Synthesis of a new analogue of BINOL based on a homodimer of substituted 1-hydroxypyrazole

Article abstract of DOI:10.1039/b010126p

A new potential ligand for asymmetric synthesis, based on a homodimer of 1-hydroxypyrazole, has been synthesized. The chemistry involved lithiation, iodine-magnesium exchange, magnesium-zinc exchange, and cross-coupling reactions. In a preliminary study, the chemical activity of the ligand as a titanium(IV) complex was investigated in the addition of diethyl zinc to benzaldehyde. Its activity was comparable to the corresponding BINOL-Ti(IV) complex.

Full text of DOI:10.1039/b010126p

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Synthesis of a new analogue of BINOL based on a homodimer of
substituted 1-hydroxypyrazole
Øystein Rist and Mikael Begtrup*
1
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy,
Universitetsparken 2, DK-2100 Copenhagen, Denmark
Received (in Cambridge, UK) 19th December 2000, Accepted 27th April 2001
First published as an Advance Article on the web 5th June 2001
A new potential ligand for asymmetric synthesis, based on a homodimer of 1-hydroxypyrazole, has been synthesized.
The chemistry involved lithiation, iodine–magnesium exchange, magnesium–zinc exchange, and cross-coupling
reactions. In a preliminary study, the chemical activity of the ligand as a titanium() complex was investigated in the
addition of diethyl zinc to benzaldehyde. Its activity was comparable to the corresponding BINOL–Ti() complex.
Introduction
Asymmetric catalysis is a major subject in today’s organic
chemistry. A vast amount of chiral ligands for catalysts have
been designed.1 We have developed methods for regioselective
introduction of various substituents in substituted N-hydroxy
azoles.2 Combining these two aspects led us to the design of
new potential ligands, based on substituted N-hydroxyazoles.
The resulting ligands hold several heteroatoms in the proximity
of the catalyst’s C2-symmetric binding site. A general structure
of such a ligand is shown in Fig. 1.
One of the key issues to be considered was the rotational
barrier around the C5–C5Ј single bond. The hydroxy groups are
fairly small, thus quite sterically demanding R-groups were
desirable.
Scheme 1
Results and discussion
The Negishi conditions used in the successful cross-coupling
Aromatic groups were first chosen for R, since these can be
introduced readily at the 4-position, using Negishi or Suzuki
cross-coupling protocols.3 Various strategies may lead to the
target molecule. First, in order to avoid a double cross-coupling
reaction or a dianionic species, the 4-substituent was introduced
prior to connecting the two pyrazole moieties. However, sub-
sequent coupling of the two ortho-substituted rings, was not
feasible, probably due to steric hindrance.
of the bipyrazolyl framework were then tried for the introduc-
tion of phenyl groups at C-4 and C-4Ј. In this case, the iodines
of the bipyrazolyl compound (3) did not react. However,
“umpolung” of the reaction by a double iodine–magnesium
exchange to the dimagnesium species, followed by magnesium–
zinc exchange, and then cross-coupling with iodobenzene,
resulted in the desired diphenyl compound (4) as shown in
Scheme 2.
Consequently, the bipyrazole framework 2 (Scheme 1)
was first established by palladium(0)-catalyzed Negishi
cross-coupling of 1-benzyloxy-5-iodopyrazole4 with 1-benzyl-
oxypyrazol-5-ylzinc() chloride, obtained from 1-benzyl-
oxypyrazole (1) by lithiation and transmetallation. This
cross-coupling sequence proceeded smoothly and in good yield.
For further functionalization, two iodines were introduced
regioselectively in the 4- and 4Ј-positions. Treating the substrate
with a large excess of iodine monochloride using potassium
carbonate as base gave a rapid introduction of the first iodine.
At room temperature, satisfactory conversion to the diiodin-
ated compound (3) took four days. Heating the reaction
resulted in side-reactions.
Scheme 2
A disadvantage of this method was that a huge excess of
phenylmagnesium chloride had to be applied to get the dimag-
nesium species. This necessitated an even bigger excess of
Fig. 1 A general structure of the new ligands.
1566
J. Chem. Soc., Perkin Trans. 1, 2001, 1566–1568
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b010126p

