Sequential suzuki-miyaura cross-coupling reactions of 4-halopyrazolyl MIDA 3-boronates: A modular synthetic entry to 3,4-bis(hetero)aromatic pyrazoles

Article abstract of DOI:10.1246/cl.2011.1434

The 1,3-dipolar cycloaddition of N-arylsydnones with ethynyl MIDA boronate produces mixtures of the corresponding regioisomeric pyrazolyl 3(4)-boronates, with the pyrazolyl 3-boronates predominating by a factor of 7:3. Further C-4 iodination of the latter opened access to 4-iodopyrazolyl MIDA 3-boronates as valuable scaffolds for the elaboration of unsymmetrically 1,3,4-trisubstituted pyrazole derivatives via Suzuki cross-coupling reactions.

Full text of DOI:10.1246/cl.2011.1434

doi:10.1246/cl.2011.1434
1434
Published on the web December 5, 2011
Sequential Suzuki-Miyaura Cross-coupling Reactions of 4-Halopyrazolyl MIDA 3-Boronates:
A Modular Synthetic Entry to 3,4-Bis(hetero)aromatic Pyrazoles
Thierry Delaunay,1 Mazen Es-Sayed,2 Jean-Pierre Vors,2 Nuno Monteiro,*1 and Geneviève Balme*1
1Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (UMR 5246 du CNRS), Université Lyon 1,
CPE Lyon, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne, France
2Bayer SAS, Bayer CropScience, 14 impasse Pierre Baizet, BP9163, 69263 Lyon Cedex 09, France
(Received July 21, 2011; CL-110615; E-mail: balme@univ-lyon1.fr, monteiro@univ-lyon1.fr)
(Het)Ar1B(OH)2
(Het)Ar2I
The 1,3-dipolar cycloaddition of N-arylsydnones with
(Het)Ar2
N
Hal
Bmida
(Het)Ar1
ethynyl MIDA boronate produces mixtures of the corresponding
regioisomeric pyrazolyl 3(4)-boronates, with the pyrazolyl
3-boronates predominating by a factor of 7:3. Further C-4
iodination of the latter opened access to 4-iodopyrazolyl MIDA
3-boronates as valuable scaffolds for the elaboration of unsym-
metrically 1,3,4-trisubstituted pyrazole derivatives via Suzuki
cross-coupling reactions.
N
N
R
N
R
cross-coupling
O
Bmida
N
[3+2]
O
B
O
O
+
N
N
O
O
N
R
N
R
Pyrazole derivatives have found numerous applications as
pharmaceuticals and agrochemicals.1 As a part of our ongoing
research program devoted to the synthesis of diverse poly-
(hetero)aromatic pyrazoles for biological screening, we needed
an efficient and modular synthetic strategy to assemble a series
of 3,4-bis(hetero)aromatic derivatives.2 To this end, flexible
protocols allowing the sequential introduction of (hetero)aryl
substituents on the prefunctionalized pyrazole nucleus via
transition-metal-catalyzed site-selective C-C bond forming
processes were highly desirable.3 Notably, the Suzuki-type
reactions were particularly attractive as they are largely
unaffected by the presence of water and are tolerant to a wide
range of functional groups. They also take advantage of the
commercial availability of numerous boronic acids.4 However,
one major drawback of this strategy is the poor synthetic
accessibility of 3,4-dihalogenated pyrazoles. Indeed, while C-4
halogenation of the pyrazole nucleus is relatively easy,5 selective
halogenation at the C-3 carbon atom adjacent to nitrogen
remains a rather difficult task.3,6 In addition, issues of cross-
coupling site-selectivity would also need to be addressed.
Within this context, we became interested in the potential
synthetic utility of 4-halopyrazole-3-boronates as alternative
scaffolds. Our approach is inspired by Harrity’s pioneering
work2a,7 on the synthesis of pyrazolyl pinacol boronates via
sydnone 1,3-dipolar cycloadditions with alkynylboronates.
Interestingly, it was reported that terminal alkynylboronate
cycloaddition provided the corresponding pyrazole-3-boronates
with good levels of regiocontrol, whereas substituted alkynes
afforded almost exclusively 4-boronates. Based on these results,
we envisaged a rapid access to 4-halopyrazole-3-boronates via
sydnone cycloaddition with a terminal alkynyl boronate ester
followed by C-4 halogenation. Besides, in order to avoid self
coupling reactions, it was decided to make use of masked
boronic acids8 that would allow us to first cross-couple at C-4
and then release the boronic acid to finally cross-couple at C-3.
The commercially available ethynyl N-methyliminodiacetic acid
(MIDA) boronate (1) developped by Burke9 was the perfect
candidate to gauge the present strategy (Scheme 1). We report
herein our preliminary results toward this goal.
2
1
Bmida
Scheme 1.
