Rapid one-pot, four-step synthesis of highly fluorescent 1,3,4,5-tetrasubstituted pyrazoles

Article abstract of DOI:10.1021/ol2004947

1,3,4,5-Tetrasubstituted pyrazoles can be rapidly and efficiently synthesized in a one-pot, four-step sequence consisting of Sonogashira coupling, addition-cyclocondensation, bromination, and Suzuki coupling. The second and the last step are microwave-ass

Full text of DOI:10.1021/ol2004947

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2082–2085
Rapid One-Pot, Four-Step Synthesis of
Highly Fluorescent 1,3,4,5-
Tetrasubstituted Pyrazoles§
€
Benjamin Willy and Thomas J. J. Muller*
Institut fu€r Organische Chemie und Makromolekulare Chemie,
€
€
€
Heinrich-Heine-Universitat Dusseldorf, Universitatsstrasse 1, D-40225 Dusseldorf, Germany
€
thomasjj.mueller@uni-duesseldorf.de
Received February 23, 2011
ABSTRACT
1,3,4,5-Tetrasubstituted pyrazoles can be rapidly and efficiently synthesized in a one-pot, four-step sequence consisting of Sonogashira coupling,
addition-cyclocondensation, bromination, and Suzuki coupling. The second and the last step are microwave-assisted, and according to sequential
catalysis, no addition of further Pd catalyst is needed for the terminal step. The title compounds show intense blue fluorescence and high quantum yields.
Pyrazoles, five-membered heterocycles with two adja-
cent nitrogen atoms, display a rich chemistry and numer-
ous applications.1 A broad spectrum of biological activity,
such as antihyperglycemic, analgesic, antiinflammatory,
antipyretic, antibacterial, and sedative-hypnotic acti-
vity, has attracted considerable interest in medicinal
chemistry.2-4 In addition, several 3,5-diaryl-substituted
pyrazoles also reversibly inhibit monoamine oxidase A
and monoamine oxidase B.5 For crop protection, 1,2-
dialkyl-3,5-diphenylpyrazoles are known as potent
herbicides.6 Furthermore, pyrazoles are pluripotent li-
gands in coordination chemistry,7 as building blocks in
heterocycle synthesis,8 as optical brighteners9 and UV
stabilizers,10 as photoinduced electron transfer systems,11
(6) Walworth, B.; Klingsberg, E. German Patent DE 2260485
19730628, 1973.
(7) For representative reviews, see, e.g.: (a) Trofimenko, S. Chem.
Rev. 1972, 72, 497–509. (b) Mukherjee, R. Coord. Chem. Rev. 2000, 203,
151–218. (c) Trofimenko, S. Polyhedron 2004, 23, 197–203. (d) Ward,
M. D.; McCleverty, J. A.; Jeffery, J. C. Coord. Chem. Rev. 2001, 222,
251–272.
(8) (a) Harb, A.-F. A.; Abbas, H. H.; Mostafa, F. H. Chem. Pap.
2005, 59, 187–195. (b) Harb, A.-F. A.; Abbas, H. H.; Mostafa, F. H.
J. Iranian Chem. Soc. 2005, 2, 115–123.
§ Dedicated to Prof. Dr. Dieter Enders on the occasion of his 65th birthday.
(1) For general reviews, see, e.g.: (a) Kost, A. N.; Grandberg, I. I.
Adv. Heterocycl. Chem. 1966, 6, 347–429. (b) Elguero, J. In Comprehen-
sive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 5, p 167. (c) Elguero, J. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier:
Oxford, 1996; Vol. 3, p 1.
(2) Wustrow, D. J.; Capiris, T.; Rubin, R.; Knobelsdorf, J. A.;
Akunne, H.; Davis, M. D.; MacKenzie, R.; Pugsley, T. A.; Zoski,
K. T.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8,
2067–2070.
(3) Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M.
J. Heterocycl. Chem. 1997, 34, 963–968.
(9) For a review on heterocycles as active ingredients in optical
brighteners, see, e.g.: Dolars, A.; Schellhammer, C.-W.; Schroeder, J.
Angew. Chem., Int. Ed. Engl. 1975, 14, 665–679.
(10) Catalan, J.; Fabero, F.; Claramunt, R. M.; Santa Maria, M. D.;
Foces-Foces, M. C.; Hernandez Cano, F.; Martinez-Ripoll, M.; Elguero, J.;
Sastre, R. J. Am. Chem. Soc. 1992, 114, 5039–5048.
