Preparation of 1,2-bis(pyrazol-1-yl)benzene: 'Modern' cross-coupling vs. the 'Classic' nucleophilic substitution approach

Article abstract of DOI:10.2174/157017809787003232

Several potential methods for the preparation of 1,2-bis(pyrazol-1-yl) benzene, a prospective ligand for transitional metals, starting from 1,2-dihalobenzenes and pyrazole have been studied. Cross-couplings of 1,2-dichloro-, - dibromo- and -diiodobenzenes

Full text of DOI:10.2174/157017809787003232

Letters in Organic Chemistry, 2009, 6, 57-59
57
Preparation of 1,2-bis(pyrazol-1-yl)benzene: “Modern” Cross-Coupling vs.
the “Classic” Nucleophilic Substitution Approach
Olga Ivashchuk and Vladimir I. Sorokin*
Department of Organic Chemistry, Southern Federal University, 344090, Rostov-on-Don, Zorge str. 7, Russia
Received June 04, 2008: Revised September 19, 2008: Accepted September 29, 2008
Abstract: Several potential methods for the preparation of 1,2-bis(pyrazol-1-yl)benzene, a prospective ligand for transi-
tional metals, starting from 1,2-dihalobenzenes and pyrazole have been studied. Cross-couplings of 1,2-dichloro-, -
dibromo- and -diiodobenzenes with pyrazole using palladium and copper catalysts were unsatisfactory because of dehalo-
genation side reactions or a lack of reactivity. On the other hand, nucleophilic aromatic substitution of fluorine in 1,2-
difluorobenzene under the action of sodium pyrazolide gave a good yield of the desired product.
Keywords: 1,2-bis(pyrazol-1-yl)benzene, pyrazole, 1,2-dihalobenzenes, C-N cross-coupling, fluorine nucleophilic substitution.
1. INTRODUCTION
1,2-bis(pyrazol-1-yl)benzene (6), is still unknown, despite
the fact that this compound could demonstrate unusual be-
havior when complexed with transition metals. Additionally,
these complexes will be interesting starting points for subse-
quent investigations into their catalytic activity.
Chelating polykis(pyrazole-1-yl)benzenes are an almost
unexplored type of ligand for transition metals, in contrast to
the well studied polykis(pyrazol-1-yl)borates (1) [1], -
methanes (2) [2] and polykis(pyrazol-1-ylmethyl)benzenes
(3) [3].
Although pyrazole-containing derivatives can be pre-
pared by the cyclization of hydrazines with difunctional
compounds [6], the preparations of 1-5 almost exclusively
use substitution methods, whereby a halogen or other func-
tional group in the starting material is displaced under the
At present, only one report on the preparation of 1,2,4,5-
tetrakis(pyrazol-1-yl)benzene (4) and its unusual metallacy-
clophane complex with copper (II) [4] has been published,
although several papers from the Elguero group, who have
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
B
N
N
N
N
1
2
3
4
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
6
5
intensively studied hexakis(pyrazol-1-yl)benzene (5) [5] are
available. However, the elementary member of this class,
action of pyrazoles. While compounds 1-3 are prepared by
the action of a pyrazole-based nucleophile on the relatively
reactive aliphatic halogen atom, the same transformation to
make compounds 4-5 requires the substitution of much less
reactive aromatic halides, which require harsh reaction con-
ditions and give lower yields. Lately, transition metal-
*Address correspondence to this author at the Department of Organic
Chemistry, Southern Federal University, 344090, Rostov-on-Don, Zorge str.
7, Russia; Fax: +7 (863) 297-51-46; E-mail: vsorokin@aaanet.ru
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

58
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Ivashchuk and Sorokin
1.76% CuO
2.4 eq. pyrazole
I
N
N
N
N
N
N
+
2 eq. KOH
DMSO, 110 °C
24 h
I
6
7
Scheme 1.
catalyzed cross-coupling reactions have been suggested as
effective methods for C-N bond formation with activated-,
non- or even deactivated haloarenes [7]. With this perspec-
tive in mind, it is interesting to compare the classic SNAr
substitution and modern cross-coupling approaches toward
the preparation of 1,2-bis(pyrazol-1-yl)benzene (6).
pyrazoles exist [10]. Despite this precedent, no data on the
reaction of azoles with 1,2-diiodobenzene is known. From
the large assortment of available catalytic systems we have
selected the three most universal and effective.
