An efficient synthesis of β-hydroxyethylpyrazoles from propylene and styrene oxide using Cs2CO3

Article abstract of DOI:10.1016/j.tetlet.2004.05.124

Bases such as caesium carbonate efficiently catalyze the regioselective ring opening of propylene and styrene oxide with various substituted pyrazoles.

Full text of DOI:10.1016/j.tetlet.2004.05.124

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5697–5701
An efficient synthesis of b-hydroxyethylpyrazoles from
propylene and styrene oxide using Cs2CO3
Virginie Duprez and Andreas Heumann*
UMR-CNRS 6180, Universitꢀe d’Aix-Marseille III, Case A62, Facultꢀe Saint-Jꢀer^ome, 13397 Marseille Cedex 20, France
Received 22 March 2004; revised 17 May 2004; accepted 18 May 2004
Available online 11 June 2004
Abstract—Bases such as caesium carbonate efficiently catalyze the regioselective ring opening of propylene and styrene oxide with
various substituted pyrazoles.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Pyrazole compounds have been used for a long time as
ligands in transition metal complexes. The heterocyclic
nucleus may coordinate directly to the metal via one or
both of the vicinalnitrogen atoms or the metalmay be
bound to several pyrazole nitrogens in a polypyrazole
system with a carbon or heteroatom linker. Since the
pioneering work of Trofimenko1 the enormous potential
of polypyrazoles (boro, alkano, etc.) was recognized for
organometallic chemistry and catalysis. In recent years
there has been a growing interest in ligand systems that
coordinate to the metal via chemically different coordi-
nation sites with variable bond strengths of the respec-
tive metal ligand bonds. SHOP (Shell Higher Olefin
Process) catalysts for the oligomerization of alkenes2 are
a well known example of such hemilabile metal–ligand
systems. In the pyrazole ring one nitrogen atom is easily
alkylated giving access to systems that possess two and
more (identicalor different) heteroatoms. In a research
project directed towards the development of new non-
metallocene polymerization catalysts we became inter-
ested in heterocyclic pyrazole ligands that also contain
functionalgroups, such as an OH, in a carbon side
chain. We chose hydroxyethylpyrazoles 1 and we report
here on the preparation of these type of pyrazoles.
Considering that in these compounds both the pyrazole
ring and also the carbon side chain is easily and selec-
tively substituted with various aliphatic and aromatic
groups, an important number of polysubstituted
hydroxyethylpyrazoles may be envisaged.
R
OH
N
R'
N
1
Several hydroxyalkylpyrazoles of type 1 are known,
though no general applicable synthesis has been
described.3–10 The most generalway would consist in the
condensation of hydroxyethylhydrazines with the
appropriate 1,3-dicarbonylcompounds. The parent
hydroxyethylpyrazole 1 (R ¼ R0 ¼ H) was prepared in
this way in 76% yield.6 Another method for the intro-
duction of the hydroxylated side chain consists in the a-
lithiation of N-alkyl groups in pyrazoles followed by the
electrophilc reaction with aldehydes or ketones.7 How-
ever, the simplest and general way to b-aminoalcohol
pyrazoles 1 consists in the nucleophilic attack of one
pyrazole nitrogen to an oxirane functional group.
An epoxide ring is sufficiently reactive in order to be
thermally cleaved even with the weakly basic pyrazole
NH groups (pKa ¼ 2.5–4). Thus, following a patent
application,4 Elguero et al.5 realized epoxide ring
opening of styrene oxide with 3,5-dimethylpyrazole in
refluxing xylene after 8 h reaction time according to path
a (3h, R1 ¼ R2 ¼ Me).11 With high-pressure conditions8
or microwave activation9 other methods were explored
for the synthesis of, mainly, monosubstituted pyrazoles
with a limited number of epoxides (styrene, cyclohexene,
methylenecyclohexane, 1,10-diphenyl-ethylene). All these
conditions do not seem appropriate for larger scale
Keywords: Amino alcohol; Epoxides; Heterocycles; Regioselectivity;
Ring opening.
