A modular sydnone cycloaddition/Suzuki-Miyaura cross-coupling strategy to unsymmetrical 3,5-bis(hetero)aromatic pyrazoles

Article abstract of DOI:10.1021/ol101087j

(Equation Presented). The [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes opens a straightforward access to 3,5-dihalopyrazoles, valuable scaffolds for the elaboration of unsymmetrically 3,5-substituted pyrazole derivatives via site-sel

Full text of DOI:10.1021/ol101087j

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3328-3331
A Modular Sydnone Cycloaddition/
Suzuki-Miyaura Cross-Coupling
Strategy to Unsymmetrical
3,5-Bis(hetero)aromatic Pyrazoles
Thierry Delaunay,† Pierre Genix,‡ Mazen Es-Sayed,‡ Jean-Pierre Vors,‡
Nuno Monteiro,*,† and Genevie`ve Balme*,†
Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS, UMR
5246 du CNRS), ESCPE Lyon, UniVersite´ Lyon 1, 43, Bd du 11 NoVembre 1918,
69622 Villeurbanne, France, and Bayer SAS, Bayer CropScience,
14 impasse Pierre Baizet, BP9163, 69263 Lyon Cedex 09, France
balme@uniV-lyon1.fr; monteiro@uniV-lyon1.fr
Received May 12, 2010
ABSTRACT
The [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes opens a straightforward access to 3,5-dihalopyrazoles, valuable scaffolds
for the elaboration of unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions. For instance,
the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus was achieved
in a one-pot operation via sequential reactions with various boronic acids.
Pyrazoles are important core structures of many pharma-
ceutical and agrochemical substances.1 In conjunction with
a recent drug development program, we needed an efficient
and modular synthetic strategy to assemble a series of 3,5-
bis(hetero)aromatic pyrazoles. Classical approaches to 3,5-
disubstituted pyrazoles are essentially based on the cyclo-
condensation of hydrazine derivatives with 1,3-disubstituted
three-carbon units, including 1,3-diketones and R,ꢀ-unsatur-
ated ketones (i.e., ynones).2,3 Because such procedures
generally suffer from a lack of commercially available
derivatives and flexibility, the development of new protocols,
allowing the sequential introduction of (hetero)aryl substit-
uents on prefunctionalized pyrazoles via regioselective cross-
coupling reactions, would be highly desirable.4 However,
while C-5 functionalization of the pyrazole nucleus via
metalation is well documented,5 the higher difficulty of
metalation at the C-3 position makes the functionalization
of this position more challenging.6 Recently, McLaughlin7
suggested the use of the tetrahydropyranyl (THP) group as
a switchable metal-directing N-protecting group to achieve
successive arylations of the pyrazole nucleus at the C-3 and
C-5 positions by the lithiation/boronation/cross-coupling
method.8 In this letter, we propose a conceptually different
strategy based on the direct assembly of N-substituted
(2) (a) Stanovnik, B.; Svete, J. Pyrazoles, In Science of Synthesis,
Houben-Weyl Methods of Molecular Transformations; Neier, R., Ed.; Georg
Thieme Verlag: Stuttgart, 2002; Vol. 12, p 15. For recent developments in
this area, see: (b) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412. (c)
Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675. Gosselin, F.; O’Shea,
P. D.; Webster, R. A.; Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J.
Synlett 2006, 3267. (d) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org.
Lett. 2005, 7, 4487.
† Universite´ Lyon 1.
‡ Bayer SAS, Bayer CropScience.
(1) (a) Lamberth, C. Heterocycles 2007, 71, 1467. (b) Eicher, T.;
Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles, 2nd ed.; Wiley
& Sons: New York, 2003; p 179.
(3) For an overview of recent advances in the synthesis of pyrazoles,
see: Fustero, S.; Simo´n-Fuentes, A.; Sanz-Cervera, J. F. Org. Prep. Proced.
Int. 2009, 41, 253.