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iodobenzene for the next step and caused formation of sub-
stantial amounts of biphenyl as a by-product. The more
reactive metal reagent isopropylmagnesium chloride was tried,
but resulted in reduction of the diiodo species. A plausible
explanation could be that the high basicity of the dianionic
species led to abstraction of a proton, probably from the
isopropyl halide formed, before transmetallation occurs.
To improve the yield and avoid the by-product, Suzuki
conditions were applied. In contrast to what was observed using
Negishi conditions, the diiodo species (3), when reacted with
phenylboronic acid, afforded the diphenyl-substituted product
(4). This indicates that the Suzuki reaction is more tolerant to
steric encumbrance than the Negishi reaction. The sequence is
shown in Scheme 3.
N-pivaloyl-o-toluidine.6 THF was distilled over sodium.
Flash chromatography was performed using silica gel (Merck
60, 70–230 mesh). NMR spectra were recorded on a 300 MHz
instrument (Varian Gemini), using TMS as an internal refer-
ence. When DMSO-d6 was used as solvent, the ppm values refer
to the DMSO-d5 signal (2.50 ppm). Melting points were meas-
ured on a Büchi apparatus, and are uncorrected. Elemental
analyses were performed by Microanalytical Laboratory,
Department of Physical Chemistry, University of Vienna,
Austria.
Synthesis
1,1Ј-Bis(benzyloxy)-5,5Ј-bipyrazolyl (2). 1-Benzyloxypyrazole
(1) (4.00 g; 23.0 mmol) was dissolved in dry THF (50 mL), and
cooled to Ϫ78 ЊC under a nitrogen atmosphere. A 1.58 M solu-
tion of n-BuLi in hexane (17.4 mL; 27.6 mmol) was added
dropwise over 10 minutes. After an additional 10 minutes, a
1 M solution of ZnCl2 in dry THF (34.4 mL; 34.4 mmol) was
added. The reaction mixture was allowed to warm to room
temperature, before addition of a solution of 1-benzyloxy-5-
iodopyrazole (6.96 g; 23.1 mmol) and tetrakis(triphenylphos-
phine)palladium(0) [Pd(PPh3)4] (1.33 g; 1.15 mmol; 5 mol%)
in dry DMF (25 mL) was added. The reaction mixture was
heated to 60 ЊC for 19 hours, then cooled to room temper-
ature and quenched by adding saturated aqueous ammonium
chloride (100 mL). Neutralization and extractive work-up with
DCM, followed by chromatography on silica gel, resulted in
pale yellow crystals. Recrystallization from EtOAc–heptane
gave the product 2 (7.02 g, 88%) as colorless needles, mp 117.0–
117.2 ЊC (Found: C, 69.62; H, 5.03; N, 16.39. C20H18N4O2
requires C, 69.35; H, 5.24; N, 16.17%); δH(CDCl3) 5.09 (4H, s,
CH2), 6.49 (2H, d, J = 2.4 Hz, H4, Pz), 7.25–7.33 (10H, m, Ph),
7.28 (2H, d, J = 2.4 Hz, H3, Pz); δC(CDCl3) 80.4 (CH2), 104.0
(C4, Pz), 124.1 (C1, Ph), 128.6 and 130.0 (C2 and C3, Ph),
129.4 (C4, Ph), 133.0 (C5, Pz), 133.1 (C3, Pz).
Scheme 3
Finally, the two benzyl groups in 4 were removed. Our first
attempt was debenzylation by hydrogenolysis as this has proven
successful for related compounds,4 but for the given compound
this was of no avail. The simple dimeric compound 2 has earlier
been successfully debenzylated by treatment with HCl and heat,
but for 4 this strategy resulted in unchanged starting material.
However, heating in concentrated sulfuric acid5 led to deben-
zylation, and upon dilution with water, the free dihydroxy com-
pound (5) precipitated as a white solid, which was isolated in
22% yield, as shown in Scheme 4.
1,1Ј-Bis(benzyloxy)-4,4Ј-diiodo-5,5Ј-bipyrazolyl (3). To
a
stirred mixture of 1,1Ј-bis(benzyloxy)-5,5Ј-bipyrazolyl (2) (0.69
g; 2.00 mmol) and potassium carbonate (1.66 g; 12.0 mmol)
in chloroform (20 mL) at room temperature under nitrogen,
iodine monochloride (1.95 g; 12.0 mmol) in chloroform (2 mL)
was added, and the reaction was stirred for four days. The reac-
tion was quenched by addition of a 1 M aqueous solution of
sodium sulfite (10 mL), and worked up as described above. The
crude product was purified by recrystallization from petroleum
ether to give the product 3 (1.09 g, 91%) as a 94% pure solid (1H
NMR). An analytical sample was obtained by chromatography;
mp 72.2–73.2 ЊC (Found: C, 40.37; H, 2.54; N, 9.07. C20H16-
N4O2I2 requires C, 40.16; H, 2.70; N, 9.37%); δH(CDCl3) 5.13
