Chemoselective and regiospecific formylation of 1-phenyl-1H-pyrazoles through the duff reaction

Article abstract of DOI:10.1080/00397911.2012.657764

The synthesis of formylated 1-phenyl-1H-pyrazole derivatives under the Duff reaction conditions is reported. Our results indicate that 1-phenyl-1H-pyrazole systems containing electron-withdrawing and electron-donating substituents at the phenyl moiety rea

Full text of DOI:10.1080/00397911.2012.657764

This article was downloaded by: [McMaster University]
On: 11 March 2013, At: 06:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Chemoselective and Regiospecific
Formylation of 1-Phenyl-1H-pyrazoles
Through the Duff Reaction
C. H. A. de Oliveira a , L. M. Mairink a , F. Pazini a , L. M. Lião b , A.
L. de Oliveira b , C. Viegas Jr. c , V. de Oliveira a , L. C. Cunha a , F.
G. F. Oliveira a , J. L. Paz Jr. d , M. N. Eberlin d & Ricardo Menegatti
a
a Laboratório de Química Farmacêutica Medicinal (LQFM), Faculdade
de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil
b Instituto de Química, Universidade Federal de Goiás, Goiânia,
Brazil
c Instituto de Ciências Exatas, Universidade Federal de Alfenas,
Alfenas, Brazil
d Thomson Mass Spectrometry Laboratory, Instituto de Química,
Universidade Estadual de Campinas, Campinas, Brazil
Accepted author version posted online: 17 May 2012.
To cite this article: C. H. A. de Oliveira , L. M. Mairink , F. Pazini , L. M. Lião , A. L. de Oliveira ,
C. Viegas Jr. , V. de Oliveira , L. C. Cunha , F. G. F. Oliveira , J. L. Paz Jr. , M. N. Eberlin & Ricardo
Menegatti (2013): Chemoselective and Regiospecific Formylation of 1-Phenyl-1H-pyrazoles Through
the Duff Reaction, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:12, 1633-1639
To link to this article: http://dx.doi.org/10.1080/00397911.2012.657764
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.

The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 1633–1639, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.657764
CHEMOSELECTIVE AND REGIOSPECIFIC
FORMYLATION OF 1-PHENYL-1H-PYRAZOLES
THROUGH THE DUFF REACTION
1
1
1
2
˜
C. H. A. de Oliveira, L. M. Mairink, F. Pazini, L. M. Liao,
A. L. de Oliveira,2 C. Viegas Jr.,3 V. de Oliveira,1
L. C. Cunha,1 F. G. F. Oliveira,1 J. L. Paz Jr.,4
M. N. Eberlin,4 and Ricardo Menegatti1
´
Laboratorio de Quımica Farmaceutica Medicinal (LQFM), Faculdade de
Farmacia, Universidade Federal de Goias, Goiania, Brazil
ˆ
Instituto de Quımica, Universidade Federal de Goias, Goiania, Brazil
Instituto de Ciencias Exatas, Universidade Federal de Alfenas,
1
´
ˆ
´
´
ˆ
2
´
ˆ
´
3
Alfenas, Brazil
4
´
Thomson Mass Spectrometry Laboratory, Instituto de Quımica,
Universidade Estadual de Campinas, Campinas, Brazil
GRAPHICAL ABSTRACT
Abstract The synthesis of formylated 1-phenyl-1H-pyrazole derivatives under the Duff
reaction conditions is reported. Our results indicate that 1-phenyl-1H-pyrazole systems con-
taining electron-withdrawing and electron-donating substituents at the phenyl moiety react
under the Duff reaction conditions to furnish formylated derivatives in good yields.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Received November 23, 2011.
Address correspondence to Ricardo Menegatti, Laboratorio de Quımica Farmaceutica Medicinal
´
(LQFM), Faculdade de Farmacia, Universidade Federal de Goias, Goiania 74 605 220, Brazil. E-mail:
´
ˆ
´
´
ˆ
rm_rj@yahoo.com
1633