* Corresponding author. Fax: +33-491288278; e-mail: andreas.
heumann@univ.u-3mrs.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.124

5698
V. Duprez, A. Heumann / Tetrahedron Letters 45 (2004) 5697–5701
preparations. In principle, there are two possible regio-
selective pathways but usually, a secondary alcohol of
type 2 or 3 is obtained via substitution of the less
substituted carbon in the epoxide in the noncatalyzed
thermalreaction. This approach offers the opportunity
to use directly the (non-negligible) pool of substituted
pyrazoles.12 In case of monosubstituted (R1 or R2 ¼ H)
or differently disubstituted pyrazoles (R1 „ R2) 2 other
regio isomers might be formed where the hydroxyethyl
side-chain is vicinalor distant to one distinct sub-
stituent. In terms of ligand coordination, all four pos-
internaland terminalepoxides into the corresponding b-
amino alcohols.15 Though primary and secondary
amines have been used extensively, to our knowledge,
the pyrazole nucleus was not transformed under these
conditions. As mentioned before, the nucleophilic ring
opening of unsymmetricalepoxides can occur at the
secondary or tertiary oxirane carbon and gives rise to 2
(or 4) isomers. Having in mind to prepare selectively
ring-substituted pyrazoles the efficient regiocontrol of
both the epoxide ring-opening and pyrazole substitution
was desired (Scheme 1).
sible regio isomers induce
a
different sterical
16
environment to the putative metalcompelx and, thus,
each compound might be useful. We chose styrene and
propylene oxide as convenient starting materials for the
alcohol part.
Among severalinorganic bases that we tried it turned
out that caesium carbonate17;18 in trifluorotoluene19
leads to the products from propylene and styrene oxide
that we expected from the thermalreaction. The resutls
with ten different pyrazoles are presented in Table 1. For
example, we were pleased to observe that the transfor-
mation of most pyrazoles is quantitative and that the
products 2h,a and 3h,a from, respectively, 1,3-dimethyl-
pyrazole or unsubstituted pyrazole can be isolated in
pure form and yields higher than 80% in multi gram
quantities (Table 1, entries 1, 2, 15 and 16).
1. Thermal conditions
We repeated the reaction described by Wolf and Flani-
gan4 and Elguero et al.5 with success and effectively, the
unsubstituted as well as the dimethylated substrates (3a,
R1 ¼ R2 ¼ H) and (3h, R1 ¼ R2 ¼ Me), respectively,
were accessible via thermolysis of styrene oxide in
moderate yields. Sometimes, better results were obtained
on heating the pyrazole and 6 under neat reaction con-
ditions without solvent. However, with monosubstituted
pyrazoles, such as tert-butylor iso-propylpyrazole only
product mixtures were obtained in fairly moderate yields
(30–50%). On the other side, thermolysis of propylene
oxide 5 and unsubstituted pyrazole easily lead to 2-hy-
droxypropylpyrazole 2a (R1 ¼ R2 ¼ H) in 66% yield at
60 °C (pressure tube, neat, excess of propylene oxide).
On reacting other pyrazoles with 5 and 6 it became
rapidly clear that the simple thermal ring opening was
not a usefulmethod for generalappilcation.
The transformation of styrene oxide required heating
and we conducted the reaction in trifluorotoluene at
reflux temperature (102 °C). More conveniently, prop-
ylene oxide reacts at room temperature and no solvent
is necessary. The amount of base as well as reaction
times were not optimized. As a good compromise we
found that with styrene oxide 0.5 equiv of Cs2CO3 led to
good and reproducible results within 16–22 h. With
propylene oxide the basic catalyst could be reduced to
0.2 equiv. Different alkyl and aryl groups in the pyrazole
ring are compatible with the reaction conditions; they do
not influence the reactivity notably. It is noteworthy that
the ring-opening of the epoxide is highly regioselective in
nearly all cases. Pyrazole and disubstituted pyrazoles
4h–k exclusively lead to the secondary amino alcohols 2
and 3. However, with 4b–g the substitution pattern of
the pyrazole ring has a pronounced influence on the
product ratio and only the tert-butyland trifluoro-
methylgroups induce fairyl good distand-seelctivities
(>80%; entries 5, 6, 9 and 10) in both series. Neverthe-
less, the different reaction products can be purified and
separated chromatographically, though not all com-
pounds were isolated in pure form.