(4) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347–1365.
(5) Chimenti, F.; Fioravanti, R.; Bolasco, A.; Manna, F.; Chimenti,
P.; Secci, D.; Befani, O.; Turini, P.; Ortuso, F.; Alcaro, S. J. Med. Chem.
2007, 50, 425–428.
(11) (a) Karatsu, T.; Shiochi, N.; Aono, T.; Miyagawa, N.; Kitamura,
A. Bull. Chem. Soc. Jpn. 2003, 76, 1227–1231. (b) Yen, Y.-P.; Huang,
T.-M.; Tseng, Y.-P.; Lin, H.-Y.; Lai, C.-C. J. Chin. Chem. Soc. 2004, 51,
393–398.
(12) (a) Sachse, A.; Penkova, L.; Noel, G.; Dechert, S.; Varzatskii,
O. A.; Fritsky, I. O.; Meyer, F. Synthesis 2008, 800–806. (b) Maeda, H.;
Ito, Y.; Kusunose, Y.; Nakanishi, T. Chem. Commun 2007, 1136–1138.
(c) Gemming, S.; Schreiber, M.; Thiel, W.; Heine, T.; Seifert, G.; Avelino
de Abreu, H.; Anderson Duarte, H. J. Lumin. 2004, 108, 143–147.
r
10.1021/ol2004947
Published on Web 03/18/2011
2011 American Chemical Society

and as units in supramolecular entities.12 Hence, numerous
methods for the synthesis of 1,3,5-substituted pyrazoles
have been established.1,13
Scheme 1. Retrosynthetic Analysis of Persubstituted Pyrazoles
With respect to the interesting electronic properties of
pyrazoles as fluorophores and the increasing quest for
tailor-made functional π-electron systems by diversity-
oriented strategies,14 as part of our program to develop
multicomponent synthesis of heterocycles,15 we have
recently disclosed an efficient, regioselective, one-pot,
three-component synthesis of trisubstituted pyrazoles.16
In addition, this highly diversity-oriented approach en-
abled us to access large Stokes shift fluorophores with a
flexible substitution pattern.
Tetrasubstituted pyrazoles have been shown to possess a
remarkable nanomolar inhibitory potential for HMG-
CoA reductase17 or p38 MAP kinase.18 Therefore, we set
out to conceptually expand our pyrazole synthesis to
persubstituted pyrazoles upon sequentially combining
several elementary steps in a consecutive one-pot fashion.
Here we communicate a consecutive one-pot, four-step, de
novo synthesis of 1,3,4,5-tetrasubstituted pyrazoles with a
highly flexible substitution pattern in good yields. As a
consequence of the increasing interest in blue-light emit-
ting molecules, the absorption and emission properties of
selected persubstituted pyrazoles have been studied with
UV/vis and fluorescence spectroscopy.
Hence, the required 4-halopyrazole 2 in turn is derived
from halogenation of the pyrazole 3. Therefore, the ana-
lysis of the intermediate alkynone precursor 4 suggests
that aroyl chlorides 5, terminal alkynes 6, and hydrazines
7 first have to be reacted in a Sonogashira cou-
pling-addition-cyclocondensation sequence to furnish
pyrazoles 3. Reaction with an electrophilic halide source
8 gives 4-halopyrazoles 2 that are finally coupled with
boronic acids 9 furnishing the title compounds 1 by Suzuki
coupling. Although all individual steps (3CR-pyrazole
formation, pyrazole halogenation, and Suzuki coupling
of 4-halopyrazoles) are well precedented, the major chal-
lenge lies in the concatenation of these steps into a one-pot
sequence. Conceptually, we envisioned a sequentially Pd-
catalyzed process;19 i.e., the catalyst source of the Sonoga-
shira stephas to be applied for a second time at a later stage
for the Suzuki coupling without further addition of
catalyst.