10.1021/ol101087j  2010 American Chemical Society
Published on Web 07/02/2010

pyrazoles bearing distinguishable halides at the C-3 and C-5
positions via cycloaddition of 4-halosydnones with 1-ha-
loalkynes and subsequent site-selective Suzuki-Miyaura
cross-coupling reactions. Our approach requires the use of
haloalkynes substituted by a removable functional group that
would enable access to pyrazole derivatives with a free C-4
position (Scheme 1).
tions. We therefore selected PMP-protected 4-halosyd-
nones 1a,b and ethyl halopropiolates 2a,b as potential
cycloaddition partners, anticipating that the carboxylic
ester group would subsequently be easily removed.
However, at this point, predictions regarding the regiose-
lectivities of the envisioned cycloadditions were not
obvious.14,15 As a preliminary experiment, an equimolar
mixture of iodosydnone 1a and bromoalkyne 2a was heated
at 140 °C in xylenes. Delightfully, the reaction was com-
pleted within 15 h, giving rise to a 3:1 mixture of regioiso-
meric 5-iodopyrazoles 3a and 4a in 84% combined yield
(Table 1, entry 1). The pyrazoles were easily separated by
silica gel chromatography, and the structure assignment of
the desired major isomer 3a (63% isolated yield) was made
on the basis of the 1H NMR spectrum of the corresponding
decarboxylated 3-bromo-5-iodopyrazole 5 that revealed a
sharp singlet at 6.6 ppm characteristic of the proton at C-4
of the pyrazole ring. The latter compound 5, our target
candidate for site-selective cross-coupling reactions, was
easily obtained in 65% isolated yield upon treatment of 3a
with 50% aq sulfuric acid at refluxing temperature (Scheme
2). It deserves mention that this cycloaddition strategy could
not provide the regioisomeric 5-bromo-3-iodopyrazoles,
which may reflect the thermal instability of the required
4-bromosydnone 1b (Table 1, entry 2).16 However, the
strategy applied nicely to the preparation of diiodopyrazoles
Scheme 1
.
Sydnone Cycloaddition/Cross-Coupling Strategy to
3,5-Bisfunctionalized Pyrazoles
The 1,3-dipolar cycloaddition of N-substituted sydnones
with acetylenic derivatives has proven to be a powerful
method for the construction of a variety of functionalized
pyrazoles, albeit this procedure often suffers from low
regioselectivities when unsymmetrical alkynes are involved.9
Although 4-halosydnones have been shown to participate
effectively in such a process to yield 5-halopyrazoles,10,11
to the best of our knowledge the use of haloalkynes in
sydnone cycloadditions has not been investigated to date.12,13
We initially planned to develop 3(5)-bromo-5(3)-
iodopyrazole model substrates 3a,b as the most favorable
scaffold candidates for regioselective cross-coupling reac-
(12) Recently, Harrity reported the synthesis of pyrazoleboronic esters
via sydnone cycloaddition with alkynylboranes and their subsequent use in
cross-coupling reactions allowing functionalization at the pyrazole C-4
position: (a) Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew.
Chem., Int. Ed. 2007, 46, 8656. Recent reports feature examples of sydnone
cycloadditions with alkynylstananes: (b) Gonza´lez-Nogal, A. M.; Calle, M.;
Cuadrado, P.; Valero, R. Tetrahedron 2007, 63, 224. (c) Nicolaou, K. C.;
Pratt, B. A.; Arseniyadis, S.; Wartmann, M.; O’Brate, A.; Giannakakou, P.
Chem. Med. Chem. 2006, 1, 41
.
(13) For previous 1,3-dipolar cycloaddition reactions of 1-haloalkynes,
see: (a) Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg,
P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett
2005, 3059. (b) Letourneau, J. J.; Riviello, C.; Ohlmeyer, M. H. J.