1634
C. H. A. DE OLIVEIRA ET AL.
INTRODUCTION
1-Phenyl-1H-pyrazoles are important compounds in many fields of chemistry,
including the dye and pharmaceutical industries, supramolecular chemistry, and
others. Formylation in position 4 of 1-phenyl-1H-pyrazole systems are often a key
step in the synthesis of other compounds, such as (1E,4E)-1,5-bis(1-phenyl-1H-
pyrazol-4-yl)-1,4-pentadien-3-one, tris-pyrazolyl-1,3,5-triazines, meso-tetrakis(1-
arylpyrazol-4-yl)porphyrins, benzylic ethers of oximes derived from 1-phenylpyrazole
compounds, and lead compounds for diabetes, in addition to derivatives with anti-
inflammatory, analgesic, and antipyretic acivities.[1–6] The formylation of 1-phenyl-
1H-pyrazoles is usually achieved under Vilsmeier–Haack conditions, in which
phosphorus oxychloride (POCl3) and dimethylformamide (DMF) are used to generate
the formyl moiety.[7] Reaction of the amide with phosphorus oxychloride generates an
electrophilic iminium cation that reacts with activated arenes.[8] The 1-phenyl-1H-
pyrazole-4-carbaldehydes have been produced under these conditions since 1957.[7]
Although the Vilsmeier–Haack reaction is an important tool for the formation
of C-C bonds in synthetic organic chemistry, it requires the use of dangerous reagents,
such as phosphorus oxychloride. This reagent is also commercially restricted in
many countries. Phosphorus oxychloride is corrosive and very toxic when inhaled.
It is controlled by the Army in Brazil and restricted because of its environmental
impact.[9] The Duff reaction presents a viable alternative because it can be used
under milder, cheaper, and safer conditions than the Vilsmeier–Haack reaction.[10,11]
In the course of a research program aimed at developing drugs for the treat-
ment of neurological disorders, we recently described the synthesis and pharmaco-
logical evaluation of new N-phenylpiperazine derivatives such as 3, which were
originally designed to be selective dopaminergic D2 or D4 receptor ligands
(Scheme 1).[12,13] In this context, we are also interested in the development of
a process that will allow us to attain intermediates such as 1a. Thus, the aim of this
work is to propose an alternative methodology for the formylation of 1-phenyl-1H-
pyrazole derivatives.
RESULTS AND DISCUSSION
The Duff reaction has been used mainly for the formylation of indole deriva-
tives (e.g., 4), which produces 6 in a modest 25% yield (Scheme 2).[14]
According to Scheme 2 and other experimental data available in the literature,
we adapted the experimental conditions by changing the solvent from acetic acid to
trifluorocetic acid. We kept the stoichiometry of 1 eq. of 1-phenyl-1H-pyrazoles 7a–q
Scheme 1. Synthesis of new N-phenylpiperazine derivatives that are selective D2 or D4 receptor lignads.

FORMYLATION OF 1-PHENYL-1H-PYRAZOLES
1635
Scheme 2. Indol formylation through the use of Duff reactions.
and 1.5 eq. of hexamethylenetetramine 5 under reflux temperature for 12 h
(Scheme 3).[14–17]
All 1-phenyl-1H-pyrazoles 7a–q used as substrates were synthesized as described
by Finar and Godfey.1 Under these conditions, a variety of substituted 1-phenyl-1H-
pyrazoles 7a–q with diverse electron-withdrawing and electron donating-subunits
were chemoselectively formylated to generate compounds 1a–p in 76.5–98.9% yields
(Table 1).
Our results indicated that the presence of substituents at the ortho-position on
the phenyl ring, as in 7h, 7n, 7k, and 7p, or at C-3 and C-5 on the pyrazole ring, as in
7o, does not interfere with the chemoselectivity, regiospecificity, or yield of the
reaction. However, when we submitted a 1-phenyl-1H-pyrazole with a strong electron-
donor substituent, 1-(4-methoxyphenyl)-1H-pyrazole 7q, to react with 1 eq. of 5, we
observed the formation of compounds 1q a and 1q b in 67.9% yields at a ratio of
94.2:5.5 respectively (entry 17).
EXPERIMENTAL
All the melting points were determined with a Marte 284594 apparatus. NMR
data were recorded using a Bruker Avance III spectrometer, operating at 500.13 MHz
to proton frequency. The samples for NMR measurements were prepared in CDCl3
containing 1% tetramethylsilane (TMS) as an internal standard. Splitting patterns
are designated as follows: s, singlet; d, doublet; dd, double doublet; ddd, double
double doublet; dddd, double double double doublet; td, triple doublet; t, triplet;
tt, triple tiplet. The infrared (IR) spectra were obtained on a Perkin-Elmer Spectrum
Scheme 3. 1-Phenyl-1H-pyrazole formylation of 7a–q through the use of Duff reactions.

