Selective β-hydroxyethylation at the N-1 position of a pyrazolone: Synthesis of benzyl 1-(β-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro- 1H-pyrazole-4-carboxylate

Article abstract of DOI:10.1055/s-2008-1042923

Selective 2-hydroxyethylation at the N-1 position of benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate with epoxides was achieved using either AlMe₃ or Mg(ClO₄)₂ under mild conditions. The epoxide ring opening was both regioselective and stereospecific. Moderate to excellent yields were obtained from mono- and disubstituted epoxides with the exception of cis-dimethyl-2-butene oxide that gave only a trace amount of the product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042923

LETTER
1005
Selective b-Hydroxyethylation at the N-1 Position of a Pyrazolone:
Synthesis of Benzyl 1-(b-Hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazole-4-carboxylate
N
-1
b
-Hydroxyeth
a
ylation of
a
r
Pyrazol
o
one n Siegmund,a Daniel Retz,a Ning Xi,a Celia Dominguez,b Roland Bürli,a Longbin Liu*a
a
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
MRSSI/CHDI, Inc., 6080 Center Drive, Suite 100, Los Angeles, CA 90045, USA
E-mail: lliu@amgen.com
b
Received 11 December 2007
Dedicated to Robert E. Ireland on the occasion of his 79th birthday
In contrast, only a few reactions are known to occur at the
N-1 position of 4-acyl pyrazolones. For example,
(Me)2SO4 (neat) at high temperature (140 °C) or MeOTs
in the presence of K2CO3 promoted N-methylation.10 Gly-
Abstract: Selective 2-hydroxyethylation at the N-1 position of ben-
zyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxy-
late with epoxides was achieved using either AlMe3 or Mg(ClO4)2
under mild conditions. The epoxide ring opening was both regiose-
lective and stereospecific. Moderate to excellent yields were ob- cosylations under Lewis acid catalysis are also known to
occur mainly at the N-1 position.11 The sodium salts of 2-
tained from mono- and disubstituted epoxides with the exception of
cis-dimethyl-2-butene oxide that gave only a trace amount of the
product.
phenyl-5-methyl-3-pyrazolone and 2,5-diphenyl-3-pyra-
zolone have been reported to react with 2-chloroethyl al-
cohol under reflux to give mixtures of O- and N-
Key words: pyrazolones, pyrazole, epoxide, hydroxyethyl, selec-
hydroxyethyl derivatives.12 Holzer et al. demonstrated
tive, trimethylaluminum, magnesium perchlorate
that epichlorohydrin, when used as solvent, reacts with the
sodium salt of 4-acylpyrazolones at the N-1 position in
modest yields.13 However, this reaction required high
temperature (110 °C) and excess epichlorohydrin to
achieve the N-1 versus O-3 selectivity. In our hands, the
Holzer protocol only afforded trace amounts of products
when benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carboxylate (1, Equation 1) was treated with
either propylene oxide or epichlorohydrin. Given that ep-
oxides are readily available and that the products derived
from epoxide openings can be further transformed at the
resulting hydroxyl group, a general procedure for cou-
pling pyrazolones and epoxides at the N-1 position would
serve as a valuable tool for accessing diverse set of pyra-
zolone derivatives.14 Herein, we describe the development
of mild conditions for the regioselective alkylation at the
N-1 position of 4-carboxyl pyrazolones with epoxides.
Tautomerism in pyrazolones has been extensively stud-
ied.1 For example, 3-oxo-2,3-dihydro-1H-pyrazole-4-
carboxylate2 can exist as tautomeric forms A, B, C, and D
(Scheme 1). Not surprisingly, transformations at N-1, C-
3–OH, and C-4 positions of pyrazolones are known3 and
often compete against one another. A perusal of the liter-
ature indicates that the majority of reactions involving 4-
acyl-3-oxo-2,3-dihydro-1H-pyrazoles occur at the C3–
OH. These include the Mitsunobu reactions,4 methyla-
5
tions with CH2N2 or TMSCHN2,6 acylations,7 and in-
tramolecular cyclizations.8 Alternatively, the C-3–OH is
first activated using POCl3 and subsequently displaced
with other nucleophiles.9
O
O
O
OH
N
4
R2O
3
R2O
O
O
R1
N
R1
O
O
O
1
N
R3
N
R3
BnO
BnO
H
N
N
A
B
N
N
H
OH
O
OH
1
2
O
O
R2O
R2O
Equation 1
R1
N
R1
N
N
R3
N
R3
C
D
The fact that pyrazoles readily react with epoxides in the
presence of a weak base (Cs2CO3),15 whereas pyrazolones
require harsh conditions (vide supra), suggests that the
carbonyl groups in pyrazolones significantly decrease the
nucleophilicity at the N-1 center. We reasoned that activa-
tion of the epoxide C–O bond might compensate for the
weaker nucleophilicity of the pyrazolone nitrogen. In this
regard, a variety of Lewis acids were screened for the re-
Scheme 1
SYNLETT 2008, No. 7, pp 1005–1008
Advanced online publication: 17.03.2008
x
x.
x
x.