The CuI/benzotriazole system, although not previously
used for pyrazole arylation, has demonstrated very good re-
sults for imidazole coupling [11]. However, even after pro-
longed heating the starting compound did not undergo any
change, as indicated by GC/MS, and was recovered at the
end of the reaction. Similar results were obtained with the
CuI/L-proline system, which had been used in several stud-
ies investigating the coupling of pyrazole with several iodo-
and even bromoarenes [12]. The sole system, with which we
finally succeeded in obtaining the coupled product, em-
ployed CuO (nanoparticle) as the catalyst [13]. But even in
this case after 24 h the reaction mixture still contained 57%
of the starting compound, and only 32% of desired com-
pound 6 along with 11% of 1-phenylpyrazole (7) detected in
the reaction mixture by GC/MS (Scheme 1).
2. RESULTS AND DISCUSSION
2.1. Cross-Coupling
It is clear from the recent literature that transition metal
catalyzed C-N bond forming reactions provide unprece-
dented versatility, universality and effectiveness. Among
these methods palladium and copper systems are the most
promising [7].
Systems composed of 1,2-dichloro-, -dibromobenzenes
and a palladium catalyst, as well as 1,2-diiodobenzene and a
copper catalyst, were selected for a coupling study with
pyrazole for the preparation of 6.
Compound
7 may have arisen from the proto-
While we did not find any examples in the literature of
azole arylation under Pd(0) catalysis, 2-dicyclohexyl-
phosphino-2ꢀ,4ꢀ,6ꢀ-triisopropylbiphenyl, namely XPhos,
which is considered one of the best ligands for Pd(0) cata-
lyzed C-N bond forming reactions [8], and Pd(OAc)2/
Pd2dba3 as Pd(0) precursors were chosen for study.
dehalogenation of 1-(2-iodophenyl)pyrazole, the product of
mono cross-coupling, and indicates the strong steric interac-
tions during the reaction that we believe are responsible for
the problems in preparing 6 by cross-coupling approaches.
2.2. Nucleophilic SNAr Substitution
Surprisingly, in all the conditions we tried only the start-
ing dihaloarenes were detected by GC/MS in the reaction
mixture. We varied numerous parameters including: the sol-
vent (toluene, dioxane, THF), the reaction temperature (60,
100, 110 °C), the precatalyst and ligand loading, the nature
of base (Cs2CO3, NaOtBu, NaOtAm) and the equivalents of
pyrazole used (1 or 2). This problem has also recently arisen
in Buchwald’s work; he connected these problems with high
basicity of pyrazole, which leads to slow reductive elimina-
tion of the Pd aryl/amido intermediate. They overcame it by
using the more bulky 2-di-tert-butylphosphino-2ꢀ,4ꢀ,6ꢀ-
triisopropylbiphenyl (tert-Butyl XPhos) as the ligand [9].
However, reproduction of these Buchwald conditions again
gave us only a starting compound, as determined by GC/MS.
We think that the main explanation for these failures are the
great steric difficulties involved with the formation of a Pd
aryl/amido intermediate in the presence of a large halogen
atom in the ortho-position to the reaction center and the
bulky ligand used. In the case of 1,2-dichlorobenzene an
additional factor effecting the reaction could be the low reac-
tivity of the C-Cl bond, since Buchwald’s work only demon-
strates the use of activated chloroarenes.
Since cross-coupling approaches gave disappointing re-
sults, we pursued a traditional SNAr substitution approach,
although it is not always so effective.
Taking into account the low reactivity of neutral pyrazole
in previous investigations, it was logical to investigate nu-
cleophilic substitution with the more reactive sodium pyra-
zolide, generated in the reaction mixture from NaH and
pyrazole. As we expected, neither 1,2-dichloro- nor 1,2-
dibromobenzene reacted with sodium pyrazolide despite
conducting the reaction in dipolar aprotic solvents (DMF and
DMSO) for up to 7 days in a sealed tube at 110°C.
On the other hand, we recently demonstrated the great
potential of fluorine electrophiles in nucleophilic substitution
for the preparation of
a
large number of varied
polykis(dialkylamino)substituted benzenes and naphthalenes
[14]. From this point of view, the use of 1,2-difluorobenzene
in the reaction with sodium pyrazolide was reasonable.
