Regiospecific synthesis of 4-alkoxy and 4-amino substituted 2-trifluoromethyl pyrroles

Article abstract of DOI:10.1021/jo061058k

A simple and regiospecific synthesis of 4-alkoxy(amino)-2-trifluoromethyl pyrroles from 5-azido-4-alkoxy-(amino)-1,1,1-trifluoro-pent-3-en-2-ones by an aza-Wittig cyclization of aminophosphoranes is described. The structures of the pyrroles and their synt

Full text of DOI:10.1021/jo061058k

Regiospecific Synthesis of 4-Alkoxy and 4-Amino Substituted
2-Trifluoromethyl Pyrroles
Nilo Zanatta,*,† Juliana M. F. M. Schneider,†,‡ Paulo H. Schneider,†,‡ Ana D. Wouters,†
Helio G. Bonacorso,† Marcos A. P. Martins,† and Ludger A. Wessjohann‡
Nu´cleo de Qu´ımica de Heterociclos (NUQUIMHE), Departamento de Qu´ımica, UniVersidade Federal de
Santa Maria, CEPs97105-900, Santa Maria, RS, Brazil, and Leibniz Institute of Plant Biochemistry,
Weinberg 3, D-06120 Halle (Saale), Germany
zanatta@base.ufsm.br
ReceiVed May 23, 2006
A simple and regiospecific synthesis of 4-alkoxy(amino)-2-trifluoromethyl pyrroles from 5-azido-4-alkoxy-
(amino)-1,1,1-trifluoro-pent-3-en-2-ones by an aza-Wittig cyclization of aminophosphoranes is described.
The structures of the pyrroles and their synthetic intermediates were supported by NMR and HRMS
analysis.
The development of a methodology for synthesizing hetero-
cyclic compounds bearing a trifluoromethyl group has received
much attention recently, because the introduction of halogenated
groups in organic molecules often improves their biological
activity, probably because of the high lipophilicity of the
trifluoromethyl group.1 The most convenient method to construct
halogenated compounds is to make use of halogen-containing
building blocks as starting reagents.2 Trifluoromethylated
4-alkoxyvinyl ketones represent interesting precursors for the
synthesis of trifluoromethyl containing compounds, especially
heterocyclic systems.3
Among the numerous heterocycles, the pyrrole core has been
one of the most prominent, because this structure is present in
many important classes of natural products,4 and many pyrrole
derivatives exhibit interesting biological activities.5 Other
examples of simple pyrrole derivatives that exhibit remarkable
activity6 are antibiotics, such as pyrrolnitrine and verrucarin E,7
and pheromones, such as methyl 4-methylpyrrole-2-carboxylate,8
the trail marker of the Texas leaf-cutting ant (Atta texana), just
to name a few. Furthermore, trifluoromethyl substituted pyrroles
(5) For some recent examples on the biological activity of pyrrole
derivatives see the following: (a) Tsantili-Kakoulidou, A.; Nicolau, I.;
Vrakas, D.; Demopoulos, V. J. Med. Chem. 2005, 1, 321. (b) You, Y.;
Gibson, S. L.; Hilf, R.; Ohulchanskyy, T. Y.; Detty, M. R. Bioorg. Med.
Chem. 2005, 13, 2235. (c) Holub, J. M.; O’Toole, C. K.; Getzel, A.; Argenti,
A.; Evans, M. A.; Smith, D. C.; Dalglish, G. A.; Rifat, S.; Wilson, D. L.;
Taylor, B. M.; Miott, U.; Glersaye, J.; Lam, L. S.; McCranor, B. J.;
Berkowitz, J. D.; Miller, R. B.; Lukens, J. R.; Krumpe, K.; Gupton, J. T.;
Burnham, B. S. Molecules 2004, 9, 135. (d) Chin, Y. W.; Lim, S. W.; Kim,
S. H.; Shin, D. Y.; Suh, Y. G.; Kim, Y. B.; Kim, Y. C.; Kim, J. Bioorg.
Med. Chem. Lett 2003, 13, 79. (e) Mach, R. H.; Huang, Y. S.; Freeman, R.
A.; Wu, L.; Blair, S.; Luedtke, R. R. Bioorg. Med. Chem. 2003, 11, 225.