Table 1. Synthesis of pyrazolyl MIDA 3-boronates 3a
Bmida Bmida
O
O
Anisole
+
Bmida
N
N
N
+
N
R
3
N
R
165 °C
N
R
2
7 : 3
1
4
Sydnone
R =
Time Yield Yield of Yield of
Entry
/h
/%b
3c/%
4c/%
1
2
3
Ph
p-FPh
p-NO2Ph
24
18
12
34
65
67
24 (3a)
41 (3b)
47 (3c)
10 (4a)
24 (4b)
20 (4c)
aReactions conducted in sealed glass tubes on 2 mmol scale.
c
bCombined isolated yields. Isolated yields.
Our studies began with an initial investigation of the
efficiency of sydnone cycloadditions with ethynyl MIDA
boronate (1). A series of N-arylsydnones 2 were thus prepared
and reacted with equimolar amounts of 1 at 165 °C in anisole
(Table 1). As expected the reactions gave rise to mixtures of
regioisomeric pyrazolyl boronates 3/4 easily separated by silica
gel chromatography, with the pyrazole-3-boronate predominat-
ing by a factor of 7:3 as determined by 1H NMR analysis of the
crude mixture of 3 and 4. These results also showed that
sydnones bearing electron-poor aryl groups at N-1 gave the best
result. The N-p-nitrophenylpyrazole 3c was of special interest as
it may ultimately open access to NH-pyrazoles upon cleavage of
the PNP group.10 The latter compound was isolated with an
acceptable 47% yield.
With the pyrazole-3-boronates in hand, we next focused our
efforts on establishing a convenient, high yielding procedure for
the preparation of 4-halopyrazole-3-boronates. Early experi-
ments following literature protocols5 based on the use of N-
halosuccinimides as halogenation reagents were disappointing.
Chem. Lett. 2011, 40, 1434-1436
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1435
Table 2. Synthesis of 4-iodopyrazolyl MIDA 3-boronatesa
Table 3. Reaction of 4-iodopyrazolyl MIDA 3-boronates with
various (hetero)aromatic boronic acidsa
I
Bmida
Bmida
NIS (1.1 equiv)
TFA (1 equiv)
(Het)Ar
Bmida
I
Bmida
(Het)ArB(OH)2 (2 equiv)
10 mol% [PdCI2(dppf)]
N
N
N
R
5
N
MeCN, µw 110°C, 20 min
N
N
R
3
N
R
6
N
K3PO4 (2 equiv)
DMF, 60°C, 4h
R
5
MIDA boronate
R =
Entry
Yield/%b
MeO
Cl
F
1
2
3
Ph (3a)
p-FPh (3b)
p-NO2Ph (3c)
95 (5a)
78 (5b)
79 (5c)
Bmida
Bmida
Bmida
Bmida
N
N
N
N
N
N
N
N
aReactions conducted on 0.7 mmol scale. Isolated yields.
b
PNP
PNP
PNP
PNP
6a ; 46%
6b ; 71%
6c ; 53%
6d ; 59%
MeO
MeO
MeO2S
O
O
Bmida
Bmida
Bmida
N
N
N
N
N
N
PNP
PFP
Ph
6e ; 83%
6f ; 53%
6g ; 40%
S
O
S
Bmida
Bmida
N
Bmida
N
N
N
N
N
PNP
PNP
PNP
Figure 1. ORTEP view of 5c.
6i ; 62%
6h ; 50%
6j ; 63%
Reactions conducted in chlorinated solvents5a proved rather
sluggish and low yielding owing to the poor solubility of the
MIDA boronates in these solvents. Noticeable improvements
came from the use of acetic acid as solvent under microwave
irradiation.5b However, after further experimentation, the best
conditions we could establish consisted of performing the
reaction in acetonitrile as solvent using NIS-TFA (N-iodo-
succinimide-trifluoroacetic acid) as iodonium donating system11
under microwave irradiation (110 °C, 20 min). Under these
conditions, a series of 4-iodopyrazole-3-boronates 5a-5c could
be obtained in 78-95% isolated yield (Table 2). The structure of
5c has been secured by X-ray analysis (Figure 1).12
aReactions conducted on 0.2 mmol scale (isolated yields);
PNP = p-NO2Ph; PFP = p-F-Ph.
Table 4. Reaction of pyrazolyl MIDA 3-boronates with various
aryl iodidesa
(Het)Ar
Bmida
Ar
(Het)Ar
Ar-I (1.5 equiv)
5 mol% Pd(OAc)2 ,10 mol% S-Phos
N
N
N
R
6
K3PO4 (2 equiv)
DMF/H2O (5:1), 60°C, 15 h
N
R
7
F
OMe
CF3
S
Having secured a reliable preparative method to the
4-iodopyrazole-3-boronates, we next focused our attention on
their application in Suzuki cross-coupling reactions at the halide
terminus. Anhydrous conditions would normally prevent pre-
mature hydrolysis of the boronate esters. Gratifyingly, under the
optimum set of reaction conditions (10 mol % [PdCl2(dppf)], 2
equiv of K3PO4, DMF, 60 °C), a variety of electron-poor and
electron-rich arylboronic acids, as well as a series of hetero-
arylboronic acids, including 2-furyl and 2(3)-thienylboronic
acids furnished the corresponding coupling products 6a-6j in
moderate to good yields after chromatographic purification
(Table 3).