2. Catalytic conditions
The acid or base catalyzed ring opening of oxiranes by
means of nitrogen-centered nucleophiles is a well known
reaction. Azidohydrins13 and aminohydrins14 are easily
prepared with high regioselectivities and a number of
reaction conditions with base or Lewis acids are de-
scribed. With strong bases, for example, it is possible to
avoid drastic conditions but observe the regioselectivity
of the uncatalyzed reaction and, thus, to transform
The composition of the reaction mixture and the struc-
ture of the products are easily determined by proton and
2
2
2
R
R
R
R
a
R
H
OH
a
b
N
N
R
N
+
N
N
N
OH
O
1
1
1
b
R
R
R
2a-k R = Me
3a-k R = Ph
4a-k
5 R = Me
6 R = Ph
7 R = Me
8 R = Ph
Scheme 1. Regiochemistry of the nucleophilic ring-opening of mono substituted oxiranes.

V. Duprez, A. Heumann / Tetrahedron Letters 45 (2004) 5697–5701
5699
Table 1. Regioselective preparation of various hydroxyethylpyrazoles from propylene oxide 5a and styrene oxide 6b in the presence of Cs2CO3
Entry
Pyrazole
Productsc 2 and 3
Side products
(isomers)d
Isolated yield(%)e
R
1
2
Pyrazole 4a
Quant
Quant
2a R ¼ Me, 95%f
3a R ¼ Ph, 80%
N
OH
R
N
N
3
4
3-Methyl-pyrazole 4b
60%
40%
40%
60%h
2b R ¼ Me, 70%g
3b R ¼ Ph, 95%g
OH
R
N
Me
N
5
6
Trifluoromethyl-pyrazole 4c
3-iso-Propylpyrazole 4d
3-tertio-Butylpyrazole 4e
80%
>90%
20%
2c R ¼ Me, 60%
3c R ¼ Ph, 80%g
OH
N
5–10%
F C
3
R
N
7
8
65%
60%
35%
40%
2d R ¼ Me, 70%g
3d R ¼ Ph, 50%
OH
N
i-Pr
R
N
9
10
90%
90%
5–10%
5–10%
2e R ¼ Me, 85%g
3e R ¼ Ph, 61%
OH
N
t-Bu
R
N
11
12
3-Phenylpyrazole 4f
80%
70%
20%
30%
2f R ¼ Me, 88%g
3f R ¼ Ph, 90%g
OH
R
N
Ph
Ph
Me
13
14
5-Methyl-3-phenylpyrazole 4g
80%
80%
20%h
20%h
2g R ¼ Me, 75%
3g R ¼ Ph, 60%
N
N
OH
Me
R
15
16
3,5-Dimethylpyrazole 4h
Quant
Quant
––
––
2h R ¼ Me, 89%f
3h R ¼ Ph, 85%f
N
N
OH
Me
CF
3
R
17
18
3,5-Bis-trifluoro-methyl-yl-pyrazole 4i
3,5-Diphenyl-pyrazole 4k
Quant
Quant
––
––
2i R ¼ Me, 70%
3i R ¼ Ph, 75%
N
N
OH
C
F
3
Ph
R
19
20
N
Quant
Quant
––
––
2k R ¼ Me, 95%
3k R ¼ Ph, 90%
N
OH
Ph
a Propylene oxide (1 mL), pyrazole (1 mmol), Cs2CO3 (0.2 mmol), rt (25 °C), 16–22 h without solvent in a small flask.
b Styrene oxide (2 mmol), pyrazole (1 mmol), Cs2CO3 (0.5 mmol), trifluorotoluene (5 mL), reflux (102 °C), 16–18 h.
c Analysis of the crude reaction product by 1H NMR after filtration and evaporation of the solvent.
d Generally not characterized; mainly compounds 2 and 3 R1 ¼ H, R2 ¼ substituent.