It was found that difluorobenzene did not react with the
nucleophile at room temperature even after prolonged stir-
ring. Stepwise increases in the temperature increased the
conversion of the starting compound to product 6, which
became 100% at 100°C (Scheme 2). Subsequent increases in
Alternatively, Cu-based catalyst systems looked more
promising, since many examples of coupling iodoarenes with

Preparation of 1,2-bis(pyrazol-1-yl)benzene
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
59
temperature did not have any effect. The optimal reaction
time was found to be 10 h, and DMSO was preferred as the
solvent over DMF, as the use of DMF resulted in a product
that was contaminated with unidentified impurities, possibly
due to solvent decomposition.
1,2-Bis(pyrazol-1-yl)benzene
Twenty-five milliliters of anhydrous DMSO was added
to 0.16 g of NaH as a 60% suspension in mineral oil (4
mmol). 0.27 g of pyrazole (4 mmol) was carefully added to
the resulting mixture under vigorous stirring (CAUTION!
Rapid hydrogen evolution), and the reaction mixture was
stirred for an additional 30 min at r.t. After the reaction mix-
ture had become a clear solution, 0.097 mL (1 mmol) of 1,2-
difluorobenzene was added, and stirring was continued for
10 h at 100°C. The mixture was cooled to r.t. and poured
into 100 mL of water. The products were extracted with
toluene; the organic layer was washed with water, dried over
Na2SO4 and evaporated to dryness. 0.15 g of 1,2-bis(pyrazol-
1-yl)benzene was isolated with a 71% yield. The product
was crystallized from a pentane-methanol mixture to obtain
4 eq. pyrazole
4 eq. NaH
F
F
N
N
N
N
DMSO, 100 °C
10 h
6 (71%)
Scheme 2.
Interestingly, attempts to prepare 1-(2-fluorophenyl)
pyrazole, which would be of interest because substitution of
the remaining fluorine by other functional groups would al-
low for the preparation of “mixed” ligands, failed. Even in
presence of one equivalent of sodium pyrazolide, only 6 was
formed. Lowering the reaction temperature and time also had
no effect, and only lowered the yields of 6, until no reaction
between difluorobenzene and the nucleophile was observed.
Simple semi-empirical calculations using the PM3 method
[15] allow us to understand this phenomenon. The calculated
charge on carbons connected to fluorine in 1,2-
difluorobenzene is +0.041, whereas the charge on the
equivalent carbon atom in 1-(2-fluorophenyl)pyrazole is
+0.073, so the introduction of the pyrazole ring activates the
remaining fluorine atom for subsequent substitution to the
extent that it is more reactive than the starting compound.
1
the pure product as white crystals. M.p. 67-68 °C. H NMR
(CDCl3): 6.28 (dd, J3 ,4 =1.9, J4 ,5 =2.4 Hz, 2H, pyrazole H-4ꢀ);
ꢀ
ꢀ
ꢀ ꢀ
6.99 (d, 2H, pyrazole H-5ꢀ); 7.50 (m, 2H, J4,5=0.1, J3,4=7.7,
J3,5= J4,6=1.2, J5,6=8.4 Hz, H-4,5); 7.68 (m, 2H, H-3,6); 7.69
(d, 2H, pyrazole H-3ꢀ). 13C NMR (CDCl3): 107.9 (2 pyrazole
C-4’); 127.3 (2 arom. C-3,6); 129.2 (2 arom. C-4,5); 130.8 (2
pyrazole C-5’); 135.0 (2 arom. C-1,2); 141.6 (2 pyrazole C-
3’). EI-MS (70 eV): 210 (100, M+), 209 (100), 182 (42), 170
(14), 155 (19), 129 (16), 102 (18), 77 (19), 52 (24), 39 (26).
Anal. Calc’d. for C12H10N4 (210.23): C, 68.56; H, 4.79; N,
26.65. Found: C, 68.55; H, 4.80; N, 26.67.
REFERENCES
[1]
[2]
[3]
Adv. Organomet. Chem.; West, R.; Hill, A.F.; Fink, M.J. Eds.;
Academic Press: San Diego, 2008; Vol. 56, pp. 1-321.
(a) Pettinari, C.; Pettinari, R. Coord. Chem. Rev., 2005, 249, 525;
(b) Pettinari, C.; Pettinari, R. Coord. Chem. Rev., 2005, 249, 663.