1636
C. H. A. DE OLIVEIRA ET AL.
Table 1. Experimental data of the reactions of substituted-1-phenyl-1H-pyrazoles under the Duff reaction
conditions
Entry
1
7a–q
T (h)
12
Compound
Yield (%)
77.9
2
12
98.5
3
4
12
12
98.0
76.5
5
6
12
12
89.2
98.9
7
12
95.4
8
9
12
12
88.8
79.3
10
12
98.6
(Continued )

FORMYLATION OF 1-PHENYL-1H-PYRAZOLES
Table 1. Continued
1637
Entry
11
7a–q
T (h)
Compound
Yield (%)
12
97.9
12
13
12
12
97.6
93.9
14
15
12
95.0
98.0
6
16
12
12
88.9
67.9
17a
aDetermined by NMR and GC-MS.

1638
C. H. A. DE OLIVEIRA ET AL.
400N Fourier transform (FT)-IR instrument in KBr plates. Microanalytical data
were obtained with a Perkin-Elmer Spectrum BXII FT-IR system, using a digital
analytical scale (Gehaka). Mass spectra (MS) were obtained with a Waters Micro-
mass GCT Premier (Milford, MA, USA) orthogonal time-of-flight mass spectro-
meter. The progress of all reactions was monitored by thin-layer chromatography
(TLC), which was performed on 2.0 Â 6.0 cm aluminium sheets precoated with silica
gel 60 (Merck) to a thickness of 0.25 mm. The developed chromatograms were
viewed under ultraviolet light (254–265 nm) and treated with iodine vapor. For
column chromatography, we used Merck silica gel (70–230 mesh). Reagents and
solvents were purchased from commercial suppliers and distilled prior the use.
Typical procedure was follows: 4.00 mmol of 1-phenyl-1H-pyrazoles 7a–p,
6.00 mmol of hexamethylenetetramine 5, and 5 mL of trifluoracetic acid were added
to a 100 mL round-bottom flask. The reaction was heated under reflux with stirring
for 12 h. At the end of the reaction, the resulting solution was neutralized with a 10%
NaHCO3 solution in an ice bath and the precipitate was filtered off under vacuum.
When necessary, the crude products were purified by column chromatography.
CONCLUSION
In conclusion, 17 1-phenyl-1H-pyrazoles 7a–q with different electron-withdrawing
and electron-donating substituents at the phenyl moiety were chemoselectively and
regiospecifically formylated with hexamethylenetetramine in trifluoroacetic acid under
reflux in good yields. Thus, this methodology could be an efficient alternative method
for the preparation of formylated 1-phenyl-1H-pyrazole derivatives under mild and
safe conditions.
Full experimental details are available online in the Supplementary Information.
ACKNOWLEDGMENTS
We are thankful to FAPEG CH02=2007, CAPES, CNPq, FAPEMIG, and
INCT-INOFAR for grants and financial support.
REFERENCES
1. Finar, I. L.; Godfrey, K. E. The preparation and properties of some derivatives of
1-phenylpyrazole. J. Chem. Soc. 1954, 2293–2298.
´
´
´
´
2. Hoz, A.; Dıaz-Ortiz, A.; Elguero, J.; Martınez, L. J.; Moreno, A. Sanchez-Migallon.
Solvent-free preparation of tris-pyrazolyl-1,3,5-triazines. Tetrahedron 2001, 57, 4397–4403.
3. Guo, C.; Ren, T.; Wang, J.; Li, C.; Song, J. Synthesis, characterization, and fluorescence
properties study of meso-tetrakis(1-arylpyrazole-4-yl)porphyrins. J. Porphyrins Phtalo-
cyanines 2005, 9, 430–435.
4. Muri, E. M. F.; Barreiro, E. J.; Fraga, C. A. M. Synthesis of new benzylic ethers of oximes
derived from 1-phenyl-pyrazole compounds. Synth. Commun. 1998, 28, 1299–1321.
5. Bischoff, A.; Subramanya, H. S.; Sundaresan, K.; Sammeta, S. R.; Vaka, A. K. PCT Int.
Appl. 2008, 157, 844.
6. Menozzi, G.; Mosti, L.; Schenone, P.; Donnoli, D.; Schiariti, F.; Marmo, E. 1-Phenyl-1H-
pyrazole derivatives with antiinflammatory, analgesic, and antipiretic activities. Farmaco
1990, 45, 167–186.