e Flash chromatography: ether or ethylacetate/petroleum ether, mixtures or crystallization from petroleum ether/ether.
f 50 mmolscael.
g The mixture was not separated.
h Three isomers.
carbon NMR analysis.20;21 Severalcharacteristic signasl
confirm the presence of the b-amino alcohol side chain
with the secondary OH group. The respective 13C signals
for CH–OH (2h, 67.4 and 3i, 74.0 ppm) and CH2–N (2h,
54.9 and 3i, 56.2 ppm) agree well with the ABM pattern
(2h, 4.06, 3.88, 3.73 and 3i, 5.26, 4.43, 4.14 ppm) in the
1H NMR spectrum. In the compounds from propylene
oxide the doublet (J ¼ 6 Hz) of the methylgroup ( 2h,
1.13 ppm) is a usefulindicator of an effective ring-
opening of the epoxide. The N-substitution of unsym-
metricalpyrazoels may occur at both nitrogen atoms
and mixtures of isomers were obtained with camphor-
pyrazole8a or menthylpyrazole.22 However, in many
cases substitution takes place at the least hindered
nitrogen with respect to the pyrazole substituent23 and
consequently the 3-substituted substrates 2 and 3
(R1 ¼ substitutent, R2 ¼ H) are the main products. In
the case of 5-methyl 3-phenylpyrazole 4g24 the structure
is confirmed by NOESY experiments and it should be
noted that the regioselective epoxide cleavage is com-
parable to the reaction of the monosubstituted 3-phenyl-
pyrazole 4f.

5700
V. Duprez, A. Heumann / Tetrahedron Letters 45 (2004) 5697–5701
Wakao, M.; Hayakawa, H.; Shimanouchi, T.; Shiro, M. J.
Org. Chem. 1996, 61, 8915.
N
N
9. Glas, H.; Thiel, W. R. Tetrahedron Lett. 1998, 39, 5509.
10. Nagao, Y.; Tamai, S.; Tanigawa, N.; Sano, S.; Kumagai,
T.; Kishi, I. Heterocycles 1998, 48, 617.
Cs2CO3 0.2eq
25˚C, 2d, neat
O
+ 4a
+ 4a
OH
11. Other known compounds 3: 3a Refs. 7–9; 3b Ref. 6; 3h
Refs. 4,5.
9
10 (70%)
12. Kirschke, K. In Methoden der Organischen Chemie (Hou-
ben–Weyl) Hetarene III/Teil 2; Schaumann, E., Ed.;
Thieme: Stuttgart, 1994; Vol. E8b, p 399.
Cs2CO3 0.2eq
N
O
N
OH
13. A recent example with CeCl3: Sabitha, G.; Babu, R. S.;
Rajkumar, M.; Yadav, J. S. Org. Lett. 2002, 2, 343.
14. Some examples: BiCl3: (a) Swamy, N. R.; Kondaji, G.;
Nagaiah, K. Synth. Commun. 2002, 32, 2307; (b) CoCl2:
Iqbal, J.; Pandey, A. Tetrahedron Lett. 1990, 31, 575; (c)
InCl3: Rajender Reddy, L.; Arjun Reddy, M.; Bhanuma-
thi, N.; Rama Rao, K. New J. Chem. 2001, 25, 221; (d)
Ln(OTf)3: Chini, M.; Crotti, P.; Favero, L.; Macchia, F.;
Pineschi, M. Tetrahedron Lett. 1994, 35, 433; (e) SmCl3:
Fu, X.-L.; Wu, S.-H. Synth. Commun. 1997, 27, 1677; (f)
Yb(OTf)3: Meguro, M.; Asao, N.; Yamamoto, Y. J.
Chem. Soc., Perkin Trans. 1 1994, 2597.
63˚C, 20h, neat
11
12 (75%)
Scheme 2.
In order to check the broader generality of our reactions
we also submitted an internal epoxide and another ali-
phatic terminaloxirane to our reaction conditions. Cyclo-
hexene oxide 9 as well as 1,2-epoxybutane 11 were easily
tansformed into the b-hydroxyalkylpyrazole derivatives
1025 and 12, respectively, in good yields and excellent
regioselectivities (Scheme 2).
