
N
intramolecular
redox
O
cyclization
11
O
NO2
N
O
5a
oxidation
CO2Et
intermolecular
redox
13
EtO2C
EtO2C
H
H
N
N
H
N
N
N
N
cyclization
O
+
O
O
N
NO2
N
O
10
15
14
reduction
cyclization
EtO2C
EtO2C
H
N
H
N
N
reduction
N
O
O
N
OH
NH2
H
17
16
10
H2O
O
N
CO2Et
N
N
oxidation
N
H
12
CO2Et
N
H
NO2
18
Scheme 4. Possible whole mechanism for the formation of compounds 10, 11, and 12.

6242
L. C. Lo´pez-Cara et al. / Tetrahedron Letters 47 (2006) 6239–6242
2. Wong, N. K.; Strong, M. J. Eur. J. Cell. Biol. 1998, 77,
338–343.
3. Norris, P. J.; Waldvogel, H. J.; Faull, R. L.; Love, D. R.;
Emson, P. C. Neuroscience 1996, 4, 1037–1047.
4. Petros, A.; Bennett, D.; Vallance, P. Lancet 1991, 338,
1157–1158.
5. McCartney-Francis, N.; Allens, J. B.; Mizel, D. E.;
Albina, J. E.; Nathan, C. F.; Whal, S. M. J. Exp. Med.
1993, 178, 749–754.
In this scheme, the oxidation processes imply the trans-
fer of one hydride ion from the D2-pyrazoline moiety to
an appropriate acceptor group that could be 20-NO2, 20-
NO or 20-NHOH, which are reduced. Alternatively, a
wider scheme can be drawn from the reduction of the
nitroso intermediate 13.
The reduction of a nitro group to the corresponding
amino needs three hydride ions to be transferred from
the D2-pyrazoline moiety. At least two of these hydride
ions must be transferred in an intermolecular manner,
while the third one can be inter- or intramolecular.
6. Moncada, S. J. Roy. Soc. Med. 1999, 92, 164–169.
´
´
7. Camacho, E.; Leon, J.; Carrion, A.; Entrena, A.; Escames,
G.; Khaldy, H.; Acuna-Castroviejo, D.; Gallo, M. A.;
˜
Espinosa, A. J. Med. Chem. 2002, 45, 263–274.
´
8. Camacho, M. E.; Leon, J.; Entrena, A.; Velasco, G.;
´
Carrion, M. D.; Escames, G.; Vivo, A.; Acuna-Castrovi-
˜
The reason why this reaction takes place during the N-
alkylation of compound 5 and not in the N-acylation
seems to be due to both temperature and reaction time.
Reaction of compound 5 with the more reactive acyl
chloride takes place at room temperature and in a short
period (3 h), while a higher temperature and a longer
reaction time are needed for the N-alkylation process.
ejo, D.; Gallo, M. A.; Espinosa, A. J. Med. Chem. 2004,
47, 5641–5650.
9. Entrena, A.; Camacho, M. E.; Carrion, M. D.; Lopez-
´
´
´
Cara, L. C.; Velasco, G.; Leon, J.; Escames, G.;
Acuna-Castroviejo, D.; Tapias, V.; Gallo, M. A.; Vivo,
˜
A.; Espinosa, A. J. Med. Chem. 2005, 48, 8174–
´
8181.
´
´
10. Carrion, M. D.; Camacho, M. E.; Leon, J.; Escames, G.;
Tapias, V.; Acuna-Castroviejo, D.; Gallo, M. A.; Espin-
˜
This hypothesis is confirmed by the fact that when com-
pound 5a is treated under the same conditions used in
the N-acylation reaction (Et3N, CH2Cl2, room tempera-
ture, 3 h) without the acylating agent, no reaction is
observed.
osa, A. Tetrahedron 2004, 60, 4051–4069.
11. Iturrino, L.; Navarro, P.; Rodriguez-Franco, M. I.;
Contreras, M.; Escario, J. A.; Martinez, A.; Pardo, M.
