An unexpected chemical behavior of 5-N-(benzotriazol-1-ylmethyl)amino-3-tert-butyl-1-phenylpyrazole

Article abstract of DOI:10.1016/S0040-4039(02)01115-2

A rearrangement product or a pyrazolic Tr?ger's base were unexpectedly obtained when 5-N-(benzotriazol-1-ylmethyl)amino-3-tert-butyl-1-phenylpyrazole was treated with electron-rich alkenes with well protic or Lewis acid catalyst, respectively, when tetrahydropyrazolopyridines were expected according with the benzotriazole methodology. The structure of the products was confirmed by NMR and X-ray diffraction techniques. Mechanisms for their formation are also proposed.

Full text of DOI:10.1016/S0040-4039(02)01115-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5617–5620
An unexpected chemical behavior of
5-N-(benzotriazol-1-ylmethyl)amino-3-tert-butyl-1-phenylpyrazole
Rodrigo Abonia,a,* Emerson Rengifo,a Jairo Quiroga,a Braulio Insuasty,a Adolfo Sa´nchez,b
Justo Cobo,b John Lowc,† and Manuel Noguerasb
aDepartment of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
bDepartamento de Qu´ımica Inorga´nica y Orga´nica, Universidad de Jae´n, 23071 Jae´n, Spain
cDepartment of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, Scotland, UK
Received 10 May 2002; revised 6 June 2002; accepted 10 June 2002
Abstract—A rearrangement product or a pyrazolic Tro¨ger’s base were unexpectedly obtained when 5-N-(benzotriazol-1-
ylmethyl)amino-3-tert-butyl-1-phenylpyrazole was treated with electron-rich alkenes with well protic or Lewis acid catalyst,
respectively, when tetrahydropyrazolopyridines were expected according with the benzotriazole methodology. The structure of the
products was confirmed by NMR and X-ray diffraction techniques. Mechanisms for their formation are also proposed. © 2002
Elsevier Science Ltd. All rights reserved.
In recent works we1 and others2 have successfully used
5-aminopyrazoles as starting materials for the synthesis
of diverse fused heterocyclic compounds. For example,
we have reported the reaction of 5-amino-3-methyl-1-
phenylpyrazole with chalcones and b-dimethylamino-
propiophenone-hydrochlorides as versatile methods for
the synthesis of new pyrazolopyridine derivatives.3
Some of these compounds have displayed interesting
biological activities.4
Continuing with our ongoing studies on the synthesis of
pyrazolopyridine derivatives and in an attempt to
obtain the new tetrahydropyrazolopyridines 3 using
benzotriazole methodology,5 the benzotriazolyl deriva-
Scheme 1. (Bt=Benzotriazol-1-yl).
Keywords: 5-N-(benzotriazol-1-ylmethyl)amino-3-tert-butyl-1-phenylpyrazole; benzotriazole; isomerization; Tro¨ger’s bases.
* Corresponding author. Fax: +57-2-3392440; e-mail: abonia@quimica.univalle.edu.co
† Present address: Department of Electronic Engineering and Physics, University of Dundee, DD14HN Scotland, UK.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01115-2