2
0
0
8
DOI: 10.1055/s-2008-1042923; Art ID: S09807ST
© Georg Thieme Verlag Stuttgart · New York

1006
A. Siegmund et al.
LETTER
action of 1 with propylene oxide (Equation 1). For exam- (in MeCN or CHCl3) promoted the complete conversion
ple, in the presence of various BF3 (complexed with Et2O, of 1 into 2 under mild conditions. For example, 2 was iso-
THF, AcOH) adducts in non-nucleophilic solvents lated in 96% yield after a mixture of 1 (0.31 g), Mg(ClO4)2
(CHCl3 or PhCl), the desired product 2 was indeed ob- (10 equiv), and propylene oxide (10 equiv) was heated at
served (less than 30% conversion by LC-MS). In general, 35 °C in MeCN for 3 hours.16
extended reaction times or higher temperatures resulted in
the formation of undesired byproducts. Only traces of
product 2 were observed in the presence of trialkyl bo-
ranes. However, with ZnMe2 a slow but steady reaction
led to ca. 80% conversion after 2 days. Ultimately, we
found that both Me3Al (in PhMe or PhCl) and Mg(ClO4)2
A number of epoxides were treated with 1 in the presence
of either Mg(ClO4)2 (method A) or Me3Al (method B).
The results are shown in Table 1.17 These transformations
were highly regioselective for the N-1 position of the
pyrazolone 1 and for the oxirane carbon bearing the least
Table 1 Reaction of Benzyl 5-Hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1) with Various Epoxidesa
O
O
BnO
Epoxide
Epoxide (equiv)
Method
Time (h)
16
Yield (%)
92
N
N
>10
Ab
3
4
OH
O
O
3
2
Ac
B
2
1.5
83
59
OH
OH
O
O
5
5
Ad
Ac
2
2
5
6
93
61
OH
OH
3
1.5
Ac
B
4
1.5
87
54
O
O
7
Cl
Cl
10
5 (R)
5 (S)
Ae
Ad
Ad
2
48
48
8a
8b
8c
57
OH
59 (S)f
58 (R)f
O
O
OH
OH
5
5
B
48
72
9
42
30
Ae
10
O
O
10
10
Ae
Ae
2
11
12
73g
<5g
OH
OH
18
a Yields refer to isolated material. Method A: Mg(ClO4)2 (1 equiv) in CHCl3 (35 °C).
b Method A: Mg(ClO4)2 (1 equiv) in CHCl3 (35 °C); Method B: Me3Al (5 equiv) in PhCl (0 °C to 23 °C).
c Mg(ClO4)2 (3 equiv) in MeCN (37 °C).
d Mg(ClO4)2 (3 equiv) in MeCN (50 °Cf).
e Mg(ClO4)2 (5 equiv) in MeCN (50 °Cf).
f The optical purity was determined to be >95% ee based on chiral HPLC analyses [Chiralpak AD-H (150 × 4.6 mm, 5 mm); isocratic CO2
(80%)–MeOH (20%) at a flow rate of 4.0 mL/min (35 °C; outlet pressure of 120 bar)].
g Racemic material.
Synlett 2008, No. 7, 1005–1008 © Thieme Stuttgart · New York

LETTER
N-1 b-Hydroxyethylation of a Pyrazolone
1007
substituents.18 In general, the reactions proceeded more
efficiently with less-hindered epoxides, such as propylene
oxide and monosubstituted epoxides (i.e., 3–6). The syn-
thesis of 7 illustrates that alkylchlorides are well tolerated
under these conditions. Notably, the epoxide ring-opening
processes were highly stereospecific. This was demon-
strated by the high optical purities (>95% ee) obtained
from the reactions of (R)- and (S)-2-isopropyloxirane
(8b,c). For geminal disubstituted epoxides, prolonged re-
action times were required and the yields were modest
(i.e. 9 and 10). There were significant rate differences in
the reactions of vicinal disubstituted epoxides: trans-2-
butene oxide was converted into 11 in 2 hours with 73%
yield, whereas the cis-isomer afforded only trace amounts
of 12 after 18 hours.