(a) Therrien, B.; Ward, T.R. Angew. Chem. Int. Ed., 1999, 38, 405;
(b) Dijkstra, H.P.; Meijer, M.D.; Patel, J.; Kreiter, R.; van Klink,
G.P.M.; Lutz, M.; Spek, A.L.; Canty, A.J.; van Koten, G.
Organometallics, 2001, 20, 3159.
In conclusion, despite the popularity of cross-coupling
methods, some time is still needed to solve all the problems
involved in their application; on the other hand, “the best
wine comes out of an old vessel,” and SNAr substitution re-
actions still have great potential in synthesis.
[4]
[5]
Jouaiti, A.; Loï, M.; Hosseini, M.W.; De Cian, A. Chem. Commun.,
2000, 2085-2086.
(a) Guerrero, A.M.; Jalon, F.A.; Manzano, B.R.; Claramunt, R.M.;
Dolores Santa Maria, M.; Escolastico, C.; Elguero, J.; Rodriguez,
A.M.; Maestro, M.A.; Mahia, J. Eur. J. Inorg. Chem., 2002, 3178;
(b) Manzano, B.R.; Jalon, F.A.; Espino, G.; Guerrero, A.; Clara-
munt, R.M.; Escolastico, C.; Elguero, J.; Aranzazu Heras, M. Poly-
hedron, 2007, 26, 4373.
EXPERIMENTAL
General
1,2-dichloro-, -dibromo-, -difluorobenzenes, Pd(OAc)2
and Pd2dba3 were purchased from Alfa Aesar. A 60% sus-
pension of NaH in mineral oil and 1,2-diiodobenzene were
purchased from Acros. XPhos, tert-Butyl XPhos and CuO
(nanoparticle) were purchased from Sigma-Aldrich. Solvents
were purified and dried according to the literature [16].
NMR spectra were recorded on a Bruker DPX-250. 1H
NMR, and 13C NMR spectra were recorded at 250 MHz and
63 MHz, respectively, both using Me4Si as an internal stan-
dard. GC/MS traces were recorded on an Agilent 6890
equipped with an Agilent 5973N mass selective detector, a
quartz capillary column HP-5MS (30 m length, internal di-
ameter 0.32 mm), and helium was used as a carrier gas at a
flow rate of 1 mL/min. Melting points were determined in
capillary on a PTP apparatus and are not corrected.
[6]
[7]
Tokmakov, G.P.; Udachin, Y.M.; Patalakha, N.S.; Denisov, L.K.;
Lantsov, A.M.; Grandberg, I.I. Chem. Heterocycl. Compd. Engl.
Transl., 1980, 16, 66.
(a) Jiang, L.; Buchwald, S.L. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Wein-
heim, 2004; Vol. 2, pp. 699-760; (b) Beletskaya, I.P.; Cherpakov,
A.V. Coord. Chem. Rev., 2004, 248, 2337.
[8]
[9]
Huang, X.; Anderson, K.W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S.L. J. Am. Chem. Soc., 2003, 125, 6653.
Anderson, K.W.; Tundel, R.E.; Ikawa, T.; Altman, R.A.; Buchwald
S.L. Angew. Chem. Int. Ed., 2006, 45, 6523.
[10]
[11]
Ley, S.V.; Thomas, A.W. Angew. Chem. Int. Ed., 2003, 42, 5400.
Verma, A.K.; Singh, J.; Sankar, V.K.; Chaudhary, R.; Chandra, R.
Tetrahedron Lett., 2007, 48, 4207.
[12]
[13]
[14]
Zhang, H.; Cai, Q.; Ma D. J. Org. Chem., 2005, 70, 5164.
Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett., 2007, 9, 3397.
Sorokin, V.I.; Ozeryanskii, V.A.; Borodkin, G.S.; Chernyshev,
A.V.; Muir, M.; Baker J. Z. Naturforsch. B Chem. Sci., 2006, 61b,
615.
Cross-coupling experiments were conducted according to
[8] and [9] if palladium was used as a catalyst, and according
to [11-13] for copper-catalyzed transformations. After the
appropriate time, the composition of the reaction mixture
was analyzed by GC/MS.
[15]
[16]
Stewart, J.J.P. MOPAC 6.0. Quantum Chemistry Program Ex-
change, University of Indiana, Bloomington, Indiana, USA, 1990.
Armarego, W.L.F.; Chai, C.L.L. Purification of Laboratory
Chemicals, Elsevier Science: New York, 2003.