Tetrahedron Lett. 2007, 48, 1739. (c) Takenaka, K.; Nakatsuka, S.;
Tsujihara, T.; Koranne, P. S.; Sasai, H. Tetrahedron: Asymmetry 2008, 19,
2492. (d) Hein, J. E.; Tripp, J. C.; Krasnova, L.; Sharpless, K. B.; Fokin,
V. V. Angew. Chem., Int. Ed. 2009, 48, 8018. For other heterocycloadditions
of alkynyl halides, see: (e) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem. 2007, 72,
4205. (f) Hurst, T. E.; Miles, T. J.; Moody, C. J. Tetrahedron 2007, 64,
(4) For reviews on site-selective cross-coupling reactions of polyhalo-
genated heteroarene derivatives, see: (a) Schro¨ter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Fairlamb, I. J. S. Chem. Soc. ReV. 2007,
36, 1036. (c) Wang, J.-R.; Manabe, K. Synthesis 2009, 1405. For a recent
insight into the origin of regioselectivities, see: (d) Legault, C. Y.; Garcia,
Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 12664.
(5) See for examples: (a) Heinisch, G.; Holzer, W.; Pock, S. J. Chem.
Soc., Perkin Trans. 1 1990, 1829. (b) Larsen, S. D. Synlett 1997, 1013. (c)
Ge´rard, A.-L.; Bouillon, A.; Mahatsekake, C.; Collot, V.; Rault, S.
Tetrahedron Lett. 2006, 47, 4665. (d) Iddon, B.; Tønder, J. E.; Hosseini,
M.; Begtrup, M. Tetrahedron 2007, 63, 56.
874
.
(14) Previous reports dealing with 3-phenylsydnone cycloaddition
involving unsymmetrical alkynyl esters have essentially concerned the case
of unsubstituted propiolates. It was established that regioisomeric mixtures
where the cycloadduct having the ester group in the 3-position predominated
were normally formed in these reactions. The observed selectivities have
been explained in terms of HOMO-LUMO interactions, the dipole LUMO
and dipolarophile HOMO interaction being suggested to be the controlling
term: (a) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George,
J. K. J. Am. Chem. Soc. 1973, 95, 7287. (b) Houk, K. N.; Sims, J.; Watts,
C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301. (b) Gotthardt, H.;
Reiter, F. Chem. Ber. 1979, 112, 1193. (b) Gotthardt, H.; Reiter, F. Chem.
Ber. 1979, 112, 1635. (c) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush,
D. M. J. Org. Chem. 1982, 47, 786. See also ref 10b.
(6) For recent achievements in this area, see: (a) Despotopoulou, C.;
Klier, L.; Knochel, P. Org. Lett. 2009, 11, 3326. (b) Paulson, A. S.;
Eskildsen, J.; Vedsø, P.; Begtrup, M. J. Org. Chem. 2002, 67, 3904.
(7) McLaughlin, M.; Marcantonio, C.; Chen, C.-Y.; Davies, I. W. J.
Org. Chem. 2008, 73, 4309.
(8) Recently, bisarylic pyrazoles have also been obtained via direct C-H
bond arylations: Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem.
Soc. 2009, 131, 3042.
(9) For an overview of recent sydnone chemistry, see: Browne, D. L.;
Harrity, J. P. A. Tetrahedron 2010, 66, 553.
(15) Quantum chemistry calculation using DFT suggested a favorable
interaction between the dipole HOMO and the dipolarophile LUMO for
the cycloaddition of 4-halosydnones (1) with ethyl halopropiolates (2).
However, simple consideration of orbital lobe sizes did not allow a
quantitative prediction of regioselectivity. See Supporting Information for
details.
(16) In accordance with literature precedents (ref 10a), bromosydnone
1b was found to be fairly unstable under the reaction conditions (elevated
temperature and non-polar solvent), although some 3-aryl-4-bromosydnones
have been previously successfully reacted with dimethyl acetylenedicar-
boxylate under similar conditions (refs 10b, c).
(10) (a) Dickopp, H. Chem. Ber. 1974, 107, 3036. (b) Dumitras¸cu, F.;
Dra˘ghici, C.; Dumitrescu, D.; Tarko, L.; Ra˘ileanu, D. Liebigs Ann./Recueil
1997, 2613. (c) Dumitras¸cu, F.; Mitan, C. I.; Dumitrescu, D.; Dra˘ghici, C.;
Ca˘proiu, M. T. ARKIVOC 2002, ii, 80. (d) Browne, D. L.; Taylor, J. B.;
Plant, A.; Harrity, J. P. A. J. Org. Chem. 2010, 75, 984
.