(3) For examples of reactions at C-4, see: (a) Bromination/
nitration: Das, S.; Mittra, A. S. J. Indian Chem. Soc. 1978,
55, 520. (b) Azirine formation: Holzer, W.; Claramunt, R.
M.; Pérez-Torralba, M.; Guggi, D.; Brehmer, T. H. J. Org.
Chem. 2003, 68, 7943.
(4) (a) Holzer, W.; Plagens, B.; Lorenz, K. Heterocycles 1997,
45, 309. (b) Subasinghe, N. L.; Ali, F.; Illig, C. R.; Rudolph,
M. J.; Lein, S.; Khalil, E.; Soll, R. M.; Bone, R. F.; Spurlino,
J. C.; Des Jarlais, R. L.; Crysler, C. S.; Cummings, M. D.;
Morris, P. E. Jr.; Kilpatrick, J. M.; Babu, Y. S. Bioorg. Med.
Chem. Lett. 2004, 14, 3043.
(5) O-Methylation was assigned based on 1H NMR chemical
shifts: (a) Ogawa, K.; Terada, T.; Honna, T. Chem. Pharm.
Bull. 1984, 32, 930. (b) Bregant, N.; Perina, I.; Malnar, M.
Croat. Chim. Acta 1977, 49, 813.
(6) (a) Holzer, W.; Plagens, B. Sci. Pharm. 1996, 64, 455; and
references cited therein. (b) Holzer, W.; Schmid, E.
J. Heterocycl. Chem. 1995, 32, 1341.
Many reactions of epoxide opening involve the use of alu-
minum reagents. For example, dialkylaluminum amides
formed in situ from trialkylaluminum and amines react
with epoxides to give b-amino alcohols.19 The examples
described herein required the use of excess Me3Al relative
to the pyrazolone, indicating that activation of the epoxide
may be the rate-limiting step.20 This is further supported
by the fact that the use of a bulkier trialkyl aluminum such
as (i-Bu)3Al, or epoxides bearing geminal substituents,
led to longer reaction times. Similarly, facile aminolysis
of epoxides by alkyl amines in the presence of Mg(ClO4)2
was ascribed to the activation of the epoxide.21 The dra-
matic rate difference observed between cis- and trans-2-
butene oxide is in agreement with coordination of Al or
Mg to the oxygen atom with concomitant nucleophilic at-
tack by the pyrazolone nitrogen from the opposite face of
the oxirane plane, thus rendering this process highly ste-
reospecific.
(7) (a) Terebenina, A.; Dimitrova, K.; Iordanov, B.;
Chervenakov, P.; Borisov, G. Izv. Khim. 1985, 18, 31; Chem.
Abstr. 1986, 104, 148787. (b) JP 59181259, 1984; Chem.
Abstr. 1985, 102, 113480.
(8) (a) Khan, M. A.; Ellis, G. P.; Pagotto, M. C. J. Heterocycl.
Chem. 2001, 38, 193. (b) Rachedi, Y.; Hamdi, M.;
Sakellariou, R.; Speziale, V. Synth. Commun. 1991, 21,
1189. (c) Wise, L. D.; Butler, D. E.; DeWald, H. A.;
Lustgarten, D. M.; Pattison, I. C.; Schweiss, D. N.;
Coughenour, L. L.; Downs, D. A.; Heffner, T. G.; Pugsley,
T. A. J. Med. Chem. 1987, 30, 1807.
(9) Holzer, W.; Hahn, K. J. Heterocycl. Chem. 2003, 40, 303.
(10) (a) Juršić, B.; Bregant, N. Synth. Commun. 1989, 19, 2087.
(b) Holzer, W.; Hahn, K.; Brehmer, T.; Claramunt, R. M.;
Pérez-Torralba, M. Eur. J. Org. Chem. 2003, 1209.
(11) (a) Sanghvi, Y. S.; Upadhya, K. G.; Dalley, N. K.; Ronibs,
R. K.; Revankar, G. R. Nucleosides Nucleotides 1987, 6,
737. (b) Anderson, J.; Cottam, H. B.; Larson, S. B. J.
Heterocycl. Chem. 1989, 27, 439. (c) Esanu, A. BE 902231,
1985; Chem. Abstr. 1986, 104, 110121.