First, we set out to develop a four-component synthesis
of 4-halopyrazoles 2, important intermediates in their own
right inthe synthesis of densely functionalizedpyrazoles by
cross-coupling.20 N-Halosuccinimide has been identified
as a suitable halogen source for the halogenation of
pyrazoles.21,22 Hence, the 4-halogenation of 3-anisyl-1-
methyl-5-phenylpyrazole (3a) with N-halosuccinimide 10
(halo = Cl, Br) in methanol was found to be quantitative
at room temperature within 10-30 min, furnishing 3-ani-
syl-4- chloro-1-methyl-5-phenylpyrazole (2a) or 3-anisyl-
4- bromo-1-methyl-5-phenylpyrazole (2d), respectively.
Our retrosynthetic analysis of 1,3,4,5-tetrasubstituted
pyrazoles 1 (Scheme 1) commences with a terminal
Suzuki coupling as one of the most reliable methodolo-
gies for connecting (hetero)aromatic sp2-hybridized
substructures.
(13) For recent pyrazole syntheses, see, e.g.: (a) Wu, X.-F.; Neumann,
H.; Beller, M. Chem.;Eur. J. 2010, 16, 12104–12107. (b) Dang, T. T.;
€
Dang, T. T.; Fischer, C.; Gorls, H.; Langer, P. Tetrahedron 2008, 64,
2207–2215. (c) Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu,
Q.-H.; Tang, Z. Tetrahedron Lett. 2008, 49, 3805–3809. (d) Wang, K.;
Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008, 10, 1691–1694. (e)
Bagley, M. C.; Lubinu, M. C.; Mason, C. Synlett 2007, 704–708. (f)
Bagley, M. C.; Davis, T.; Dix, M. C.; Widdowson, C. S.; Kipling, D.
Org. Biomol. Chem. 2006, 4, 4158–4164. (g) Heller, S. T.; Natarajan,
S. R. Org. Lett. 2006, 8, 2675–2678. (h) Deng, X.; Mani, N. S. Org. Lett.
2006, 8, 3505–3508. (i) Gosselin, F.; O’Shea, P. D.; Webster, R. A.;
Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J. Synlett 2006, 3267–
3270. (j) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 7079–7082. (k) Ahmed, M. S. M.; Kobayashi, K.; Mori, A.
€
Org. Lett. 2005, 7, 4487–4489. (l) Muller, T. J. J.; Karpov, A. S. Ger.
Offen. DE 10328400 A1 20050113, 2005.
€
(14) (a) Muller, T. J. J.; D’Souza, D. M. Pure Appl. Chem. 2008, 80,
€
609–620. (b) Muller, T. J. J. In Functional Organic Materials - Synthesis,
Strategies, and Applications; M€uller, T. J. J., Bunz, U. H. F., Eds.; Wiley-
VCH: Weinheim, 2007; pp 179-223.
€
(15) For reviews, see: (a) Muller, T. J. J. Top. Heterocycl. Chem. 2010,
€
€
(19) For a review, see, e. g.: Muller, T. J. J. Top. Organomet. Chem.
2006, 19, 149–205.
25, 25–94. (b) Willy, B.; Muller, T. J. J. Curr. Org. Chem. 2009, 13, 1777–
€
1790. (c) Willy, B.; Muller, T. J. J. ARKIVOC Part I 2008, 195–208. (d)
€
D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095–1108. (e)
(20) For recent selected examples of cross-coupling reactions with
halo pyrazoles, see, e. g.: (a) Vasilevsky, S. F.; Klyatskaya, S. V.; Elguero, J.
Tetrahedron 2004, 60, 6685–6688. (b) Zoppellaro, G.; Baumgarten, M.
Eur. J. Org. Chem. 2005, 2888–2892. (c) Hanamoto, T.; Koga, Y.; Kido,
E.; Kawanami, T.; Furuno, H.; Inanaga, J. Chem. Commun. 2005, 2041–
2043. (d) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli,
M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787–1789. (e) Paulson, A. S.;
Eskildsen, J.; Begtrup, M.; Vedsø, P. J. Org. Chem. 2002, 67, 3904–3907.
(21) Li, G.; Kakarla, R.; Gerritz, S. W. Tetrahedron Lett. 2007, 48,
4595–4599.
€
Muller, T. J. J. Targets Heterocycl. Syst. 2006, 10, 54–65.
€
(16) (a) Willy, B.; Muller, T. J. J. Eur. J. Org. Chem. 2008, 4157–4168.
(b) For a related three-component synthesis according to our concept,
see: Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu, Q.-H.; Tang,
Z. Tetrahedron Lett. 2008, 49, 3805–3809.
(17) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.;
Newton, R. S. J. Med. Chem. 1990, 33, 31–38.