R. Eur. J. Med. Chem. 1987, 22, 445–451.
12. Bougrin, K.; Soufiaoui, M.; El Yazidi, M. Tetrahedron
Lett. 1995, 36, 4065–4068.
An interesting and related transformation has been
described in the condensation of 1,5-diketones with
2- and 4-nitroanilines.25 In these reactions, the formation
of 1,4-dihydropyridine system is expected. Nevertheless,
the dihydropyridine moiety aromatizes until the corre-
sponding pyridinium salt and a reduction is observed
of the 2- or 4-nitro group to the corresponding amine.
13. Sabitha, G.; Kumar Reddy, G. S. K.; Reddy, Ch. S.;
Fatima, N.; Yadav, J. S. Synthesis 2003, 8, 1267–1271.
14. Garanti, L.; Sala, A.; Zecchi, G. J. Org. Chem. 1977, 42,
1389–1392.
15. Jung, M. E.; Min, S. J.; Houk, K. N.; Ess, D. J. Org.
Chem. 2004, 69, 9085–9089.
16. Pinto, D. C.; Silva, A. M.; Levai, A.; Cavaleiro, J. A.;
Patonay, T.; Elguero, J. Eur. J. Org. Chem. 2000, 2593–
2599.
17. Zolfigol, M. A.; Azarifar, D.; Mallakpour, S.; Moham-
madpoor-Baltork, I.; Forghaniha, A.; Malekia, B.;
Abdollahi-Alibeik, M. Tetrahedron Lett. 2006, 47, 833–
836.
In conclusion, the unexpected aromatization observed in
the N-alkylation of D2-pyrazoline derivative 5a is due to
the participation of the 20-NO2 group that acts as a
hydride acceptor.
18. Zolfigol, M. A.; Choghamarini, A. G.; Sharamirian, M.;
Safaiee, M.; Mohammadpoor-Baltork, I.; Mallakpour, S.;
Abdollahi-Alibeik, M. Tetrahedron Lett. 2005, 46, 5581–
5584.
Acknowledgments
19. Eldin, S. M.; Gaber, H. M.; Ghabrial, S. S. Phosphorus,
Sulfur Silicon Relat. Elem. 2002, 177, 803–810.
20. Gaber, H. M. Phosphorus, Sulfur Silicon Relat. Elem.
2003, 178, 417–424.
This work was partially supported by grants from the
´
Ministerio de Ciencia y Tecnologıa (SAF2002-01688)
´
and from the Fondo de Investigacion Sanitaria
(PI021181).
21. Cristiano, M. L. S.; Gago, D. J. P.; Rocha Gonsalves, A.
M.; Johnstone, R. A. W.; McCarron, M.; Varejao, J. M.
˜
T. B. Org. Biomol. Chem. 2003, 1, 565–574, and references
cited therein.
Supplementary data
22. Tanaka, T.; Kawabata, H.; Hayashi, M. Tetrahedron Lett.
2005, 46, 4989–4991.
23. Zoltewicz, J. A.; Helmick, L. S.; Oestreich, T. M.; King,
R. W.; Kandetzki, P. E. J. Org. Chem. 1975, 58, 1947–
1949.
Supplementary data associated with this article for spec-
troscopic data (1H, 13C NMR, and MS LSIMS) of com-
pounds 10, 11, and 12 can be found, in the online
version, at doi:10.1016/j.tetlet.2006.06.141.
24. Bandaev, S. G.; Eshnazarov, Yu. Kh.; Nasyrov, I. M.;
Mochalov, S. S.; Shabarov, Yu. S. Metalloorganicheskaya
Khim. 1989, 2, 1323–1327.
References and notes
25. Maslow, K. V.; Egorov, A. G.; Akimova, T. I.;
Kaminski, V. A. Chem. Heterocycl. Compd. 2002, 38,
560–563.
1. Yew, D. T.; Wong, H. W.; Li, W. P.; Lai, H. W.; Yu, W.
H. Neuroscience 1999, 89, 675–686.