(11) The capability of 4-halosydnones to undergo palladium-catalyzed
cross-coupling reactions has drawn recent attention on these mesionic
compounds; see: (a) Browne, D. L.; Taylor, J. B.; Plant, A.; Harrity, J. P. A.
J. Org. Chem. 2009, 74, 396. (b) Turnbull, K.; Krein, D. M.; Tullis, S. A.
Synth. Commun. 2003, 33, 2209
.
Org. Lett., Vol. 12, No. 15, 2010
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Table 1. [3 + 2]-Cycloaddition of PMP-Protected Halosydnones
with Halopropiolates
Table 2. Suzuki Site-Selective Coupling of
3-Bromo-5-iodopyrazole 5 with Various Boronic Acidsa
entry sydnone alkyne ratio yield of 3 (%)b yield of 4 (%)b
X1 (1)
I (1a)
Br (1b) I (2b)
X2 (2)
Br (2a)
3:4a
3:1
c
1
2
3
3a; 63
4a; 21
4b; ND
4c; 28
3b; NDd
3c; 58
I (1a) I (2b)
1.5:1
a Ratio determined by 1H NMR analysis of the crude product mixture.
b Isolated yields. c See text. d ND: not detected
3c/4c in good yield (86%), albeit with poorer regioselectivity
(Table 1, entry 3).
Scheme 2. Decarboxylation of 4-Ethoxycarbonylpyrazole 3a
a Reactions conducted on 0.2 mmol scale. Conditions: 1.1 equiv of
(Het)Ar1B(OH)2, 10 mol % Pd(PPh3)4, 3 equiv of K3PO4, DMF-H2O (4:
1), 50 °C, 2-3 h. b Isolated yields. c Reaction performed at 80 °C.
investigated as a model reaction. Pleasingly, the desired
coupling reaction proceeded as expected with optimal
conditions being 1.3 equiv of the boronic acid and 80 °C
for the reaction temperature. Under these conditions, the bis-
heteroaromatic pyrazole 7a was obtained in 77% isolated
yield (Scheme 3).
Having secured a reliable preparative method to the
dihalogenopyrazole 5, we next focused our attention on its
application in Suzuki-Miyaura reactions. Gratifyingly, early
investigations involving a series of aryl and heteroaryl
boronic acids as coupling partners including 3-pyridyl,
4-pyridyl, 2-furyl, 2-thienyl, and 3-thienyl boronic acids
established the cross-coupling reaction to be highly site-
selective of the C-5 position, the desired monocoupled
products being exclusively formed. Thus, an optimal set of
reaction conditions (1.1 equiv of the boronic acid, 10 mol
% Pd(PPh3)4, 2 equiv of K3PO4, DMF-H2O (4:1), 50 °C,
2-3 h) was determined that allowed access to a diversity of
5-(hetero)aromatic pyrazoles 6 in good to excellent isolated
yields. Illustrative examples are shown in Table 2. It should
be noted that the poor yield obtained in the case of
indolylpyrazole 6g is due to the inherent instability of the
requisite N-Boc(2-indolyl)boronic acid (Table 2, entry 7).