15. Harris, C. E.; Fisher, G. B.; Beardsley, D.; Lee, L.;
Goralski, C. T.; Nicholson, L. W.; Singaram, B. J. Org.
Chem. 1994, 59, 7746.
In summary, caesium carbonate is a good catalyst for
the regioselective ring-opening of terminal epoxides
under very mild reaction conditions. Propylene oxide
reacts at room temperature whereas styrene oxide re-
quires refluxing temperature in trifluorotoluene as sol-
vent. The transformation is generaland preparativeyl
useful; the observed regioselectivities, with respect the
ring substitution of the pyrazole, but also the generation
of secondary alcohols are acceptable and these type
substrates have already found an application as ligands
16. The catalysis of Li2CO3, Na2CO3, K2CO3, BaCO3, only
lead to trace amounts of aminoalcohols.
17. Caesium carbonate has been found previously to be a
usefulreagent for seelctive N-alkylation: Salvatore, R. N.;
Shin, S. I.; Flanders, V. L.; Jung, K. W. Tetrahedron Lett.
2001, 42, 1799.
18. Review: Fl essner, T.; Doye, S.J. Prakt. Chem. 1999, 341, 186.
19. Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
20. Typical procedure with propylene oxide: the pyrazole
(1 mmol), propylene oxide (1 mL) and Cs2CO3 (72 mg,
0.2 mmol) are stirred for the indicated time at room
temperature. The propylene oxide is evaporated and the
residue taken up in dichloromethane (1 mL) and stirred
with brine (1–2 · 0.2 mL). The organic solution is sepa-
rated from the aqueous phase, and dried over MgSO4.
After filtration the solvent is evaporated. Often, the
product is pure enough for further use, however, it can
be purified with flash chromatography or by recrystalliza-
tion (petroleum ether/ether or petroleum ether/ethylace-
tate mixtures). 1-(3,5-Dimethylpyrazol-1-yl)-propan-2-ol
(2h): Mp 51–52 °C (petroleum ether/ether). Found: C,
62.17; H, 8.98; N, 18.01. Anal. Calcd for C8H14N2O: C,
62.31%; H, 9.15%; N, 18.17%. 1H NMR: d ¼ 5:73 (s, 1H),
4.06 (m, 2H), 3.88 (dd, J ¼ 4, 14 Hz, 1H), 3.73 (dd, J ¼ 8,
14 Hz, 1H), 2.16 (s, 3H), 2.13 (s, 3H), 1.13 (d, J ¼ 6 Hz,
3H). 13C NMR d ¼ 148:1, 139.99, 105.23, 54.94, 20.62,
13.74, 11.4.
21. Typicalprocedure with styrene oxide: a mixture of the
pyrazole (1 mmol), styrene oxide (240 mg, 2 mmol) and
Cs2CO3 (163 mg, 0.5 mmol) in trifluorotoluene is stirred
and refluxed (102 °C) during (in general) one night. After
cooling the reaction mixture is filtered and the residue
extracted with ether or dichloromethane (5–10 mL). The
combined solutions are dried over MgSO4, filtered and the
solvent evaporated. Excess styrene can be evaporated at
50–60 °C under 0.1 mm high vacuum. Often, the product is
pure enough for further use, however, it can be purified
with flash chromatography or by recrystallization (petro-
leum ether/ether or petroleum ether/ethylacetate mix-
tures). 2-(3,5-Diphenyl-1-pyrazolyl)-1-phenylethanol (3k):
Mp 85 °C (pentane/toluene). Found: C, 81.06; H, 5.97; N,
8.20. Anal. Calcd for C23H20N2O: C, 81.15%; H, 5.92%; N,
8.23%. 1H NMR: d ¼ 7:94–7:99 (m, 2H), 7.29–7.52 (m,
13H), 6.67 (s, 1H), 5.4 (br, 1H), 5.26 (dd, J ¼ 4, 8 Hz, 1H),
26
in metalcatayl zed reactions.