(12) (a) Alberty, J. E.; Hukki, J.; Laitinen, P.; Myry, J. Arzneim.
Forsch. 1967, 17, 214; Chem. Abstr., 1967, 67, 43734.
(b) Sammour, A.; Raouf, A. A.-E.; Elkasaby, M.; Hassan, M.
A. Egypt. J. Chem. 1972, 15, 429.
In summary, a simple and efficient method for installing
b-hydroxyethyl groups to the N-1 position of 5-methyl-3-
oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate
has been developed. Under theses conditions, various sub-
stituted epoxides were coupled with modest to excellent
yields. It is anticipated that this methodology will be ap-
plicable to other pyrazolones.
(13) Chiba, P.; Holzer, W.; Landau, M.; Bechmann, G.; Lorenz,
K.; Plagens, B.; Hitzler, M.; Richter, E.; Ecker, G. J. Med.
Chem. 1998, 41, 4001.
(14) The only other example relevant to epoxide opening is found
in the reaction of pyrazolone with the intermediate derived
from pyrimidone and epichlorohydrin under basic
conditions, possibly proceeded via an epoxide intermediate
formed in situ: Krivonogov, V. P.; Kozlova, G. G.; Sivkova,
G. A.; Spirikhin, L. V.; Abdrakhmanov, I. B.; Murinov, Yu.
I.; Tolstikov, G. A. Russ. J. Org. Chem. 2003, 39, 257.
(15) Duprez, V.; Heumann, A. Tetrahedron Lett. 2004, 45, 5697.
(16) The structure of 2 was confirmed based on an alternative
synthesis in ca. 10% overall yield (Scheme 2).
Acknowledgment
We thank Drs. Zheng Hua and Kyung-Hyun Gahm for performing
the chiral HPLC analyses, and Drs. Tae-Seong Kim, Liz Doherty,
and Mark Norman for their helpful suggestions.
References and Notes
(17) General Procedures for Method A
To a stirring suspension of 1 (15.0 g, 49 mmol) in dry MeCN
(100 mL) at 0 °C was added Mg(ClO4)2 (33 g, 146 mmol) in
3 portions over 1 min. After the reaction temperature
returned to 0 °C, the epoxide was added. The flask was
equipped with a reflux condenser and was heated for the
specified time and temperature. The solution was then
concentrated under reduced pressure, dissolved in CHCl3
(100 mL), chilled to 10 °C, and quenched with ice-cold
water (200 mL). The resulting biphasic solutions were
stirred for 1 h and separated. The aqueous layer was
extracted with CHCl3 (2 × 50 mL), and the combined organic
(1) For a detailed discussion on the tautomerism of pyrazolones,
see: (a) Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt,
R. M.; Pérez-Torralba, M.; Alkorta, I.; Elguero, J.
Tetrahedron 2004, 60, 6791; and references cited therein.
(b) Katritzky, A. R.; Maine, F. W. Tetrahedron 1964, 20,
299.
(2) For the synthesis of 4-acyl/carboxyl pyrazolones, see:
(a) Jensen, B. S. Acta Chem. Scand. 1959, 13, 1668.
(b) Lopez, R.; León, G.; Oliva, A. J. Heterocycl. Chem.
1995, 32, 1377.
Synlett 2008, No. 7, 1005–1008 © Thieme Stuttgart · New York

1008
A. Siegmund et al.
LETTER
ppm] data are provided for compounds listed in Table 1:
Compound 4: 0.95 (d, J = 6.26 Hz, 3 H), 2.65 (s, 3 H), 3.38
(dd, J = 14.87, 1.76 Hz, 1 H), 3.43 (s, 1 H), 3.65 (dd,
J = 14.97, 9.88 Hz, 1 H), 3.94–4.05 (m, 1 H), 5.23 (s, 2 H),
7.20–7.39 (m, 5 H) 7.39–7.49 (m, 5 H).
O
O
1. POCl3, DMF
2. NaClO2
methylallyl
bromide
N
N
N
N
3. BnBr, K2CO3
120 °C
Compounds 5 and 6: 0.74 (t, J = 7.43 Hz, 3 H), 1.18–1.37
(m, 2 H), 2.67 (s, 3 H), 3.55 (d, J = 13.30 Hz, 1 H), 3.61–3.77
(m, 2 H), 5.27 (d, J = 3.52 Hz, 2 H), 7.27–7.39 (m, 5 H),
7.41–7.51 (m, 5 H).