(f) Bleicher, K. H.; Wuthrich, Y.; Adam, G.; Hoffmann, T.; Sleight, A. J.
Bioorg. Med. Chem. Lett. 2002, 12, 3073.
(6) (a) Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafi, A.;
Manetti, F. Bioorg. Med. Chem. 2003, 11, 515. (b) Biava, M.; Porretta, G.
C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F. Bioorg. Med. Chem. 2004,
12, 1453. (c) Sbardella, G.; Mai, A.; Artico, M.; Loddo, R.; Setzu, M. G.;
La Colla, P. Bioorg. Med. Chem. Lett. 2004, 12, 1537.
(7) Enders, D.; Maassem, R.; Han, S. Liebigs Ann. 1996, 1565. (b) Ha¨rri,
E.; Loeffler, W.; Sigg, H. P.; Sta¨helin, H.; Stoll, C.; Tamm, C. HelV. Chim.
Acta 1962, 45, 839. (c) Pfa¨ffli, P.; Tamm, C. HelV. Chim. Acta 1969, 52,
1921.
† Universidade Federal de Santa Maria.
‡ Leibniz Institute of Plant Biochemistry.
(1) (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635. (b) Welch, J. T.
Tetrahedron 1987, 43, 3123.
(2) Martins, M. A. P.; Sinhorin, A. P.; Rosa, A.; Flores, A. F. C.;
Wastowski, A. D.; Pereira, C. M. P.; Flores, D. C.; Beck, P.; Freitag, R.
A.; Brondani, S.; Cunico, W.; Bonacorso, H. G.; Zanatta, N. Synthesis 2002,
2353.
(3) (a) Sanin, A. V.; Nenajdenko, V. G.; Smoko, K. I.; Denisenko, D.
I.; Balenkova, E. S. Synthesis 1997, 842. (b) Zanatta, N.; Rosa, L. S.;
Cortelini, M. F. M.; Beux, S.; Santos, A. P. D.; Bonacorso, H. G.; Martins,
M. A. P. Synthesis 2002, 2404. (c) Bonacorso, H. G.; Lopes, I. S.;
Wastowski, A. D.; Zanatta, N.; Martins, M. A. P. J. Fluorine Chem. 2003,
120, 29. (d) Bonacorso, H. G.; Wentz, A. P.; Zanatta, N.; Martins, M. A.
P. Synthesis 2001, 1505.
(4) (a) Braun, R. U.; Zeiter, K.; Muller, T. J. J. Org. Lett. 2001, 3, 3297.
(b) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 2, p 207. (c) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford 1996; Vol. 2, p 119. (d) Fu¨rstner, A. Synlett 1999, 1523. (e) Boger,
D. L.; Patel, M. Tetrahedron Lett. 1987, 28, 2499.
(8) Sonnet, P. J. Med. Chem. 1971, 15, 97.
10.1021/jo061058k CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/05/2006
6996
J. Org. Chem. 2006, 71, 6996-6998

Synthesis of Substituted 2-Trifluoromethyl Pyrroles
TABLE 1. Reaction Conditions and Yields for the Synthesis of
Compounds 2 and 3
SCHEME 1
reaction
compd
R
conditionsa
yield (%)b
product
1a
1b
1c
1d
2a
2b
2c
2d
Me
Et
i-Pr
n-Bu
Me
Et
a
a
a
a
b
b
b
b
95
94
93
93
90
70
88
74
2a
2b
2c
2d
3a
3b
3c
3d
Reagents and conditions. (a) (1) Br2, CH2Cl2, 0 °C to rt, 2 h; (2) Py,
0 °C to rt, 1 h. (b) NaN3, acetone, 0 °C to rt, 1 h.
i-Pr
n-Bu
are rare compounds; however, they have been shown to exhibit
significant insecticidal and acaricidal activity.9
a Reaction conditions: (a) (1) Br2, CH2Cl2, 0 °C to rt, 2 h; (2) Py, 0 °C
to rt, 1 h. (b) NaN3, acetone, 0 °C to rt, 1 h. b Yields of pure isolated
products.