Acknowledgements
We thank Borealis S. A. for financial support. Marius
ꢀ
Reglier’s and Alphonse Tenaglia’s critical discussions
are gratefully acknowledged.
References and notes
1. (a) Trofimenko, S. Chem. Rev. 1993, 93, 943; (b)
Trofimenko, S. Scorpionates, the coordination chemistry
of poly(pyrazolyl)borate ligands; Imperial College: Lon-
don, 1999.
2. Keim, W. Angew. Chem., Int. Ed. Engl. 1990, 29, 235.
3. Finar, I. L.; Utting, K. J. Chem. Soc. 1960, 5272.
4. Wolf, M.; Flanigan, D. J., U.S. 3 303 200, 1967; Chem.
Abstr. 1967, 67, 76002k.
5. Elguero, J.; Fruchier, A.; Jacquier, R. Bull. Soc. Chim. Fr.
1969, 2064.
6. Butler, D. E.; Alexander, S. M. J. Org. Chem. 1972, 37,
215.
7. Katritzky, A. R.; Jayaram, C.; Vassilatos, S. N. Tetra-
hedron 1983, 39, 2023.
8. (a) Kotsuki, H.; Hayakawa, H.; Wakao, M.; Shimanou-
chi, T.; Ochi, M. Tetrahedron: Asymmetry 1995, 6, 2665;
(b) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishi-
zawa, H. J. Org. Chem. 1996, 61, 984; (c) Kotsuki, H.;

V. Duprez, A. Heumann / Tetrahedron Letters 45 (2004) 5697–5701
5701
4.43 (dd, J ¼ 4, 14 Hz, 1H), 4.3 (dd, J ¼ 8, 14 Hz, 1H). 13
C
NMR d ¼ 151:56, 146.6, 141.29, 133.32, 130.47, 129.5,
129.25, 129.16, 129.11, 128.9, 128.49, 128.29, 126.4,
126.13, 103.8, 74.01, 56.16.
J ¼ 3:6, 13.8 Hz, 1H), 4.03 (dd, J ¼ 7:2, 13.8 Hz, 1H). 13
C
NMR d ¼ 148:5, 145.6, 131.0, 129.4, 129.0, 126.3, 125.8,
106.1, 67.4, 55.7, 20.5, 13.8; (b) The regioisomer 8g
(R1 ¼ Ph, R2 ¼ Me) was prepared in the presence of
SnCl4 1H NMR: d ¼ 7:73–7:76 (m, 2H), 7.15–7.34 (m,
2H), 6.98–7.01 (m, 2H), 6.32 (s, 1H), 5.21–5.24 (m, 1H),
4.1–4.4 (m, 3H), 1.99 (s, 3H). 13C NMR d ¼ 150:2, 140.9,
138.1, 133.3, 128.7, 128.6, 127.9, 127.6, 126.52, 125.5,
103.2, 65.8, 64.1, 11.1 ppm.
22. Bovens, M.; Togni, A.; Venanzi, L. M. J. Organomet.
Chem. 1993, 451, 28.
23. (a) Bol, J. E.; Maase, B.; Gonesh, G.; Driessen, W. L.;
Goubitz, K.; Reedijk, J. Heterocycles 1997, 45, 1477; (b)
ꢀ
Review: Ref. 12; (c) The, K. I.; Peterson, L. K.;
Kiehlmann, E. Can. J. Chem. 1973, 51, 2448.
25. Barz, M.; Herdtweck, E.; Thiel, W. R. Tetrahedron:
Asymmetry 1996, 7, 1717.
26. Duprez, V.; Blom, R.; Bouzga, M.; Heumann, A., in
preparation.
24. (a) Compound 3g: (R1 ¼ Ph, R2 ¼ Me) 1H NMR:
d ¼ 7:7–7:8 (m, 2H), 7.20–7.40 (m, 8H), 6.2 (d, J ¼ 0:8 Hz,
1H), 5.08 (dd, J ¼ 3:6, 7.2 Hz, 1H), 4.9 (s, 1H), 4.14 (dd,