(2H, d, J = 10.1 Hz, CH2), 5.19 (2H, d, J = 10.1 Hz, CH2), 7.15–
7.18 and 7.26–7.33 (10H, m, Ph), 7.50 (2H, s, H3, Pz);
δC(CDCl3) 61.2 (C4, Pz), 81.3 (CH2), 125.3 (C1, Ph), 128.8 and
129.6 (C2 and C3, Ph), 129.5 (C4, Ph), 132.8 (C5, Pz), 138.6
(C3, Pz).
Scheme 4
The racemic compound was subjected to preliminary tests as
a catalyst ligand in the addition of diethylzinc to benzaldehyde.
The titanium() complex of ligand 5 was prepared in situ by
reaction with titanium tetraisopropoxide, and the chemical
activity of this complex in the above-mentioned reaction was
comparable to the corresponding BINOL–Ti() complex.
Currently, the rotational barrier of the compound is being
determined experimentally in order to establish whether the
barrier is sufficiently high to allow optical resolution.
Conclusion
The synthesis of a new ligand type for asymmetric synthesis has
been developed. The ligand is based on a C2-symmetric
homodimer of 1-hydroxypyrazole. In the key step, two iodine
atoms were introduced and then replaced by two phenyl groups,
using cross-coupling conditions. Subsequent deprotection
afforded the free ligand, which coordinated to Ti(). The Ti()
complex served as a catalyst in the addition of diethylzinc to
benzaldehyde.
1,1Ј-Bis(benzyloxy)-4,4Ј-diphenyl-5,5Ј-bipyrazolyl
(4).
Method A. 1,1Ј-Bis(benzyloxy)-4,4Ј-diiodo-5,5Ј-bipyrazolyl (3)
(0.60 g; 1.00 mmol) was dissolved in dry THF (10 mL) under
nitrogen. After cooling to 0 ЊC, a 1.2 M solution of phenyl-
magnesium chloride in THF (4.2 mL; 5.0 mmol) was added and
the temperature was allowed to rise to room temperature. After
5.5 hours, a 1 M solution of ZnCl2 in dry THF (7.5 mL,
7.5 mmol) was added, followed by addition of a solution of
iodobenzene (2.04 g; 10.0 mmol) and Pd(PPh3)4 (0.12 g; 0.10
mmol; 10 mol%) in dry DMF (7.5 mL). The reaction mixture
was heated to 70 ЊC for 17 hours, then cooled and quenched by
addition of saturated ammonium chloride (50 mL), and worked
up as above. The crude product was purified by chromato-
graphy to give the product 4 (0.35 g, 70%) as a colorless oil;
Experimental
General
All chemicals and solvents used were of synthesis quality unless
otherwise stated. The solution of n-BuLi was titrated using
J. Chem. Soc., Perkin Trans. 1, 2001, 1566–1568
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δH(CDCl3) 4.86 (2H, d, J = 9.9 Hz, CH2), 5.12 (2H, d, J = 9.9
Hz, CH2), 7.06–7.09 (4H, m, H3 Bn), 7.16–7.25 (16H, m,
H2 ϩ H4 Bn, Ph), 7.70 (2H, s, H3, Pz); δC(CDCl3) 80.8 (CH2),
120.1 and 122.4 (C1, Ph and Bn), 126.5, 128.7, 129.1, and 129.6
(C2 and C3, Ph and Bn), 127.4 and 129.3 (C4, Ph and Bn),
131.5 (C3, Pz), 131.7 (C4, Pz), 133.3 (C5, Pz).
Method B. 1,1Ј-Bis(benzyloxy)-4,4Ј-diiodo-5,5Ј-bipyrazolyl
(3) (0.50 g; 0.84 mmol) and phenylboronic acid (0.82 g; 6.7
mmol) were dissolved in DME (20 mL). A 2 M aqueous solu-
tion of potassium carbonate (6.7 mL) was added, and the
mixture was bubbled with nitrogen for 25 minutes. Bis(tri-
phenylphosphine)palladium() dichloride was added and the
reaction mixture was heated to 70 ЊC for 24 hours under nitro-
gen. After cooling to room temperature, the reaction was
quenched by addition of saturated sodium hydrogen carbonate
(40 mL) and water (40 mL). Work-up as above followed by
chromatography gave the product 4 (0.34 g, 80%) as a colorless
oil. NMR data obtained were similar to those given above.
propoxide (133.9 mg, 0.47 mmol). After 10 minutes, 1 M
diethylzinc in toluene (0.95 ml, 0.95 mmol) was added. The
reaction was left for another 10 minutes before it was cooled to
0 ЊC, and benzaldehyde (50 mg, 0.47 mmol) was then added.
After 7.5 hours the reaction was quenched by addition of 4 M
aqueous hydrochloric acid. Extractive work-up using diethyl
ether gave 42.3 mg (66%) of 1-phenylpropan-1-ol; δH(CDCl3)
0.90 (3H, t, J = 7.42 Hz, CH3), 1.78 (2H, m, CH2), 2.92 (1H, br
s, OH), 4.59 (1H, t, J = 6.68 Hz, CH), 7.33 (5H, s, Ph). The
crude product contained 5% unchanged benzaldehyde.
Acknowledgements
The authors wish to express their gratitude to the Norwegian
National Research Council for financial support.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1566–1568