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tive 2 was prepared from the 5-aminopyrazole 1 and
1-hydroxymethylbenzotriazole as a white solid in 84%
yield (Scheme 1).6
removing selectively the Bt− ion and trapping the cationic
species 6 formed (Scheme 4) with an electron-rich alkene
that would yield 3.
Treatment of compound 2 with electron-rich alkenes to
afford product 3 with PTSA as catalyst yielded the
unexpected isomeric compound 4 in 90% yield instead of
the expected 3. The same rearrangement product was
obtained without the presence of the alkenes. Compounds
2 and 4 were completely characterized by spectroscopic
(IR, NMR, and mass spectrometry) and analytical mea-
surements, and by X-ray diffraction for both com-
pounds.6–9
On the contrary, a white solid mixture of two compounds,
one of them AgBt, was isolated. After removing the AgBt,
spectroscopical and analytical analyses of the remaining
product indicate that the structure of the white solid
surprisingly corresponded to the pyrazolic Tro¨ger’s base
9 (75% yield based on 1) (Scheme 3). No expected product
3 was isolated, but traces of free pyrazole 1 were detected
by TLC in the reaction mixture. Recently, we have
obtained compound 9 (and analogues) from the reaction
of pyrazole 1 and formaldehyde in ethanol and acetic acid
as catalyst.12
The rearrangement from 2 to 4 can be explained based
mainly on the higher nucleophilicity of the pyrazole ring
versus the alkene, and on the cation-stabilizing character
of the Bt moiety.10 So, the p-toluenesulfonic acid helps
the migration of the BtCH2+ fragment from 5-NH to 4-C
positions through the cationic species 5, as shown in
Scheme 2. The high yield obtained for 4 indicates no
competitive reaction of the vinyl ether due to its lower
reactivity.
Formation of compound 9 could occur according to the
mechanism shown in Scheme 4.
In this sequence, compound 9 could be formed from a
first dimerization of the cationic species 6 to form the
intermediate diazocinic 7 which reacts with a third species
6 to yield the intermediate 8. Compound 8 can lose a
molecule of pyrazole 1 by an intramolecular nucleophilic
attack (catalyzed by the HNO3 formed in situ), affording
the Tro¨ger’s base 9. It is worth emphasizing that pyrazole
1 was detected by TLC of the reaction mixture. Alterna-
tively, intermediate 7 could react with a molecule of 2 to
afford 9, previous elimination of both BtH (trapped by
Ag+) and pyrazole 1 molecules. Formation of Tro¨ger’s
bases by benzotriazole methodology has not already been
reported.
The results indicate that compound 2 is the kinetic
product while 4 is the thermodynamic one. We also
observed that compound 2 slowly converts into 4 even
in the neutral alcoholic solution; the rate speeds up when
the acid is added. It is worth mentioning that attempts
to cyclize compound 4 under (i) conditions were also
unsuccessful.
A Lewis, like Ag+ ion was used instead of a protic acid
in order to obtain the product 3 (it reacts fast and easily
with BtH and Bt derivatives to produce an insoluble white
precipitate of AgBt),11 then compound 2 was treated at
room temperature with a methanolic solution of AgNO3
(1 equiv.) and dodecylvinylether (1 equiv.) (Scheme 3).
This experiment was carried out with the purpose of
In conclusion, the benzotriazolyl-derivative 2 behaves in
an unusual manner under the present reaction conditions,
compared with their anilino, diazepino and indolino
analogues previously reported as effective starting mate-
rials for the synthesis of interesting fused heterocyclic
compounds,5 due to its higher nucleophilic character.
Scheme 2.
Scheme 3.