The 2- or 5-substituted pyrroles are easily synthesized by
aromatic electrophilic substitution,10 whereas a special strategy
is necessary to obtain 3- or 4-substituted pyrroles.11 Furthermore,
pyrroles bearing electron-donor substituents are not very stable.12
Probably for this reason, alkoxy and alkylamino substituted
pyrroles are not as often reported as the pyrroles bearing
electron-withdrawing substituents.13 Therefore, it is important
to note that there is a clear demand for the development of a
modular and simple reaction to strategically access substituted
pyrroles.14
In this paper, we wish to report a simple and regiospecific
synthesis of new 4-alkoxy and 4-amino substituted 2-trifluoro-
methyl pyrroles from the Staudinger reaction of the readily
available 5-azido-1,1,1-trifluoro-4-alkoxy(amino)-pent-3-en-2-
ones with triphenyl- or trimethyl-phosphine, followed by an
intramolecular aza-Wittig cyclization of iminophosphoranes. To
the best of our knowledge, no description of the use of such
compounds for the synthesis of 4-alkoxy or 4-amino substituted
2-trifluoromethyl pyrroles has been reported.
TABLE 2. Reaction Conditions and Yields for the Synthesis of
Compounds 5a-f and 6a-f
reaction
compd
R1
R2
conditionsa yield (%)b product
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
Me
Et
Me
Et
c
c
c
c
c
c
d
d
d
d
d
d
79
89
82
90
92
76
72
78
81
61
64
77
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
-(CH2)4-
-(CH2)5-
-(CH2)2-O-(CH)2-
Bn
Me
Et
Bn
Me
Et
-(CH2)4-
-(CH2)5-
-(CH2)2-O-(CH)2-
Bn
Bn
a Reaction conditions: (c) HNR1R2, CH3CN, 0 °C to rt, 8 h; (d) Me3P,
THF, 0 °C to rt, 8 h. b Yields of pure isolated compounds.
with bromine and pyridine in dichloromethane.17 The subsequent
reaction with sodium azide furnished the 5-azido-4-alkoxy-1,1,1-
trifluoro-methyl-pent-3-en-2-ones 3a-d (Scheme 1, Table 1).17
In a second strategy, the bromination of 1a was carried out
first, followed by the trans-etherification of the brominated 2a
with alcohols. In addition, the trans-etherification reaction was
performed on the azido compound 3a to reduce the number of
reactions. However, the trans-etherification reaction using both
2a and 3a gave a complex mixture of products, proving to be
impractical.
Scheme 1 outlines the synthesis of the key intermediates 3a-
d, which starts with the preparation of the enone 1a, whose
synthesis has been published previously.15 To increase the
number of substituents (R), trans-etherification reactions of 1a
were performed with alcohols such as ethanol, 2-propanol, and
butanol with a catalytic amount of p-toluenesulfonic acid,
furnishing compounds 1b-d.16 The brominated compounds
2a-d were prepared in good yields from the reaction of 1a-d
(9) Black, B. C.; Hollingworth, R. M.; Ahammadsahib, K. I.; Kukel, C.
D.; Donovan S. Pestic. Biochem. Physiol. 1994, 50, 115.
Having obtained the 5-azido-1,1,1-trifluoro-4-methoxy-pent-
3-en-2-ones 3, we concentrated our efforts on the synthesis of
the pyrrole rings. The reaction was initially carried out with
the azido compound 3a, to determine the best reaction conditions
(Table 2). It is well-known that the azido function can be easily
reduced with phosphines to iminophosphoranes, which can effect
an aza-Wittig attack on an electron-deficient carbon.18
A similar reaction was presented by Montforts et al.,12a where
2-azido-ethylidene-malonic acid methyl esters reacted with
triphenylphosphine to give a series of 2-methoxy-1-H-pyrrole-
3-carboxylic acid methyl esters. According to the study of Dieter
and Yu,13 the inability to control olefin stereochemistry in the
γ-amino-R,â-enone adduct I (Figure 1) could pose serious
problems to the pyrrole formation, unless both stereoisomers
could be cyclized to the corresponding pyrrole as is possible
(10) Jones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Academic
Press: London, 1977; references therein.
(11) (a) Pavri, N. P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649. (b)
Chen, N.; Lu, Y.; Gadamasetti, K.; Hurt, C. R.; Norman, M. H.; Fotsch, C.