Compound 7: 2.68 (s, 3 H), 3.21–3.34 (m, 2 H), 3.65–3.78
(m, 1 H), 3.80–3.90 (m, 1 H), 4.02–4.12 (m, 1 H), 5.16–5.31
(m, 2 H), 5.73 (br s, 1 H), 7.28–7.35 (m, 5 H), 7.36–7.51 (m,
5 H).
O
N
O
BnO2C
BnO2C
1. OsO4
2. NaIO4
N
N
N
3. NaBH4
OH
Compound 8: 0.68 (d, J = 6.85 Hz, 3 H), 0.74 (d, J = 6.85
Hz, 3 H), 1.49 (dd, J = 12.81, 6.75 Hz, 1 H), 2.67 (s, 3 H),
3.25 (br s, 1 H), 3.46–3.53 (m, 1 H), 3.58–3.64 (m, 1 H),
3.70–3.80 (m, 1 H), 5.29 (q, J = 12.78 Hz, 2 H), 7.28–7.41
(m, 6 H), 7.42–7.50 (m, 4 H).
Compound 9: 0.95 (s, 6 H), 2.65 (s, 3 H), 3.77 (s, 2 H), 4.79
(s, 1 H), 5.21 (s, 2 H), 7.23 (d, J = 7.43 Hz, 2 H), 7.27–7.33
(m, 1 H), 7.37 (q, J = 7.50 Hz, 3 H), 7.42–7.47 (m, 2 H), 7.50
(t, J = 7.73 Hz, 2 H).
Scheme 2
layers were washed with NH4Cl (sat.), dried over MgSO4,
and concentrated. The crude product was purified on SiO2
(120 g) chromatography eluting with a gradient of 1–2.5% of
MeOH–CH2Cl2.
General Procedure for Method B
To a stirring suspension of 1 (5.0 g, 16 mmol) in
chlorobenzene (25 mL) at 0 °C was added a solution of
Me3Al (2.0 M in toluene, 24 mL, 49 mmol) under nitrogen.
To the resulting clear solution was added the epoxide, and
the mixture was stirred at 23 °C. The reaction was monitored
by LCMS and more epoxide was added if the reaction
stalled. Upon completion, the mixture was diluted with THF
(100 mL), quenched with Na2SO4·10H2O (6 g), and stirred
for 24 h. The salts were removed by filtration (glass frit) and
washed with EtOAc (100 mL). The filtrate was washed with
HCl (1 N, 20 mL) and NH4Cl (sat., 20 mL), dried over
MgSO4, and concentrated. The crude product was purified
on SiO2 (40 g) chromatography eluting with 25–75% of
EtOAc in hexane.
Compound 10: 0.74 (t, J = 7.53 Hz, 3 H), 0.82–0.93 (m, 1
H), 1.02 (s, 3 H), 1.23–1.43 (m, 2 H), 2.72 (s, 3 H), 3.68–3.89
(m, 2 H), 5.30–5.33 (m, 2 H), 7.21–7.27 (m, 3 H), 7.29–7.37
(m, 3 H), 7.42–7.53 (m, 4 H).
Compound 11: 1.05 (d, J = 6.1 Hz, 3 H), 1.41 (d, J = 7.2 Hz,
3 H), 2.12 (d, J = 3.3 Hz, 1 H), 3.75–3.85 (m, 1 H), 2.70 (s,
3 H), 3.87–3.97 (m, 1 H), 5.29 (s, 2 H), 7.22–7.29 (m, 3 H),
7.29–7.35 (m, 2 H), 7.35–7.42 (m, 1 H), 7.42–7.51 (m, 4 H).
(19) Overman, L. E.; Flippin, L. A. Tetrahedron Lett. 1981, 22,
195.
(20) For an example of epoxide activation with AlMe3, see:
Schreiber, S. L. J. Am. Chem. Soc. 1980, 102, 6163.
(21) (a) Chini, M.; Croti, P.; Macchia, F. Tetrahedron Lett. 1990,
31, 4661. (b) Schoffers, E.; Tran, S. D.; Mace, K.
Heterocycles 2003, 60, 769. (c) Saladino, R.; Ciambecchini,
U.; Hanessian, S. Eur. J. Org. Chem. 2003, 4401.
(18) All compounds were characterized by 1H NMR and LC-MS
to be >95% pure except for 3 that was further derivatized via
the mesylate. Selected 1H NMR [(400 MHz, CHCl3-d1), d in
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