(18) Graneto, M. J.; Kurumbail, R. G.; Vazquez, M. L.; Shieh, H.-S.;
Pawlitz, J. L.; Williams, J. M.; Stallings, W. C.; Geng, L.; Naraian, A. S.;
Koszyk, F. J.; Stealey, M. A.; Xu, X. D.; Weier, R. M.; Hanson, G. J.;
Mourey, R. J.; Compton, R. P.; Mnich, S. J.; Anderson, G. D.;
Monahan, J. B.; Devraj, R. J. Med. Chem. 2007, 50, 5712–5719.
(22) Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.;
Guzenb, K. P.; Cella, R. Tetrahedron Lett. 2005, 46, 6833–6837.
Org. Lett., Vol. 13, No. 8, 2011
2083

With these conditions in hand, we next probed the con-
catenation of the three-component pyrazole synthesis and
the halogenations to a consecutive one-pot, four-compo-
nent synthesis. The consecutive coupling-addition-
cyclocondensation reaction of aroyl chlorides 5, terminal
alkynes 6, and hydrazines 7 furnished the intermediate
pyrazoles 3. Simple addition of N-halosuccinimide 10
(halo = Cl, Br) and stirring for 30 min at room tempera-
ture gives the 4-halopyrazoles 2 in good to excellent yields
(Scheme 2).
potassium carbonate, water, and catalytic amounts of
triphenylphosphane25 furnished tetrasubstituted pyrazoles
1
1 in excellent regioselectivity (>95:<5 according to H
NMR) and inmoderate togoodyields aslight yellow solids
(Scheme 3).
Scheme 3. One-Pot, Four-Step Synthesis of 1,3,4,5-Tetrasub-
stituted Pyrazoles 1
Scheme 2. Four-Component Synthesis of 4-Halopyrazoles 2
The complete four-component coupling-addition-
cyclocondensation-halogenation sequence is essentially
a quantitative spot-to-spot transformation (as monitored
with TLC). For each step, almost equimolar, stoichio-
metric amounts of substrates were applied, illustrating the
highly economical nature of this process. The sequential
halogenation is limited to chlorination and to bromination.
Several attempts to achieve iodination with N-iodosuccini-
mide, iodine, iodomonochloride, or iodomonobromide in a
one-pot fashion were met with failure.
With this efficient four-component synthesis of 4-bro-
mopyrazoles2 in hand, the stage was set for completing the
sequence to persubstituted pyrazoles. For one-pot meth-
odologies, the notion of sequential catalysis is particularly
intriguing because the same catalyst is supposed to operate
for a second time. Encouraged by previous studies with the
intermediacy of 3-halofurans23 and 3-iodopyrroles,24 we
probed the subsequent transformation of the intermediate
4-bromopyrazoles 2 in a one-pot fashion, i.e., without
isolation. Therefore, upon reacting acid chlorides 5 and
terminalalkynes 6 underSonogashira conditions, followed
by cyclocondensation with methyl hydrazine (7a) and
bromination withN-bromosuccinimide(10b), theconclud-
ing Suzuki coupling with boronic acids 9 in the presence of
The structures of the tetrasubstituted pyrazoles 1 were
unambiguouslyassignedbyspectroscopic characterization
(1H NMR, 13C NMR, and IR spectroscopy, mass spectro-
metry) and combustion analysis. The scope of this novel
four-step, one-pot synthesis is rather broad because elec-
tron-rich, electron-poor, (hetero)aromatic, and in the case
of alkynes also aliphatic substituents are well tolerated.
Moreover, the implementation of dielectric heating in the
initial and the terminal step significantly reduces reaction
times. By addition of triphenylphosphane, the catalytic
activity of the palladium species can be restored after
the oxidative halogenation. It is quite remarkable that
the catalyst can be reactivated that easily. With respect to
the overall yields of this one-pot sequence ranging from 22
to 61%, an average yield of 68-88% per step appears to be
quite efficient. The stepwise synthesisof pyrazole1a(three-
component pyrazole synthesis, 93%; bromination, 100%;
Suzuki coupling, 68%) furnishes an overall yield of 63%
(25) If triphenylphosphane was omitted the Suzuki coupling did not
proceed.