Finally, we evaluated the effectiveness of the Suzuki cross-
coupling reactions at the C-3 position. To this end, in situ slow-
release of the corresponding boronic acids through hydrolysis
of the MIDA boronates under aqueous basic conditions was
envisaged in order to minimize any undesired protodeborona-
tion. We thus applied to a series of pyrazolyl MIDA 3-boronates
reaction conditions similar to those developed by Burke and co-
S
O
N
N
N
N
N
N
PNP
PNP
PNP
7c ; 47%
Cl
7a ; 75%
7b ; 55%
MeO2S
O
O
N
N
N
N
PNP
Ph
7d ; 53%
7e ; 43%
aReactions conducted on 0.2 mmol scale (isolated yields).
workers13 and consisting of Pd(OAc)2/S-Phos as catalyst system
and K3PO4 as base in aqueous DMF. Under these conditions, a
small array of 3,4-bis(hetero)aromatic pyrazoles 7a-7e could be
produced in acceptable yields (Table 4).
Chem. Lett. 2011, 40, 1434-1436
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1436
In summary, 4-iodopyrazolyl MIDA 3-boronates are readily
accessible in two steps from sydnones and commercially
available ethynyl MIDA boronate. They have been shown to
be valuable scaffolds for the rapid elaboration of 3,4-bis(hetero)-
arylpyrazole derivatives by means of sequential Suzuki cross-
coupling reactions and should find broader applications in the
preparation of chemical libraries of potentially biologically
active compounds.14
4
5
D. G. Hall, Boronic Acids, Wiley-VCH, Weinheim, 2005.
a) Z.-G. Zhao, Z.-X. Wang, Synth. Commun. 2007, 37, 137.
b) G. Li, R. Kakarla, S. W. Gerritz, Tetrahedron Lett. 2007,
48, 4595.
For leading references, see: J. Eskildsen, P. Vedsø, M.
Begtrup, Synthesis 2001, 1053; A. S. Paulson, J. Eskildsen,
P. Vedsø, M. Begtrup, J. Org. Chem. 2002, 67, 3904; C.
Despotopoulou, L. Klier, P. Knochel, Org. Lett. 2009, 11,
3326.
6
This research was assisted financially by a grant to T. D.
from Bayer CropScience. We thank Dr. E. Jeanneau (Centre de
Diffractométrie Henri Longchambon, Université Lyon 1) for the
X-ray crystallographic analysis.
7
8
D. L. Browne, J. F. Vivat, A. Plant, E. Gomez-Bengoa,
J. P. A. Harrity, J. Am. Chem. Soc. 2009, 131, 7762.
M. Tobisu, N. Chatani, Angew. Chem., Int. Ed. 2009, 48,
3565; E. P. Gillis, M. D. Burke, Aldrichimica Acta 2009, 42,
17.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
9
J. R. Struble, S. J. Lee, M. D. Burke, Tetrahedron 2010, 66,
4710.
10 D. L. Browne, J. P. A. Harrity, Tetrahedron 2010, 66, 553,
and references cited therein.
References and Notes
11 A.-S. Castanet, F. Colobert, P.-E. Broutin, Tetrahedron Lett.
2002, 43, 5047.
1
C. Lamberth, Heterocycles 2007, 71, 1467; T. Eicher, S.
Hauptmann, The Chemistry of Heterocycles: Structures,
Reactions, Synthesis, and Applications, 2nd ed., John Wiley
& Sons, New York, 2003, p. 179.
12 Single crystals of 5c suitable for X-ray diffraction studies
were grown from slow evaporation of an acetonitrile
solution. Crystallographic data reported in this manuscript
have been deposited with Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-839625.
Copies of the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge, CB2 1EZ, U.K.; fax: +44 1223 336033;
or deposit@ccdc.cam.ac.uk).
2
For recent works with respect to the synthesis of 3,4-
diarylpyrazoles, see: a) D. L. Browne, M. D. Helm, A. Plant,
J. P. A. Harrity, Angew. Chem., Int. Ed. 2007, 46, 8656. b) R.
Goikhman, T. L. Jacques, D. Sames, J. Am. Chem. Soc.
2009, 131, 3042. c) E. Arbačiauskienė, G. Vilkauskaitė,
G. A. Eller, W. Holzer, A. Šačkus, Tetrahedron 2009, 65,
7817.
3
For a previous contribution of our laboratory to this field,
see: T. Delaunay, P. Genix, M. Es-Sayed, J.-P. Vors, N.
Monteiro, G. Balme, Org. Lett. 2010, 12, 3328; T. Delaunay,
M. Es-Sayed, J.-P. Vors, N. Monteiro, G. Balme, Eur. J. Org.
Chem. 2011, 3837.
13 D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc.
2009, 131, 6961.
14 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 1434-1436
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/