FORMYLATION OF 1-PHENYL-1H-PYRAZOLES
1639
7. Finar, I. L.; Lord, G. H. Formylation of the pyrazole nucleous. J. Chem. Soc. 1957, 3314–3315.
¨
8. Vilsmeier, A.; Haack, E. Uber die Einwirkung von Halogenphosphor auf Alkyl-
formanilide: Eine neue Methode zur Darstellung secunda¨rer und tertia¨rer p-Alkylamino-
benzaldehyde. Ber. 1927, 60, 119–122.
9. Kapias, T.; Griffiths, R. F. Spill behaviour using REACTPOOL, part III: Results for
accidental releases of phosphorus trichloride (PCl3) and oxychloride (POCl3) and general
discussion. J. Hazardous Materials 2001, 81, 223–249.
10. Duff, J. C.; Bills, E. J. Reactions between hexamethylenetetramine and phenolic
compounds, part I: A new method for the preparation of 3- and 5-aldehydosalicylic acids.
J. Chem. Soc. 1932, 1987–1988.
11. Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajfez, F. Hexamethylenetetramine,
a versatile reagent in organic synthesis. Synthesis 1979, 3, 161–176.
12. Menegatti, R.; Cunha, A. C.; Ferreira, V. F.; Perreira, E. F. R.; El-Nabawi, A.; Eldefrawi,
A. T.; Albuquerque, E. X.; Neves, G.; Rates, S. M. K.; Fraga, C. A. M.; Barreiro, E. J.
Design, synthesis, and pharmacological profile of novel dopamine D2 receptor ligands.
Bioorg. Med. Chem. 2003, 11, 4807–4813.
13. Neves, G.; Menegatti, R.; Antonio, C. B.; Grazziottin, L. R.; Vieira, R. O.; Rates, S. M.
K.; Noel, F.; Barreiro, E. J.; Fraga, C. A. M. Searching for multi-target antipsychotics:
Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and
5-HT1A receptors. Bioorg. Med. Chem. 2010, 18, 1925–1935.
14. Verbiscar, A. J. Synthesis of 1-p-chlorobenzyl-7-azaindole-3-alpha-piperidylmethanol as
a potential antimalarial agent. J. Med. Chem. 1972, 15, 149–152.
15. Lindoy, A. F.; Meehan, G. V.; Svenstrup, N. Mono- and diformylation of 4-substituted
phenols: A new Application of the Duff reaction. Synthesis 1998, 7, 1029–1032.
16. Johansson, A.; Abrahamsson, M.; Magnuson, A.; Huang, P.; Martensson, J.; Styring, S.;
Hammarstro¨, L.; Sun, L.; Akermark, B. Synthesis and photophysics of one mononuclear
Mn(III) and one dinuclear Mn(III,III) complex covalently linked to a ruthenium(II)
tris(bipyridyl) complex. Inorg. Chem. 2003, 42, 7502–7511.
17. Lalehzari, A.; Desper, J.; Levy, C. J. Double-stranded monohelical complexes from an
unsymmetrical chiral Schiff-base ligand. Inorg. Chem. 2008, 47, 1120–1126.