J. Org. Chem. 2000, 65, 2603. (c) Marcotte, F.-A.; Lubell, W. D. Org.
Lett. 2002, 4, 2601. (d) Marcotte, F.-A.; Rombouts, F. J. R.; Lubell, W. D.
J. Org. Chem. 2003, 68, 6984. (e) Kagoshima, H.; Akiyama, T. J. Am.
Chem. Soc. 2000, 122, 11741. (f) Wasserman, H. H.; Power, P.; Petersen,
A. K. Tetrahedron Lett. 1996, 37, 6657.
(12) (a) Montforts, F. P.; Schwartz, U. M.; Maib, P.; Mai, G. Liebigs
Ann. Chem. 1990, 1037. (b) Breuil-Desvergnes, V.; Compain, P.; Vate`le,
J.-M.; Gore´, J. Tetrahedron Lett. 1999, 40, 8789.
(13) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283 and references therein.
(14) For recent examples see the following: (a) Salamone, S. G.; Dudley,
G. B. Org. Lett. 2005, 7, 4443. (b) Song, G.; Wang, B.; Wang, G.; Kang,
Y.; Yang, T.; Yang, L. Synth. Commun. 2005, 35, 1051. (c) Dieltiens, N.;
Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak, R.; Verpoort, F.
Tetrahedron Lett. 2004, 45, 8995. (d) Tracey, M. R.; Hsung, R. P.; Lambert,
R. H. Synthesis 2004, 918. (e) Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang,
L.; Suo, J. Tetrahedron Lett. 2004, 45, 3417. (f) Dhawan, R.; Arndtsen, B.
A. J. Am. Chem. Soc. 2004, 126, 468. (g) Abdelrazek, F. Synth. Commun.
2005, 35, 2251. (h) Delayen, A.; Goossens, L.; Houssin, R.; Henichart, J.
P. Heterocycles 2005, 65, 1673.
(17) Martins, M. A. P.; Sinhorin, A. P.; Zimmermann, N. E. K.; Zanatta,
N.; Bonacorso, H. G. Synthesis 2001, 1959.
(18) (a) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197. (b) Singh, P.
N. D.; Klima, R. F.; Muthukrishnan, S.; Murthy, R. S.; Sankaranarayanan,
J.; Stahlecker, H. M.; Patel, B.; Gudmundsdo´ttir, A. D. Tetrahedron Lett.
2005, 46, 4213.
(15) Colla, A.; Clar, G.; Martins, M. A. P.; Krimmer, S.; Fischer, P.
Synthesis 1991, 483.
(16) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828.
J. Org. Chem, Vol. 71, No. 18, 2006 6997

Zanatta et al.
SCHEME 2
SCHEME 3
FIGURE 1. Structures of precursors used in the synthesis of pyrroles.
for the compounds in structure II (Figure 1). An anti relationship
between the carbon-carbon double bond of the methyl azido
and the carbonyl groups of intermediate III could hinder the
formation of the corresponding pyrroles. However, the low
energy barrier of the carbon-carbon double bond observed in
compounds such as 3 and 5 (Schemes 2 and 3, respectively),
which is driven by the electron “push-pull” effect of the
carbonyl (π-acceptor) and the 4-alkoxy or 4-amino groups (π-
donor), allows one to draw resonance structures such as III and
IV (Figure 1), where the rotation around the C3-C4 bond is
less restricted. Thus, because of the easy interconversion
between the E and Z isomers (structures IV and V), the azido
intermediates 3 and 5 can be completely converted to the
corresponding pyrroles 4 and 6 regardless of the configuration
of the carbon-carbon double bond.
Thus, through the reaction of compounds 3 with an equimolar
amount of triphenylphosphine in THF, the desired 4-alkoxy-2-
trifluoromethyl pyrroles 4a-d were isolated in moderate to good
yields after short reaction times (Scheme 2).
We attempted to improve the yields by changing reaction
conditions, such as temperature, reaction times, and amount of
phosphine. It was observed that the utilization of 2 equiv of
phosphine did not improve the yields and, when the reaction
was carried out in THF under reflux, the product was not
observed, probably owing to the decomposition of the starting
material. Compounds 4a-d that resulted in oils after purification
were not very stable and needed storage at -4 °C.