€
(23) (a) Karpov, A. S.; Merkul, E.; Oeser, T.; Muller, T. J. J. Chem.
Commun 2005, 2581–2583. (b) Karpov, A. S.; Merkul, E.; Oeser, T.;
Muller, T. J. J. Eur. J. Org. Chem. 2006, 2991–3000.
€
(24) Merkul, E.; Boersch, C.; Frank, W.; Muller, T. J. J. Org. Lett.
2009, 11, 2269–2272.
(26) Vollmer, F.; Rettig, W.; Birckner, E. J. Fluoresc 1994, 4, 65–69.
(27) (a) Swaminathan, M.; Dogra, S. K. J. Photochem. 1983, 21, 245–
250. (b) Swaminathan, M.; Dogra, S. K. Indian J. Chem. Sect. A 1983,
22A, 853–857.
€
2084
Org. Lett., Vol. 13, No. 8, 2011

including purification by column chromatography after
each step. Assuming an average time of 60 min per
chromatographic separation, solvent evaporation and dry-
ing, the total time for the stepwise process adds up to 300
min. In comparison, the novel four-step one-pot synthesis
gives rise to the isolation of tetrasubstituted pyrazole 1a in
54% yield, yet within 180 min, i.e., only 60% of the time
needed for a stepwise scenario.
state, the overlap between absorption and emission bands
is essentially absent.26 This effect, which is known for 3,5-
diaryl pyrazoles with large Stokes shifts,27 is particularly
favorable for applications as fluorescent dyes.
Although persubstituted pyrazoles are particularly in-
teresting in medicinal and crop protection chemistry, our
initial interest is in their peculiar electronic properties as
potential intense blue light emitters.16a Expectedly, the
electronic absorption spectra of the tetrasubstituted pyr-
azoles 1 display broad longest wavelength absorption
bands in the near-UV between 240 and 311 nm with molar
extinction coefficients ranging from 14300 to 50800 L
mol-1 cm-1 (see the Supporting Information for complete
data sets). Most interestingly all representatives reveal
strong blue luminescence in solution with emission maxima
between 373 and 395 nm (Figures 1 and 2). The solid-state
emissions are red-shifted and appear with bluish-green
luminescence. In comparison to related 1,3,5-trisubstituted
pyrazoles 3, the tetrasubstituted pyrazoles 1 exhibit even
larger Stokes shifts ranging from 5300 to 15500 cm-1. In
addition, the fluorescence efficiency is quite high as reflected
by fluorescence quantum yields Φf ranging between 0.29
and 0.72.
Figure 2. Solution (left) and solid state (right) emission of com-
pound 1b in CH2Cl2 (λmax,exc = 254 nm).
In conclusion, we have developed a rapid, one-pot, four-
step synthesis of persubstituted pyrazoles based upon a
consecutive Sonogashira coupling-cyclocondensation-
halogenation-Suzuki coupling sequence in a highly effi-
cient manner. By virtue of the intermediacy of 4-halopyr-
azoles obtained by a four-component synthesis, most
interestingly, the same catalyst could be engaged for a
second time to perform a Suzuki coupling in the sense of a
sequentially Pd-catalyzed process. Persubstituted pyra-
zoles display intense blue fluorescence in solution with
large Stokes shifts. With this rapid, diversity-oriented
synthetic approach to fine-tunable fluorophores (with
fluorescence quantum yields up to 0.72) in hand, detailed
photophysical and computational investigations for the
development of tailor-made emitters in OLED applica-
tions and fluorescence labeling of biomolecules, surfaces,
or mesoporous materials will be the focus of future studies.
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie. The authors are grateful
€
to Dipl.-chem. Marco Teiber (University of Dusseldorf)
Figure 1. Normalized absorption (;) and emission spectra (---)
of compound 1b (recorded in CH2Cl2 at 298 K and at c(1b) =
10-3 M (absorption) and c(1b) = 10-6 M (emission)).
for photography of luminescent samples, to the BASF SE
for generous donations of chemicals, and the CEM GmbH
for research cooperation.
Interestingly, the emission bands in a margin of 20 nm
are almost insensitive to pyrazole substitution. Due to
large Stokes shifts, originating from kite and butterfly
distortions of the heterocyclic framework in the excited
Supporting Information Available. Experimental de-
tails, NMR, absorption, and emission spectra of com-
pounds 1 and 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
2085