We then investigated the reactivity of the remaining
halogen atom at C-3 toward Suzuki-Miyaura cross-coupling
reactions. As we anticipated the possibility of introducing
two different (hetero)aryl substituents at the C-5 and C-3
positions of the pyrazole nucleus in a one-pot sequential
fashion, preliminary test experiments were made using the
same set of reaction conditions and, preferably, using the
same Pd catalyst. The cross-coupling of 3-bromo-5-(2-
thienyl)-pyrazole 6e with 3-pyridylboronic acid was thus
Scheme 3
One-pot double Suzuki-Miyaura cross-coupling reactions
are rare17 and often require additional base, catalyst, or ligand
to cross-couple the second boronic acid efficiently. To our
delight, a sequential addition, one-pot protocol for the
synthesis of 7a could be set up as follows: dihalogenopy-
razole 5 (1.0 equiv) and 2-thienylboronic acid (1.1 equiv)
underwent the Suzuki-Miyaura cross-coupling reaction
under the previous conditions (10 mol % Pd(PPh3)4, 2 equiv
of K3PO4, DMF-H2O (4:1), 50 °C). Once the reaction had
reached completion as judged by TLC (ca. 2 h), 3-pyridyl-
3330
Org. Lett., Vol. 12, No. 15, 2010

boronic acid (1.3 equiv) was added, and the reaction was
left to stir overnight at 80 °C to afford 7a in 54% isolated
yield. Most importantly, the developed protocol was also
efficient in the preparation of a large array of 3,5-bis(het-
ero)arylpyrazoles in satisfying yields. It is worth noting that
yields of illustrative examples shown in Scheme 4 refer to
Scheme 5. Deprotection of N-PMP-Pyrazole 7e
Scheme 4. One-Pot Suzuki Bis-Coupling of
3-Bromo-5-iodopyrazole 5 with Different Boronic Acidsa
Finally, as illustrated with the synthesis of 8 (Scheme 5),
it was shown that the PMP-protecting group may be easily
removed with ceric ammonium nitrate,18 thus expanding the
synthetic potential of our strategy.
In summary, we have developed an efficient three-step
synthetic entry to unsymmetrical 3,5-bis(hetero)aromatic
pyrazole derivatives with an inherent scope for diversifica-
tion. The procedures are simple and seem well suited for
the rapid generation of compound libraries of analogues from
a given set of readily available 4-halosydnones, 1-haloalkynes
and boronic acids.
Acknowledgment. This research was assisted financially
by a grant to T.D. from Bayer CropScience. We thank
Michael Schindler (Bayer CropScience AG, Monheim,
Germany) for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds; DFT
calculations for compounds 1a,b and 2a,b; 1H and 13C NMR
spectra for compounds 3a, 5, 6a-g, 7a-h, and 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101087J
(17) For illustrative examples, see: (a) Farooq, M. I.; Hussain, M.; Obaid-
Ur-Rahman, A.; Ali, A.; Ullah, I.; Zinad, D. S.; Langer, P. Synlett 2010,
411. (b) Tikad, A.; Routier, S.; Akssira, M.; Guillaumet, G. Org. Biomol.
Chem. 2009, 7, 5113. (c) Beaumard, F.; Dauban, P.; Dodd, R. H. Org.
Lett. 2009, 11, 1801. (d) Varello, S.; Handy, S. T. Synthesis 2009, 138. (e)
Handy, S. T.; Wilson, T.; Muth, A. J. Org. Chem. 2007, 72, 8496. (f) Handy,
S. T.; Zhang, Y. Synthesis 2007, 3883. (g) Handy, S. T.; Sabatini, J. J.
Org. Lett. 2006, 8, 1537. (h) Molander, G. A.; Yokoyama, Y. J. Org. Chem.
2006, 71, 2493. (i) Couty, S.; Barbazanges, M.; Cossy, J. Synlett 2005,
905. (j) Uozomi, Y.; Kikouchi, M. Synlett 2005, 1775. (k) Hodgetts, K. J.;
Kershaw, M. T. Org. Lett. 2002, 4, 1363.
a Reactions conducted on 0.2 mmol scale. Conditions: 1.1 equiv of
(Het)Ar1B(OH)2, 10 mol % Pd(PPh3)4, 3 equiv of K3PO4, DMF-H2O (4:
1), 50 °C, 3 h; then 1.3 equiv of (Het)Ar2B(OH)2, 80 °C, 18 h
single runs and are for pure, isolated products. The low yield
obtained in the synthesis of 7f was attributed to the poor
stability of (p-CO2Me)phenyl boronic acid under the reaction
conditions.
(18) Butler, R. N.; Hanniffy, J. M.; Stephens, J. C.; Burke, L. A. J.
Org. Chem. 2008, 73, 1354.
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