We observed that the methoxy group of 3a could also be
replaced by an amino group, to obtain 4-amino substituted
2-trifluoromethyl pyrroles. The precursors for these derivatives
were achieved when compound 3a underwent a reaction with a
series of secondary amines in acetonitrile19 (Scheme 3). Initially,
the cyclization step was also performed using triphenylphosphine
as the azido reducing agent. However, the triphenylphosphin-
oxide byproduct formed during the course of the cyclization
reaction was very difficult to separate from the obtained 4-amino
pyrroles 6 by means of column chromatography, distillation,
or recrystallization.
This problem was circumvented by changing the triphenyl-
phosphine reagent to trimethylphosphine. Since the trimeth-
ylphosphinoxide is soluble in water, it was easily removed by
the extraction step, and products were further purified by
distillation in a Kugelrohr oven and recrystallization from a
dichloromethane/hexane mixture. The 4-amino pyrrole products
6a-f were obtained in better yields (Table 2) than the 4-alkoxy
pyrrole derivatives 4a-d, probably because compounds 6 are
more stable than compounds 4. However, the attempted cy-
clization of 5, derived of primary amines, rendered a complex
mixture of products.
In summary, we have developed a simple, efficient, and
regiospecific synthetic procedure for the preparation of new
4-alkoxy and 4-dialkylamino substituted 2-trifluoromethyl pyr-
roles, using mild conditions in order to not set off the
decomposition of the products. In addition, this study showed
that 5-azido-1,1,1-trifluoro-4-alkoxy(amino)-pent-3-en-2-ones 3
and 5 are convenient key intermediates for the synthesis of
4-alkoxy and 4-dialkylamino substituted 2-trifluoromethyl pyr-
roles, since they are easily obtained in good yields and the
cyclization step does not depend on the E/Z configuration of
the carbon-carbon double bond of 3 and 5 for the cyclization
to take place.
Experimental Section
General Procedure for the Synthesis of 4-Alkoxy-pyrroles
4a-d. A solution of Ph3P in THF (1M, 1.0 mL) was slowly added
to a stirred solution of azido compounds 3 (1.0 mmol) in dry THF
(4 mL) with a syringe at room temperature. After 8 h, the THF
was removed in vacuo, and the oil residue was distilled in a
Kugelrohr glass oven, affording the pyrroles as yellow oils.
General Procedure for the Synthesis of 4-Dialkylamino-
pyrroles 6a-f. In a 25 mL round-bottom flask, a solution of azido
compounds 5 (1.0 mmol) in dry THF (5 mL) was cooled to 0 °C
with an ice bath. Me3P (1 M in THF, 1.0 mL) was slowly added to
this solution with a syringe. The reaction was allowed to reach
room temperature, and stirring was continued for an additional 8
h. The THF was removed in vacuo, and the residue (for 6a, and
6c-f) was dissolved in a 1:1 mixture of hexane/CH2Cl2 (2 mL)
for crystallization by cooling. Compound 6b was purified in a
Kugelrohr glass oven and obtained as an orange oil.
Acknowledgment. The authors thank the financial support
of the Conselho Nacional de Desenvolvimento Cient´ıfico e
Tecnolo´gico, CNPq (Universal Grant No. 477682/01-4), and
the fellowship from CAPES (J. M. F. M. Schneider).
Supporting Information Available: Representative experi-
mental procedure, characterization data (1H and 13C NMR, HRMS-
(ESI), and IR), and selected 1H and 13C NMR and HRMS spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Zanatta, N.; Squizani, A. M. C.; Fantinel, L.; Nachtigall, F. M.;
Bonacorso, H. G.; Martins, M. A. P. Synthesis 2002, 2409. (b) Bonacorso,
H. G.; Duarte, S. H. G.; Zanatta, N.; Martins, M. A. P. Synthesis 2002,
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L. M. L.; Zanatta, N.; Martins, M. A. P. Synth. Commun. 2002, 32, 335.
(d) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7267. (e) Gorbunova,
M. G.; Gerus, I. I.; Kukhar, V. P. Synthesis 1999, 738.
JO061058K
6998 J. Org. Chem., Vol. 71, No. 18, 2006