R. Abonia et al. / Tetrahedron Letters 43 (2002) 5617–5620
5619
Scheme 4.
In an ongoing experiment, we are planning to block or
deactivate 5-amino group by alkylation or acetylation,
respectively, of compound 1, and in this way to try to
prevent the formation of compounds 4 or 9 and so to
induce the reaction with the vinyl ethers to form com-
pounds 3. Compound 4 is also synthetically interesting
and we will try in a future work to find its synthetic
applicability.
5. (a) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org.
Chem. 1995, 60, 3993–4001; (b) Katritzky, A. R.; Abonia,
R.; Yang, B.; Qi, M.; Insuasty, B. Synthesis 1998, 1487–
1490; (c) Abonia, R.; Albornoz, A.; Insuasty, B.;
Quiroga, J.; Meier, H.; Hormaza, A.; Nogueras, M.;
Sa´nchez, A.; Cobo, J.; Low, J. N. Tetrahedron 2001, 57,
4933–4938.
6. 5-N-(Benzotriazol-1-ylmethyl)amino-1-phenyl-3-tert-butyl-
pyrazole 2.
A solution of 5-amino-1-phenyl-3-tert-
butylpyrazole 1 (1.0 g, 4.65 mmol), 1-hydroxymethylben-
zotriazole (0.7 g, 4.69 mmol) and 5 mL of ethanol was
heated to reflux for 3 min. After cooling, the precipitate
formed was filtered and washed with ethanol. White solid
Acknowledgements
1
(84% yield; mp 180°C). IR (cm−1) 3286 (NH); H NMR
Authors are grateful to COLCIENCIAS and Universi-
dad del Valle for financial support. Also, we are grate-
ful to the Ministerio de Educacio´n, Cultura y Deportes
(Programa de Cooperacio´n con Iberoame´rica, AECI)
of Spain, for partial financial support of this work.
(DMSO-d6, 300 MHz) l 1.17 (s, 9H), 5.74 (s, 1H, 4-H),
6.00 (d, J=9.0 Hz, 2H, CH2), 7.11 (t, J=9.0 Hz, 1H,
NH), 7.32–7.53 (m, 7H), 7.99 (br d, 2H); 13C NMR
(DMSO-d6, 75 MHz) l 30.0, 31.8, 58.5 (CH2), 85.8 (4-C),
111.2, 119.0, 123.6, 124.0, 126.5, 127.2, 129.1, 132.2,
138.7, 145.4 (two C), 160.8; MS: (70 eV) m/z (%) 346
(0.5, M+), 229 (52), 212 (100); Anal. calcd for C20H22N6:
C, 69.34; H, 6.40; N, 24.26. Found: C, 69.28; H, 6.43; N,
24.23.
References
1. (a) Quiroga, J.; Mej´ıa, D.; Insuasty, B.; Abonia, R.;
Nogueras, M.; Sa´nchez, A.; Cobo, J.; Low, J. N. Tetra-
hedron 2001, 57, 6947–6953; (b) Quiroga, J.; Cruz, S.;
Insuasty, B.; Abonia, R. Heterocycl. Commun. 2000, 6,
275–282; (c) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonia,
R.; Cobo, J.; Sa´nchez, A.; Nogueras, M.; Low, J. N. J.
Heterocycl. Chem. 2001, 38, 53–60.
2. (a) Elnagdi, M. H.; Elmoghayer, M. R.; Elgemeie, G. E.
Adv. Heterocycl. Chem. 1987, 41, 319–376; (b) Elnagdi,
M. H.; Elmoghayer, M. R.; Sadek, K. U. Adv. Hetero-
cycl. Chem. 1990, 48, 223–299.
3. (a) Quiroga, J.; Insuasty, B.; Cruz, S.; Herna´ndez, P.;
Bolan˜os, A.; Moreno, R.; Hormaza, A.; De Almeida, R.
H. J. Heterocycl. Chem. 1998, 35, 333–338; (b) Insuasty,
B.; Quiroga, J.; Meier, H. Trends Heterocycl. Chem. 1997,
5, 83–89.
4. (a) Hardy, C. R. Adv. Heterocycl. Chem. 1984, 36, 343–
409; (b) Orth, R. E. J. Pharm. Sci. 1968, 57, 537–556 and
references cited therein.
7. 5-Amino-4-(benzotriazol-1-ylmethyl)-1-phenyl-3-tert-butyl-
pyrazole 4. To a solution of 0.3 g (0.867 mmol) of 1 in 15
mL of absolute methanol were added 20–30 mg of p-
toluenesulfonic acid, and the mixture was stirred at room
temperature for 1 h (TLC control). The solvent was
removed under reduced pressure, the residue was re-dis-
solved in ethyl acetate, washed with a 10% NaOH solu-
tion and dried with anhydrous sodium sulfate. The
solution was concentrated and purified by column chro-
matography on silica gel with a mixture 80:20 (hex-
ane:ethyl acetate) as eluent, yielding 0.27 g (90%) of
compound 4 as white crystals (mp 124°C). IR (cm−1
)
1
3401, 3293 (5-NH2); H NMR (CDCl3, 300 MHz) l 1.45
(s, 9H), 4.38 (br s, 2H, 5-NH2), 5.70 (s, 2H, CH2),
7.15–7.82 (m, 8H), 8.01 (d, 1H); 13C NMR (CDCl3, 75
MHz) l 30.0, 33.5, 43.8 (CH2), 94.6 (4-C), 110.3, 120.4,
124.3, 124.6, 126.2, 129.8 (two C), 132.9, 138.7,
146.0 (two C), 158.1; MS: (70 eV) m/z (%) 346 (70,

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R. Abonia et al. / Tetrahedron Letters 43 (2002) 5617–5620
M+), 227 (100), 212 (20); Anal. calcd for C20H22N6: C,
10. Katritzky, A. R. J. Heterocycl. Chem. 1999, 36, 1501–
69.34; H, 6.40; N, 24.26. Found: C, 69.30; H, 6.38; N,
1521.
11. This compound is readily obtained as a white insoluble
precipitate by treatment of methanolic or aqueous solu-
tions of benzotriazole with an aqueous AgNO3 solu-
tion.
12. Abonia, R.; Albornoz, A.; Larrahondo, H.; Quiroga, J.;
Insuasty, B.; Insuasty, H.; Hormaza, A.; Sa´nchez, A.;
Nogueras, M. J. Chem. Soc., Perkin Trans. 1, 2002, (13),
1588–1591.
24.24.
8. For X-ray structure of compound 2, see: Glidewell, Ch.;
Low, J. N.; Cobo, J.; Nogueras, M.; Sa´nchez, A.;
Rengifo, E.; Abonia, R. Acta Crystallogr. 2002, C58,
314–317.
9. For X-ray structure of compound 4, see: Low, J. N.;
Cobo, J.; Nogueras, M.; Sa´nchez, A.; Rengifo, E.; Abo-
nia, R. Acta Crystallogr. 2002, E58, o53–o54.